tmp980C TMP

Download as pdf or txt
Download as pdf or txt
You are on page 1of 34

Chapter 9

Mesenchymal Stem Cells Their Antimicrobial Effects


and Their Promising Future Role as Novel Therapies of
Infectious Complications in High Risk Patients
K.A. Al-Anazi and A.M. Al-Jasser
Additional information is available at the end of the chapter
http://dx.doi.org/10.5772/60640

Abstract
Mesenchymal stem cells (MSCs) are heterogeneous progenitor cells that have the
capacity of self-renewal and multi-lineage differentiation. These adult stem cells can
be derived from several sources including bone marrow (BM), peripheral blood, cord
blood, placenta, amniotic fluid, skin and adipose tissue. They have certain distin
guishing features and their immunomodulatory and immunosuppressive properties
enable them to have several therapeutic and clinical applications. Recently, MSCs
have gained enormous potential as they can potentially cure various intractable and
chronic diseases and as they have shown effectiveness in the treatment of various
infections in animal models and in early clinical trials. MSCs are essential constituents
of the framework that supports organ integrity and tissue barriers. Suppression of
both T and B cells allows them to be major players in the innate response to bacterial
infection and in controlling inflammatory response. Human BM-MSCs possess direct
antibacterial activity against Gram-negative bacilli and they have been shown to
improve survival and reduce mortality in animal models having septic complications.
BM-MSCs are effective in treating sepsis and acute respiratory distress syndrome in
high-risk patients such as those with malignant hematological disorders, recipients of
solid organ and hematopoietic stem cell transplantation (HSCT) and patients
receiving advanced level of care in intensive care units. Additionally, human BMMSCs can act as drug delivery vehicles by enhancing the effectiveness of conventional
antimicrobials and thus they may prevent the evolution of drug-resistant microbes.
MSCs contain a subset of interleukin-17+ that is capable of inhibiting the growth of

2015 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,
and reproduction in any medium, provided the original work is properly cited.

166

Progress in Stem Cell Transplantation

Candida albicans (C. albicans). Also, CD 271+ BM-MSCs may provide a long-term
protective intracellular niche in the host where Mycobacterium tuberculosis (M.TB)
organisms remain viable but in a dormant state. Two recent clinical trials in humans
that included 57 patients have shown that autologous transplantation of MSCs can
successfully treat multidrug resistant (MDR) strains of M.TB. Animal studies have
demonstrated that MSCs enhance host defenses against malaria. MSC therapy
improves liver function and promotes hepatocellular regeneration in patients with
hepatic fibrosis caused by schistosomiasis. Transplantation of MSCs has been shown
to reverse right ventricular dilatation, cardiomyopathy and advanced cardiac
involvement caused by Trypanosoma cruzi infection.
Autologous MSC transfusion in patients having liver cirrhosis secondary to hepatitis
B or C infection improves liver function tests. Transfusion of MSCs can confer
resistance to human immunodeficiency virus (HIV)and may restore immune reconsti
tution in infected individuals. Also, MSCs obtained from Wharton's jelly of the
umbilical cord may become a novel therapy to reverse immune deficiency in
individuals infected with HIV1, particularly immune non-responders. Additionally,
recent studies have demonstrated that hematopoietic stem cell-based gene therapy
may ultimately offer a curative therapeutic option for HIV disease. MSCs improve
murine models of acute myocarditis induced by infection with Coxsackie B3 virus.
There is low risk of transmission of human herpes viruses by transplantation of MSCs
from healthy seropositive donors. Cytomegalovirus (CMV) infection impairs the
immunosuppressive and antimicrobial effector functions of human MSCs, thus overt
CMV infection in recipients of HSCT may undermine the clinical efficacy of MSCs in
treating graft versus host disease (GVHD). The therapeutic applications of BM-MSCs
in recipients of HSCT include: prevention and treatment of GVHD, induction of faster
engraftment, immune reconstitution, healing of inflammation as well as prevention
and treatment of various infectious complications.
Thus, taking into consideration the remarkable success in the utilization of MSCs in
the treatment of various infections in animal models and in human clinical trials, it is
reasonable to predict that MSCS may become very promising novel therapeutic
modalities as they have the potential to control or even cure various infectious
complications in high-risk patients. However, the field is still in its infancy and plenty
of research and clinical trials are required to refine their therapeutic indications.
Banking of MSCs is vital to make them available for use. Finally; strict guidelines,
standardization techniques and quality control measures are urgently required for
collection, cryopreservation and clinical utilization of MSCs.
Keywords: Mesenchymal stem cells, Bone marrow, Wharton's jelly, Sepsis, Multi
drug resistance

Mesenchymal Stem Cells Their Antimicrobial Effects and Their Promising Future Role as Novel Therapies
http://dx.doi.org/10.5772/60640

1. Introduction
Mesenchymal stem cells (MSCs) - also called fibroblastoid cells, giant fat cells with blanket
cells, spindle-shaped flattened cells or very small round cells - have an inherent ability of selfrenewal, proliferation and differentiation toward mature tissues depending on the surround
ing microenvironment [1, 2]. Such characteristic, intrinsic to stem cells, makes MSC very
attractive for utilization in cell therapy and regenerative medicine [2]. The discovery of MSCs
can be dated to the 1960s and can be credited to the work of AJ Friedenstein during which he
observed that bone marrow (BM) is the source of MSCs in postnatal life [1].
MSCs comprise only a tiny fraction of BM and other tissues. BM-derived MSCs [BMMSCs] constitute 0.0001% to 0.01% of all nucleated BM cells [2]. Adipose tissues contain
100, 000 MSCs in each gram of fat. Adipose tissue-derived MSCs (AT-MSCs) represent an
attractive cell source for stem cell therapy. Transplantation of up to 2x108 cells / kg of
autologous human adipose tissue-derived MSCs may be safe when given by slow intrave
nous infusion [2]. The sources of MSCs, their distinguishing features and their therapeu
tic indications are included in Table 1 [1-4].
Sources of MSCs

Distinguishing features of MSCs

Therapeutic indications of MSCs

1- Bone marrow

(A) They must be plastic adherent

1- In stem cell transplantation:

2- Peripheral blood

(B) They must be capable of

- Prevention and treatment of graft versus

3- Blood of umbilical cord

differentiating into:

host disease

4- Placenta

osteoblasts, adipocytes

- Enhancement of engraftment

4- Amniotic fluid

and chondrocytes

2- In cardiology; treatment of:

5- Synovial fluid

(C) Findings on flowcytometry:

- Coronary artery disease

6- Dental tissues e.g. pulp

[1] positive surface molecules:

- Myocardial infarction

7- Palatal tonsil

- CD 105

- Dilated cardiomyopathy

8- Fallopian tubes

- CD 73

3- Critical limb ischemia

9- Fat: adipose tissue

- CD 90

4- Repair of skeletal tissues

10- Parathyroid glands

[2] negative surface molecules:

5- Non-healing chronic wounds

- CD 45

6- Chronic spinal cord injuries

- CD 34

7- Liver injury

- CD 14

8- Regenerative medicine

- CD 11

9- Osteogenesis imperfecta

- CD 19

10- Amyotrophic lateral sclerosis

- CD 79

11- Acute respiratory distress syndrome

- HLA - DR

12- Severe autoimmune disorders: systemic


lupus erythromatosis, rheumatoid arthritis,
multiple sclerosis and systemic sclerosis

MSCs: mesenchymal stem cells


Table 1. Sources, basic features and therapeutic indications of MSCs

167

168

Progress in Stem Cell Transplantation

Study and

Type of MSCs, route of

Results and proposed

year of

administration of MSCs

mechanism(s) of action

publication

and sepsis model

Hau SR et al

- MSCs harvested from

- Increased survival of mice

2013

compact bone of mice

- Decreased organ injury

- Intravenous injection of

- Increased neutrophil phagocytosis

MSCs into tail veins

- Decreased circulating bacteria

of mice
- CLP, in vivo method
- Polymicrobial sepsis
Mei SHJ et al

- Bone Marrow-MSCs

- Significant reduction in mortality in septic mice

2010

- Intravenous administration

receiving appropriate anti-microbial therapy.

- CLP

- Significant increase in bacterial clearance partly

- In vivo method

due to increased phagocytic activity of host


immune cells

Luo CT et al

- Bone marrow-MSCs

- Decreased circulating bacteria

2014

- Intravenous administration

- Alleviation of sepsis - related acute kidney injury

- CLP

- Improved survival of mice.

- Polymicrobial sepsis

- Inhibition of IL-17 secretion


- After MSC therapy, the following interleukins and
inflammatory mediators were reduced in kidney tissues: Il-6,
IL-7, TNF-, INF-, CXCL1, CXCL2, CXCL5, CCL2 and CCL3

Gupta N et al

- Bone marrow - MSCs

- Increased survival of mice

2012

- Intratracheal injection

- Inhibition of bacterial growth

- Unstimulated mouse MSCs

- Increased lipocalin-2 in bronchoalvealar lavage fluid.

- E. Coli pneumonia

- Increased phagocytic activity

- In vitro study
Nemeth K et al

- Bone marrow - MSCs

- Reduced mortality of mice

2009

- Activated MSCs

- Improved organ function

- CLP

- The beneficial effects of MSCs were eliminated by:

- In vivo study

macrophage depletion or pre-treat-IL-10 receptors.


- MSCs reprogram macrophages by releasing postaglandin E2.

Gonzalez-

- Human and murine

- Systemic infusion of adipose tissue-derived MSCs resulted in:

Rey et al

adipose tissue-MSCs

increased survival of mice in addition to significant

2008

- Intraperitoneal injection

amelioration of severity

- CLP and endotoxin injection

of colitis and sepsis.

- Colitis and sepsis model, in vivo


study
Chang C-L

- Apoptotic adipose tissue- MSCs - Protection of major organs from damage

Et al

- Rat model

- Improved prognosis and reduced mortality of animals treated

2012

- Penile venous transfusion

with MSCs.

Mesenchymal Stem Cells Their Antimicrobial Effects and Their Promising Future Role as Novel Therapies
http://dx.doi.org/10.5772/60640

Study and

Type of MSCs, route of

Results and proposed

year of

administration of MSCs

mechanism(s) of action

publication

and sepsis model

Yang R et al

- CLP

- Increased circulating levels of TNF-

- Peritoneal sepsis, acute kidney

- Reduction in the numbers of: helper and cytotoxic T-cells, T-

injury

regulatory cells in peripheral blood and spleens of animals.

- IL-17 producing MSCs

- Inhibition of growth of Candiada albicans

2013

- Mechanism of action: stimulation of IL-17 production.

Sung P-H

- Rat model

- Adipose tissue MSC therapy was superior to healthy adipose-

et al

- Adipose tissue - MSCs

derived MSC therapy in preventing major organ damage in rats

2013

- CLP

treated with CLP-induced sepsis syndrome.

- Sepsis syndrome, kidney and


lung injury
MSCs: mesenchymal stem cells; IL: interleukin
TNF: tumor necrosis factor; CLP: cecal ligation puncture
INF: interferon
Table 2. Studies using murine MSCs in infection or sepsis models

Study and year

Type of MSCs, route of

of publication

administration and sepsis model

Results and possible mechanism(s) of action

Meisel

- Human MSCs

- Inhibition of gram-positive bacteria

R et al

- Interferon stimulated MSCs

- Inhibition of intracellular CMV and HSV-1 replication

2011

- In vitro study

- Increased indoleamine -2,3- dioxygenase

Krasnodembskaya - Human BM-MSCs murine model - Increased antimicrobial activity and decreased bacterial
A et al

- Intravenous admin istration of

growth in bronchoalveolar lavage.

2010

MSCs

- Decrease in lung bacterial load.

- Intratracheal E.coli, Pseudomonas

- Inhibition of bacterial growth in vitro

aeruginosa and Staphylococcus

- IV MSCs + neutralizing antibodies to IL-37: reduced

aureus pneumonia

bacterial clearance.

Krasnodembskaya - Human BM - MSCs

- Increased survival due to increased clearance of bacteria

A et al

- Intravenous administration

from circulation.

2012

- Murine Gram-negative

-Increased phagocytic activity of mononuclear cells in

peritoneal sepsis

spleens of mice.
- Marked reduction in circulating bacteria in the blood of
treated mice.
- Increased number of platelets inhibitor -1 (PAI-1)
- No change in cytokine levels in plasma and peritoneal fluid.

Kim ES et al

- Human umbilical cord blood -

- Increased survival of treated mice

MSCs

- Reduced bacterial burden in pneumonia model.

169

170

Progress in Stem Cell Transplantation

Study and year

Type of MSCs, route of

of publication

administration and sepsis model

2011

- Intrathecal administration

Results and possible mechanism(s) of action


- Acute lung injury induced by E.coli was attenuated by:

- E. coli induced acute lung injury down-modulation of inflammatory process and enhancement
- In vivo study in mice

of bacterial clearance
- Anti-inflammatory mechanisms involved.

Casatella MA et al

- Human MSCs

- Enhancement of neutrophil function

2011

- In vitro study

- Proposed mechanisms: IL- 6, INF- and GM-CSF

Maqbool M et al

- Human MSCs

- Inhibition of neutrophil apoptosis

2011

- In vitro study

- Unknown mechanism of action


- No elucidation of molecular mechanisms that govern
protection of neutrophils from serum-induced apoptosis

Rafaghello L et al

- Human BM-MSCs and

- Inhibition of apoptosis of resting and IL-8 activated

2008

neutrophils

neutrophils with both MSCs and MSC-conditioned media

- In vitro, MSC - conditioned

- Recombinant IL-6 was found to protect neutrophils from

media

apoptosis

- Delivery method: co-culture

- Effect was mediated by IL-6

- Effect of BM-MSCs on neutrophil


survival and effector function.
Lee JW et al

- Human BM derived MSCs

- Increased macrophage phagocytosis

2013

- Ex-vivo perfused human lung

- Reduced alveolar bacterial burden

injured and intrabronchial

- Intrabronchial KGF-7 caused: increased alveolar

E. coli delivery

macrophage phagocytosis and decreased bacterial load.

- Bacterial induction of acute

- KGF duplicated most of the antimicrobial effects of MSCs.

lung injury

- In vitro: KGF-7 positive monocytes increased bacterial

* IV or intrabronchial injection

killing and monocyte survival and FGF-7 blocking antibodies

of MSCs

nullified antimicrobial effects ex vivo and in vitro.

MSCs: mesenchymal stem cells; IV: intravenous


IL: interleukin; KGF: keratinocyte growth factor
IFN: interferon; GM-CSF: granulocyte monocyte-colony stimulating factor
Table 3. Studies using human MSCs in infection or sepsis models

Based on current clinical trials and irrespective of the treated disease condition or the mode of
administration, MSC therapy appears relatively safe [3, 5]. Therapeutic applications of MSCs
raise a series of concerns about the safety of culture-expanded MSCs for human use [4].
However, further large scale clinical trials with rigorous reporting of adverse events are
required to further define the safety profile of MSCs [5]. Complications of MSC therapies
include: (1) febrile reactions during or shortly after transfusion, (2) tumor modulation and
malignant transformation, (3) increased risk of cancer, particularly hematologic malignancy,
(4) genetic manipulation, induction of genetic instability and evolution of chromosomal

Mesenchymal Stem Cells Their Antimicrobial Effects and Their Promising Future Role as Novel Therapies
http://dx.doi.org/10.5772/60640

abnormalities, (5) increased incidence of infectious complications, particularly in recipients of


hematopoietic stem cell transplantation (HSCT) having graft versus host disease (GVHD)
treated with MSCs, and (6) persistence of human Parvovirus B19 in multipotent MSCs, express
ing the erythrocyte P antigen, that are used to improve the outcome of HSCT and in regener
ative medicine [1, 6-9]. Therefore, strict control and safety measures are needed in the
production of MSCs for cell-based therapies in order to minimize or abolish the risk of
malignant transformation [1]. It is also essential to establish standardized manufacture
guidelines for the isolation, expansion, preservation and delivery of MSCs for safety evaluation
and clinical applications [4].

2. MSCs and sepsis


Sepsis is the leading cause of death in the intensive care units and it ranks among the top 10
causes of death in the general population worldwide. Despite the advances in medical care,
mortality rates from sepsis remain as high as 30%-50% in severe cases [10]. Sepsis is a systemic
inflammatory response that is typically triggered by bacterial or other microbial infection and
it involves a complex interaction between the microbial pathogen and the host immune system
[11, 12]. The inflammatory response, designed to control infection, affects end-organ perfusion
and exacerbates tissue injury leading to multi-organ failure [11]. In the early phase of sepsis,
endogenous proinflammatory cytokines and coagulation pathways become hyperactive and
their adverse effects cause multi-organ failure, collapse of the circulatory system and ulti
mately death of the affected individual [12].
Sepsis is associated with a surge of systemic signaling molecules including cytokines and
growth factors that may become uncontrollable [11]. Stem cells have profound effects on the
inflammatory response and coagulation cascade that are activated during sepsis [13]. Stem
cells have been shown to modulate more than 3000 genes in experimental sepsis models. They
enhance the clearance of pathogens and repair of injured tissues in sepsis. In addition, stem
cells have been found to have an impact on cell leak that is encountered during sepsis [13].
2.1. MSCs in sepsis and experimental sepsis models
Mesenchymal stroma is an essential component of tissue barriers and it participates in
protecting the body from infections. A breach in the integrity of tissue barriers such as trauma
can lead to translocation of bacteria and colonization of vital organs, thus ultimately leading
to multiple organ failure and sepsis [14]. Tissue injury compromises barrier function and
increases the risk of infection and sepsis. Tissue injury can induce recruitment of MSCs from
BM and promote their proliferation so as to reconstitute the integrity of injured tissues and
mediate natural debridement [14]. MSCs can modulate systemic response to bacterial infection
and support tissue repair in addition to healing after being recruited at the sites of tissue injury
[14]. Sepsis is a devastating condition characterized by systemic activation of inflammatory
and coagulation pathways in response to microbial invasion of sterile body organs or tissues
[15]. Severe sepsis, sepsis with at least one dysfunctional organ, is a leading cause of death in

171

172

Progress in Stem Cell Transplantation

intensive care units (ICUs) as it is associated with mortality rates ranging between 30% and
50% [15].
The development of experimental sepsis models to elucidate the pathophysiology and
progression of clinical sepsis spans over the last 8 decades. The following transitions in animal
models took place since the 1930s: endotoxemia, bacteremia, ischemia and bowel perforation
and finally cecal ligation puncture (CLP) and the colon ascends stent peritonitis (CASP) models
[15]. Genetic differences in mice and possibly humans are associated with differences in the
inflammatory process initiated in response to sepsis and that ultimately affect the outcome of
sepsis. Hence, transgenic animal models have been extensively utilized in sepsis research [15].
Upon stimulation by endotoxins or proinflammatory mediators, activated neutrophils release
a chromatin material composed of DNA and antimicrobial granular proteins in the form of
neutrophil extra-cellular traps (NETs). The formation of NETs, NETOSIS, is an emerging field
in sepsis research [15]. However, the presence of NETOSIS is distinct from that of necrosis and
apoptosis. NETOSIS can be experimentally induced by endotoxins such as lipopolysaccharides
(LPS), Gram-negative as well as Gram-positive bacteria, fungi and proinflammatory cytokines
such as activated platelets and interleukin-8 (IL-8). NET formation has been found to cause
host tissue and cellular damage [15]. LPS-induced endotoxemia in mice as well as plasma
obtained from humans with severe sepsis were able to trigger NETOSIS. In vitro, NET
formation resulted in endothelial cell damage while in vivo it caused hepatotoxicity in LPSchallenged mice [15]. In septic hosts, NETs can exacerbate sepsis by releasing high concentra
tions of potent proteases, forming a chromatin meshwork and trapping host cells (erythrocytes,
leukocytes and platelets) that can potentiate inflammation, coagulation and ischemia in
involved tissues [15].
Microparticles are a heterogenous population of small membrane-coated vesicles that are
released by several cell lines upon activation or apoptosis [16]. Exosomes are a specialized
category of microparticles with specific functions in immune response and protein sorting.
Exosomes are released mainly from antigen presenting cells, although they have been
identified after activation of platelets and mast cells and in body fluids such as urine or
bronchoalveolar lavage [16]. Although the role of exosomes in sepsis remains deeply unex
plored, accumulating data suggest that microparticles and exosomes play a role in the three
pathways clearly involved in the pathogenesis of sepsis: inflammation, thrombosis and
vascular dysfunction [16].
Human MSCs possess antimicrobial and immunosuppressive effects that are partly mediated
by the tryptophan catalyzing enzyme indoleamine-2, 3-dioxygenase (IDO) [17]. Upon stimu
lation by inflammatory cytokines, MSCs exhibit broad spectrum antimicrobial effector
functions directed against various clinically relevant pathogens and these effects are depend
ent on IDO and/or the antimicrobial peptide LL-37 [17]. MSCs have antiapoptotic, antifibrotic
and angiogenic properties. Interferon (IFN-) primes MSC-mediated immunoregulatory
effects and induces nitrous oxide (NO) production in MSCs. NO exerts antiapoptotic effects
on cardiomyocytes and has antiviral properties [18].
The role of microparticles and exosomes in mediating vascular dysfunction suggests that they
may represent novel pathways in paracrine transcellular signaling in vascular microenviron

Mesenchymal Stem Cells Their Antimicrobial Effects and Their Promising Future Role as Novel Therapies
http://dx.doi.org/10.5772/60640

ment [16]. Further studies may aid in the clarification of their exact effects in sepsis and the
development of additional interventional strategies for the prevention and treatment of sepsis
[16]. Examples of experimental sepsis and infection models that utilized human as well as
murine MSCs are shown in Tables 2 and 3 [19-35].
MSCs function at several levels of the inflammatory response, particularly in the early phase
of sepsis, to regulate a wide panel of inflammatory cytokines and inhibit leukocyte infiltration
into several target organs [12]. In an endotoxemic rat model, human AT-MSCs had the
following beneficial effects: (1) modulation of host responses, (2) reduction of inflammatory
cytokine levels in serum and lung, (3) reduction of alveolar inflammatory cell infiltration in
the lung, (4) reduction of liver injury, and (5) improvement of tissue hypoperfusion [12]. As
systemic administration of human-AT-MSCs at the onset of endotoxemia ameliorated the
serological and histological signs of endotoxemia, they may become attractive candidates for
cell therapy in the treatment of endotoxemia and septic shock [12].
Increasing evidence suggests that BM-MSCs secrete molecules that inhibit the effector function
of immune cells [11]. AT-MSCs are a recently discovered cell population with much in common
to their BM-derived counterparts. Both BM-MSCs and AT-MSCs have been shown to be
effective in certain pre-clinical studies as they effectively inhibit the activation of T-cells [11].
Cellular immunotherapy for septic shock (CISS) trial is the first trial of stem cell therapy
in humans [13]. It has 2 phases and the objectives of this Canadian trial are as follows: (1)
in phase I, to establish safety and patient tolerability of stem cells and to find the optimal
dose of stem cells to be administered, and (2) in phase II, to look at loose surrogates of
efficacy for patients with septic shock [13]. The study has two arms: (1) an observational
arm, where patients do not receive stem cells, and (2) an interventional arm, where patients
receive stem cells with three different dose schedules [13]. The study is expected to address
many aspects of stem cell therapy in patients having septic shock such as safety, tolera
ble dose and feasibility of use [13, 36].
In animal models of Staphylococcal toxic shock syndrome, MSCs have been shown to: (1)
enhance bacterial clearance, and (2) suppress proinflammatory cytokine production, but
they failed to prolong survival in experimental models [37, 38]. MSC therapy has also been
shown to: (1) enhance antibiotic therapy in chronic Staphylococcal infections, and (2) enhance
the effectiveness of conventional antibiotics in the treatment of antibiotic-resistant microbi
al infections [39, 40]. In patients with sepsis, the clinical application of MSC-based thera
py is feasible, well tolerated and may be beneficial [36]. Studies have also shown that MSCs
not only modulate the systemic inflammation, but also improve cardiac function in patients
having endotoxemia [41]. Additionally, BM-MSCs can uptake and release antimicrobials,
for example ciprofloxacin, into infected deep environment such as chronic osteomyelitis or
deep seated abscesses [42]. Also, MSCs can act as drug delivery system for antibiotics or
vehicles for targeted therapies in order to enhance effects of antimicrobials and other
targeted therapies [42, 43].

173

174

Progress in Stem Cell Transplantation

2.2. Conclusions that can be drawn from experimental models


MSCs may be a potential new therapeutic modality in the prevention and reduction of sepsisassociated lung injury [21]. Decreased systemic and pulmonary cytokine levels may prevent
acute lung injury and organ dysfunction. Genetic effects downregulate inflammation-related
genes such as IL-10 and IL-6 and upregulate genes involved in the promotion of phagocytosis
and bacterial killing [20]. The bacterial clearance effect could be party due to the upregulation
of lipocalin -2 production by MSCs. However, lipocalin-2 antibodies have been found to block
antimicrobial effects of MSCs [22].
In peritoneal sepsis models using murine MSCs; the following mechanisms were involved:
down regulation of Th1 inflammatory responses, reduced inflammatory cytokines and
chemokines as well as increased IL-10 level and induction of IL-10 T-regulatory cells [24].
Apoptotic AT-MSCs represent an endogenous therapeutic strategy that may be enhanced for
maximum clinical benefits [25]. Treatment with apoptotic AT-MSCs caused attenuation of
sepsis syndrome induced lung and kidney parenchymal injury through suppression of
inflammation, apoptosis and oxidative stress and enhancement of anti-oxidation and antiapoptosis in rodent models [27].
Human BM-MSCs possess direct antimicrobial activity that is mediated by secretion of human
cathelicidin hCAP-18/IL-37 [29]. Human MSCs participate in the innate response against
Gram-negative bacteria through the secretion of the antimicrobial peptide IL-37 [29]. MSCs
inhibit apoptosis of both resting and activated neutrophils and they increase the viability of
resting and activated neutrophils in various culture serum concentrations [33]. MSCs can
restore alveolar fluid clearance, reduce inflammation and exert antimicrobial activity party
through keratinocyte growth factor (KGF) secretion [35]. Lastly, cultured or banked human
BM-MSCs may be effective in treating sepsis in high-risk patients [23].

3. MSCs and viral infections


Fetal membrane derived MSCs [FM-MSCs] are susceptible to herpes simplex virus-1 (HSV-1),
HSV-2, varicella zoster virus and human cytomegalovirus (CMV) in vitro, while Epstein-Barr
virus (EBV), human herpes virus-7 (HHV-7) and HHV-8 are capable of entering into FM-MSCs,
but only limited gene expression occurs, thus resulting in non-productive infection. Therefore,
FM-MSCs should be screened for the presence of herpes viruses before xenotransplantation
[44]. Transcription factor nuclear factor (NF-kB) may affect the efficacy of CMV infection of
MSCs. NF-kB inhibitors exacerbate the infection by the activation of human CMV in MSCs thus
close attention should be given to human CMV infection once an NF-kB inhibitor is prescribed
in clinical settings [45].
Human CMV is a leading cause of life-threatening complications in immunocompromised
individuals, such as those with acquired immune deficiency virus (AIDS) and recipients of solid
organ transplant (SOT) as well as HSCT [46]. Human CMV infects a wide range of cell types
including fibroblasts, monocytes, granulocytes and BM cells such as myeloid progenitor cells

Mesenchymal Stem Cells Their Antimicrobial Effects and Their Promising Future Role as Novel Therapies
http://dx.doi.org/10.5772/60640

and MSCs. Following primary infection, human CMV establishes a lifelong latency in the host
[46]. CD34+ progenitor cells have been recognized as the most likely reservoir for latent CMV
infection in the BM, while CD34+ cells from the blood of healthy human CMV carriers have
been demonstrated to contain the latent human CMV. The interaction between human CMV
and BM-MSCs is complex and it is possible that BM-MSCs infected with human CMV may
play a role in the development of human CMV-associated pathology [46]. Frequent virus
reactivation in BM cells and subsequent productive human CMV infection of MSCs may be
the underlying cause of various pathological processes [46]. CMV-infected MSCs lose their
cytokine-induced immunosuppressive capacity and become no longer able to restrict micro
bial growth [17]. IDO expression is substantially impaired following CMV infection of MSCs
and the interaction between CMV infection of MSCs and IDO expression critically depends
upon (1) having an intact virus, (2) the number of infected MSCs, and (3) the viral load [17]. It
is recommended that patients scheduled for MSC therapy should undergo thorough evalua
tion for an active CMV infection and receive CMV-directed therapy prior to the administration
of MSCs as overt CMV infection in recipients of MSCs may undermine the clinical efficacy of
MSC therapy [17].
MSCs could express receptors that permit their infection by human immunodeficiency virus
(HIV)-1 [47]. Highly active antiretroviral therapy (HAART) significantly decreases mortali
ty and morbidity in patients with HIV-1 infection, but immune non-responders (INRs) with
full viral suppression still fail to reverse the immune deficiency state [48]. In a pilot
prospective controlled clinical trial that had enrolled 13 patients with HIV-1 infection, it
was found that umbilical cord or more precisely Whartons jelly derived-MSC transfu
sions were not only well tolerated, but also found to efficiently improve immune reconsti
tution in INR patients, suggesting that MSC therapy may be used as a novel therapeutic
approach to reverse immune deficiency in INR-HIV-1 infected individuals [48]. Another
study suggested that HIV-1 infected individuals could be cured if the HAART therapy is
administered before the virus is able to establish its reservoir in the body [49]. Human Tlymphotropic virus (HTLV)-1 could infect and replicate in human BM-MSCs possibly by
involvement or infiltration of CD4+ T-lymphocytes [50].
Although pre-clinical studies have shown that MSC therapy can induce anti-inflammatory
effects and enhance repair of the injured lung and despite the clinical and pathological
similarities between acute lung injury and severe influenza infection, it was found that MSC
therapy may not be effective for the prevention and/or treatment of acute severe influenza [51].
It is well established that MSCs can be infected by adenoviruses and that these viruses are widely
used as gene transfer vectors [52]. Recent studies revealed that the cationic polymer polybrene
can potentiate Adenovirus-mediated transgene delivery into MSCs and should be routinely
used as a safe, effective and inexpensive augmenting agent for Adenovirus-mediated gene
transfer in MSCs [52].
Coxsackie virusB3 (CVB3) causes myocarditis not only by immune mediated mechanisms but
also by inducing direct cardiomyocyte injury [18]. MSCs improve murine acute CVB3-induced
myocarditis via antiapoptotic and immunomodulatory mechanisms that occur in a NOdependent manner and require priming with IFN- [18]. MSCs have the potential to treat acute

175

176

Progress in Stem Cell Transplantation

CVB3-induced myocarditis since MSCs (1) cannot be infected with CVB3, (2) have antiapoptotic
and antiviral effects, and (3) improve cardiac function in experimental models of acute CVB3induced myocarditis [18].
Several lines of evidence indicate that human BM-MSCs can maintain hepatitis B virus (HBV)
infection in vitro and support the replication of HBV-DNA. Human BM-MSCs may be a useful
tool for investigating the HBV life-cycle and the mechanism of initial virus-cell infection [53].

4. MSCs and Mycobacterium tuberculosis


Persisters are a small fraction of quiescent bacterial cells that survive lethal antibiotics or
stresses but are capable of reactivation under certain circumstances. Despite the discovery of
persisters more than 70 years ago, the mechanisms of persistence are still poorly understood
[54]. A number of pathways and genetic abnormalities have recently been identified and they
may explain the mechanisms of persistence. These pathways include: DNA repair or protec
tion, toxin-antitoxin modules, phosphate metabolism, antioxidative defense, efflux and
macromolecule degradation [54]. However, more sensitive techniques are required to have a
better understanding of the mechanisms of persistence. Once the underlying mechanisms are
elucidated, cellular therapies, vaccination and targeted treatments are likely to make signifi
cant improvements in the management of persistent infections [54].
Bacterial persistence is the hallmark of tuberculosis (TB). The remarkable success of Mycobac
terium TB (M.TB) as a human pathogen is attributed to its ability to program itself into entering
prolonged periods of dormancy thus resulting in a latent TB infection [55]. Thus, M.TB can
successfully evade the host immune system to establish a persistent infection [56, 57]. M.TB
suppresses T-lymphocyte responses by recruiting MSCs into the site of infection and these
cells can inhibit T-lymphocyte responses further by producing NO [56, 57]. Recruitment of
MSCs into the tuberculous granuloma plays a vital role in the pathogenesis of M.TB infection
as these MSCs infiltrate into the sites of infection and position themselves between the
harbored pathogen and the effector T-cells [56, 57]. Targeting MSCs or NO is a feasible strategy
to design future therapeutic and preventive interventions against M.TB infections [56, 57].
Macrophage apoptosis is a rather essential process in the development and maintenance of
immunity as its augments the adaptive immune response through dendritic cell activation and
subsequent antigen presentation and also reduces bacterial viability [58]. CD4+T-cells play a
crucial role in host defense against M.TB infections [59]. Animal studies have shown that
isoniazid (INH) treatment causes dramatic reduction in M.TB antigen-specific immune
responses and the induction of apoptosis in activated CD4+ cells thus rendering treated animals
vulnerable to TB reactivation and reinfection [59]. The finding that anti-TB treatment may be
associated with further immune impairment should be taken into consideration in designing
new anti-TB therapies [59].
Studies have shown that (1) M.TB may maintain long-term intracellular viability in BMderived CD271+/CD45-MSC population in vitro, and (2) viable M.TB organisms have been
detected in CD271+/CD45-MSCs isolated from individuals who had successfully completed

Mesenchymal Stem Cells Their Antimicrobial Effects and Their Promising Future Role as Novel Therapies
http://dx.doi.org/10.5772/60640

months of anti-TB chemotherapy [57, 60, 61]. Thus, CD271+BM-MSCs are capable of providing
an antimicrobial protective intracellular niche in the host in which dormant M.TB can reside
for long periods of time [57, 60, 61].
4.1. The role of autologous MSC transplantation in the treatment of TB
Recently, autologous transplantation of MSCs has successfully been utilized in the treatment
of infections caused by multi-drug resistant TB (MDR-TB) and even extensively drug resistant
TB (XDR-TB) [57, 62, 63]. In one study, 27 patients in whom previous anti-TB drug therapy
had been unsuccessful were included and they received autologous MSC transplantation [62].
Positive clinical responses were obtained in all patients, bacterial discharge from lung was
abolished in 20 patients and resolution of tissue damage and lung cavitation were achieved in
11 patients 4 months after MSC infusion [62]. Also, persistent remission of the tuberculous
process was obtained in 56% of patients who had follow-up for 2 years post MSC transplan
tation [62]. In a second phase 1 clinical trial, 30 patients with MDR and XDR-TB received
autologous MSC transplantation after 4 weeks of starting anti-TB therapy [63]. Six months
post-autologous MSC transplantation (1) no major adverse events were encountered and (2)
70% of patients showed radiological improvement, while 16.7% of patients showed stable
radiological appearances [63]. Eighteen months post-MSC transplantation, 53% of the patients
were cured while 10% of transplanted patients had evidence of treatment failure [63]. There
fore, combining standard anti-TB chemotherapy with autologous MSCT may become a
promising maneuver to enhance the efficacy of treatment in patients with drug-resistant
pulmonary TB [57, 62, 63].

5. MSCs and parasites


Plasmodium berghei infection in mice leads to massive recruitment of MSCs in secondary
lymphoid organs [64, 65]. Also, infusion of MSCs into naive mice can confer host resistance
against malaria by (1) augmentation of IL-12 production, (2) suppression of IL-10 production,
(3) inhibition of hemozoin, and (4) dramatic reduction in regulatory T-cells in spleens of
animals [64, 65]. Leishmania parasites can survive in different tissues and organs for decades
even after treatment [66]. Several studies have shown that intracellular parasites can persist
and remain viable in fibroblasts in latent, inactive or dormant forms [66, 67]. Also, Leishma
nia parasites could remain viable in inactive forms in AT-MSCs in vitro [66]. Therefore,
screening for leishmaniasis is essential in recipients of HSCT living in areas that are endemic
for leishmaniasis [66].
MSCs ameliorate liver injury and reduce fibrosis in mouse models of Schistosoma japonicum (S.
japonicum). When combined with praziquantel, the preceding effects are enhanced [68, 69].
Infusion of MSCs in mice infected with S. mansoni caused (1) reduction of hepatic fibrosis, (2)
amelioration of liver injury by induction of liver regeneration, thus ultimately leading to (3)
improvement in liver function tests [70]. IFN- activated murine MSCs (1) could not inhibit
the growth of a highly virulent strain of Toxoplasma gondii (BK), (2) strongly inhibited the

177

178

Progress in Stem Cell Transplantation

growth of a type II strain of Toxoplasma gondii (ME4a), and (3) inhibited the growth of Neospora
caninum [71].
5.1. MSCs in Chagas disease
Chagas disease is caused by infection with Trypanosoma cruzi (T. cruzi) [72, 73]. Up to 30% of
infected individuals develop cardiac symptoms related to a chronic chagasic dilated form of
cardiomyopathy (CMP) [72]. Cardiac manifestations of Chagas disease include congestive
cardiac failure, arrhythmias, heart block, thromboembolism, stroke and sudden death [73].
Available therapies include treatment of heart failure and arrhythmias, antiparasitic therapy,
resynchronization treatment, heart transplantation and stem cell therapies [73].
The use of cell therapies to improve cardiac function has been attempted experimentally for
more than two decades [72]. The use of BM-derived cells to treat cardiac diseases gained
impulse based on the observation that stromal BM cells could be induced to differentiate into
cardiomyocytes in vitro and when transplanted into cryoinjured rat hearts improved myo
cardial function and promoted angiogenesis [72, 74, 75]. Another significant development was
that hematopoietic stem cells (HSCs) obtained from transgenic mice expressing enhanced
green fluorescent protein, when transplanted into infarcted hearts of syngenic mice, differen
tiated into cardiac muscle and vascular cells [72, 76]. Since then, many laboratories reported
that HSCs and stromal cells derived from BM improved myocardial function in animal models
of both cryoinjured and ischemic heart lesions [72]. In one study, cardiac MSCs were isolated
from hearts of green fluorescent protein transgenic mice then injected into left ventricular (LV)
walls of mice chronically infected with T. cruzi [77]. Results of the study showed (1) cardiac
MSCs demonstrated adipogenic, osteogenic and differentiation potentials, (2) histological
analysis showed that mice treated with cardiac MSCs had a significant reduction in inflam
matory cells but no reduction in fibrotic areas, and (3) molecular studies showed that cell
therapy significantly decreased TNF- expression and increased transforming growth factorbeta in heart samples [77]. The results clearly demonstrated that cardiac MSCs exert a protec
tive effect in cardiac chagasic CMP primarily by immunomodulation [77]. In another model
of chagasic CMP, direct LV injection of co-cultured skeletal myoblasts and stromal BM-derived
cells improved heart function in chronically infected chagasic rats as measured by echocar
diography [72, 78]. Injection of the co-cultured cells increased ejection fraction and decreased
diastolic and end-systolic volumes [72, 78]. Intraperitoneal administration of MSCs into a
mouse model of chronic chagasic CMP reduced inflammation and fibrosis in hearts of mice
but had no effect on cardiac function as shown by another study involving an experimental
animal model [79].
After the encouraging results in animal models, a clinical trial examining the feasibility and
safety of intracoronary injection of autologous BM cell transplantation in patients with
congestive cardiac failure due to chronic chagasic CMP was performed [72, 80]. Results of the
trial showed that the procedure was safe and effective as cell therapy induced small but rather
significant improvements in both ejection fraction and quality of life in patients included in
the study [72, 80]. In an experimental cardiac ischemia model, the administration of granulo
cyte-colony stimulating factor (G-CSF) had beneficial effects on cardiac structure and function

Mesenchymal Stem Cells Their Antimicrobial Effects and Their Promising Future Role as Novel Therapies
http://dx.doi.org/10.5772/60640

[81]. Repeated administration of G-CSF in another experimental model of chronic chagasic


CMP, which closely resembled human disease, induced beneficial effects on (1) cardiac
structure as inflammation and fibrosis were reduced, and (2) cardiac function [81].
Based on the promising results of the previous safety trial, a larger multicenter, randomized,
double-blinded and placebo-controlled trial was designed to test the efficacy of intra-coronary
injection of BM-derived mononuclear cells (MNCs) in patients with chronic chagasic CMP [72,
82]. Although no serious adverse events were observed, this efficacy trial showed no additional
benefit of intracoronary injection of BM- MNCs in chagasic patients with low ejection fraction,
that is, intracoronary injection of BM-MNCs neither improved LV function nor improved
quality of life in patient with chronic chagasic CMP [72, 82]. After the initial homing experi
ments, it was demonstrated that BM MNCs from non-chagasic syngeneic donors significantly
reduced cardiac inflammation and fibrosis in mice with chronic T. cruzi infection. This
improvement was maintained for up to 6 months after cell therapy [72, 83]. Using magnetic
resonance imaging (MRI), it was demonstrated that BM-MNCs prevented and reversed the
right ventricular dilatation induced by T. cruzi infection. Thus, histological improvement
achieved by BM-MNC transplantation was paralleled by a functional correlate [72, 84].
One of the most striking observations after cell therapy in mice, chronically infected with T.
cruzi, was related to the pattern of gene expression examined by microarray [72, 85]. While
chagasic mice had 1702 out of 9390 (18%) cardiac genes with expression altered by infection
after BM-MNC therapy, 96% of these genes were restored to normal levels although additional
109 genes had their expression altered by therapy [72, 85]. Transplantation of BM-MNCs in
experimental mice showed immunomodulatory effects in chronic chagasic CMP and caused
reversion of gene expression alterations in hearts of mice infected with T. cruzi [85]. In a chicken
model of Chagas disease, the genetic alterations resulting from kDNA integration in the host
genome caused an autoimmune-mediated destruction of heart tissues even in the absence of
T. cruzi parasites [86]. In animal models of Chagas disease, microarrays were used to analyze
global gene expression [87]. Eight distinct categories of mRNAs were found to be differentially
regulated during infection and the dysregulation of several key genes was identified. These
findings provide insights into the pathogenesis of chagasic CMP and provide new targets for
intervention [87].
It is expected that within a few years, scientists will be able to find the (1) best animal model,
(2) appropriate stem cell dose, (3) appropriate stem cell type, (4) injection route, and (5) disease
status that will result in benefits for chronic chagasic CMP patients [72]. Despite the success
of stem cell therapy in animals, preclinical models of Chagas disease have not translated into
successful human studies [88]. Addressing the challenges associated with future research and
providing solutions to have acceptable levels of safety and strict quality controls would enable
successful clinical applications of stem cell therapies in chagasic CMP [88].
Ultimately, transplantation of BM-derived cells may prove to be an important therapeutic
modality in the treatment of end-stage chagasic heart disease [89]. Identifying which cell
type(s) is responsible for the effects observed in both animal studies and preliminary human
experiments will be an important step in further improving this treatment [89]. Since the
percentage of stem cells (either hematopoeitic or mesenchymal) is minimal in the mononuclear

179

180

Progress in Stem Cell Transplantation

fraction, use of purified stem cell population has the potential to significantly increase the
therapeutic benefit of cell therapy in chagasic CMP [89].

6. MSCS and fungal infections


Despite the availability of new antifungal agents, mortality and morbidity related to invasive
fungal infections is still high, particularly in patients with hematological malignancies and in
recipients of SOT and HSCT [90, 91]. The recent advances in the immunopathogenesis of
invasive aspergillosis have provided critical information to augment host immunity against
fungal pathogens [90, 91]. Potential approaches for enhancement of the host immune system
to combat invasive fungal infections include (1) administration of effector and regulatory cells
such as granulocytes, antigen-specific T-cells, natural killer cells and dendritic cells, and (2)
administration of cytokines, interferons and growth factors such as INF-, G-CSF and
granulocyte monocyte-colony stimulating factor (GM-CSF) [90, 91]. Although promising
results have been obtained from animal studies, limited data are available to draw conclusions
on risks and benefits in clinical settings [90, 91]. So, appropriately designed, multicenter and
international clinical trials are needed in order to improve the outcome of invasive fungal
infections in immunocompromised individuals [90, 91]. MSC therapy in HSCT recipients has
been found to facilitate faster control of invasive fungal infections [92].
Studies have shown that human cathelicidin LL-37 and its fragments LL13-37 and LL 17-37
exhibit similar potencies in inhibiting the growth of Candida albicans (C. albicans) [93]. However,
death of (C. albicans) cells may not solely be due to increased permeability caused by LL13-37,
but can also be due to certain intracellular targets [93]. In patients with severe refractory
neutrophilic bronchial asthma, administration of MSCs appears to play a significant role in
decreasing inflammation and ameliorating disease manifestations by mediating Aspergillusinduced inflammation through inhibition of the Th17 signaling pathway [94].

7. MSCs and wound healing


Chronic non-healing wounds are a serious medical problem [95]. Biofilms, which are bacterial
communities attached to a surface and become protected by a polysaccharide coating, are
believed to contribute significantly to the persistence of chronic wounds by altering the host
immune response. Current treatment options are ineffective and do not significantly target
biofilms [95]. It has been shown that the paracrine factors secreted by reprogrammed MSCs
accelerate wound healing and reduce bacterial growth in biofilm-infected wounds in mice [95].
Therefore, clinical studies are needed to test the efficacy of these paracrine factors in the
eradication of biofilms in patients with non-healing wounds [95].
In an in vitro study, MSCs have recently been shown to exert measurable antimicrobial
activities in a synovial fluid setting, suggesting that they may have future application as
adjunct therapy for peri-prosthetic joint infections [96]. Also, AT-MSCs have been shown to

Mesenchymal Stem Cells Their Antimicrobial Effects and Their Promising Future Role as Novel Therapies
http://dx.doi.org/10.5772/60640

enhance closure of enterocutaneous fistula and aided in the recovery and healing of wounds
in a rat model [97].

8. MSCs and lung injury


Melatonin, the chief secretary product of the pineal gland, is an indirect antioxidant that acts
to stabilize cell membranes thereby making them less susceptible to oxidative insults and
ultimately suppressing inflammatory reactions [98]. Combined melatonin and apoptotic ATMSCs treatment has been found to be superior to either regimen alone in ameliorating lung
injury in the setting of CLP-induced sepsis in a rodent model [98]. Also, adult tissue-derived
MSCs have been shown to have antimicrobial effects that inhibit bacterial growth in lung
tissues [96].
BM-derived MSCs have unlimited potential clinical applications in acute lung injury, due to
various pulmonary disorders and they exert their effects by various mechanisms [99]. Vibrio
vulnificus sepsis can induce acute lung damage and pulmonary edema. BM-derived MSCs can
downregulate inflammatory cytokines and reduce lung injury caused by Vibrio vulnificus sepsis
in mice [100]. BM-MNCs were able to diminish pulmonary inflammation, lung elastance, lung
modeling and fibrosis resulting in lower mortality in acute respiratory distress syndrome
(ARDS) experimental models [101]. However, the benefits of BM-MNCs depend on several
factors including the type of initial insult as they were shown to exert different effects on
endothelial cell activation and adhesion molecules. Therefore, further studies are needed to
clarify their mechanisms and to examine this novel therapy in clinical trials [101].
Multipotent MSCs have shown remarkable therapeutic effects in preclinical models of both
ARDS and sepsis [102]. Initial research focused on the ability of MSCs to engraft at sites of
tissue injury [102]. Recent literature shows increasing evidence suggesting that MSCs exert
their therapeutic effects through mechanisms that are unrelated to long-term incorporation
into tissues of the host [102]. One of the most compelling pathways is their capacity to interact
with injured tissue through the release of soluble bioactive factors [102].

9. MSCs and neutrophils


MSCs participate in the regulation of inflammation and innate immunity by responding to
pathogen-derived signals and by regulating the function of innate immune cells [103]. MSCs
derived from the BM and peripheral tissues share common basic cell-biological functions [103].
MSCs contribute to the resolution of infection and inflammation by promoting the antimicro
bial activity of polymorphonuclear leukocytes, a property that is exhibited by MSCs derived
from either BM or peripheral glandular tissues [103]. MSCs rescue neutrophils from nutrientor serum-deprived cell death. Whether this effect is exerted through a specific signaling
pathway or confining neutrophils in a resting state by MSCs requires further evaluation [33].

181

182

Progress in Stem Cell Transplantation

Both multipotent adult progenitor cells (MAPCs) and MSCs are adult stem cells that can be
derived from BM and are currently utilized in tissue engineering due to their immunomodu
latory and trophic effects [104]. The use of stem-cell-based immunotherapy is very promising
as in vitro studies have shown comparable suppressive effects of both human MSCs and
human MAPCs [104]. However, the broader expansion capacities of human MAPCs make
them more attractive than human MSCs for clinical use [104]. Neutrophils release many lysisinducing factors and cause local tissue damage. Conversely, neutrophils themselves could
become a target in controlling sepsis [105].

10. Antimicrobial effects of MSCs


Multipotent, BM-MSCs (MP-BM-MSCs) are culture-expanded, nonhematopoietic stromal cells
with immunomodulatory properties that are currently being investigated as novel cellular
therapies in the prevention and treatment of clinical diseases that are associated with immune
dysfunction [106]. Preclinical studies suggest that MP-BM-MSCs may protect against infec
tious challenge through direct or indirect pathways [106]. Direct effects exerted by MP-BMMSCs on the pathogen are manifested by reduction of pathogen burden by inhibition of growth
through soluble factors and enhancement of antimicrobial function of immune cells [106].
Indirect effects exerted by MP-BM-MSCs on the host include: (1) attenuation of proinflamma
tory cytokine and chemokine induction, (2) reduction of proinflammatory cells immigration
into the sites of tissue injury or infection, and (3) reduction of immunoregulatory soluble and
cellular factors that preserve organ function. These preclinical studies provide insights into
the future therapeutic applications of MP-BM-MSCs [106].
Through toll-like receptor (TLR) signaling and immune crosstalk between MSCs and immune
effector cells, MSCs become capable of maintaining a critical balance between (1) promotion
of pathogen clearance during the initial phase of inflammatory response, and (2) suppression
of inflammation to preserve host integrity and to facilitate tissue repair [106]. The presumed
or suggested roles of MP-BM-MSCs during infection can be divided into five phases as shown
in Table 4 [106].
Human BM-MSCs have direct antimicrobial activity, against Gram-positive as well as Gramnegative bacteria, which is mediated in part through the secretion of human cathelicidin hCAPLL-37 [107]. Also, evidences suggest that MSCs position themselves between the acid fast
bacilli harbored in the BM and the host protective T-cells. Hence MSCs can be a potential target
for the treatment of latent TB [108]. Targeting MSCs is not expected to lead to the evolution of
new resistance in the pathogen as MSCs do not need to be directly targeted and as the host
immune response needs to be manipulated [108]. Upon stimulation of inflammatory cytokines,
human MSCs exhibit broad-spectrum antimicrobial effector function directed against a range
of clinically relevant bacteria, protozoal parasites and viruses [28]. Human MSCs act as
immunosuppressants that concurrently exhibit potent antimicrobial effector function thus
encouraging further evaluation in clinical trials [28]. Human multipotent MSCs exhibit broadspectrum antimicrobial activity mediated by IDO [28].

Mesenchymal Stem Cells Their Antimicrobial Effects and Their Promising Future Role as Novel Therapies
http://dx.doi.org/10.5772/60640

Phase

Main effect / mechanism

Details and explanations

Detection of pathogens and

- Engagement of TLR-mediated signaling pathways

damage signals

- Recruitment of MSCs at the sites of infection

Activation of host immune

- Maintenance of quiescent HSC pool

response

- BM emigration of activated HSCs

- Mobilization and emigration of immune effector cells from BM.


- Thymic development to augment response of immune effector cells
3

Elimination of pathogens

- Production of microbiocidal soluble factors


- Containment of infectious pathogen within micro-environment
(pathogen phagocytosis)

Induction of proinflammatory

- Antioxident soluble factor (HO-1)

gradients

- Antiinflammatory soluble factors such as: IDO, PGFZ, IL-10, TGF-B,


TGF-6,
HLA-G5 and Galectin-1

Modulation of proinflammatory - Activation of function, differentiation and migration of immune effector


host immune response

cells.
- Augmentation of wound healing
- Enhancement of revascularization
- Inhibition of tissue toxicity
- Modulation of inflammation and organ dysfunction.

TLR: toll-like receptor; HSC: hematopoietic stem cell; IL: interleukin; IDO: indoleamine-2, 4-dioxygenase
Table 4. Accepted roles MSCs during infection

Human gut microbial communities reside in an open ecosystem subject to disruptions ranging
from dietary change to toxin exposure and pathogen invasion [109]. Host inflammatory
mechanisms to remove harmful organisms and restrict bacteria to gut lumen commonly target
conserved molecular patterns found on pathogens and commensals alike, yet healthy gut
microbial communities can remain stable for years in humans [109]. A delicate balance between
microbial resilience and host tolerance thus allows for commensal persistence throughout a
diverse range of perturbations while preventing commensal overgrowth or depletion, either
of which could have deleterious effects on the host [109]. Thus, antimicrobial peptide resistance
mediates the resilience of prominent gut commensals during inflammation [109]. Stem cell
differentiation can be regulated by TLR activation. Activation of TLRs on MSCs increases
osteogenesis and decreases adipogenesis [110]. Upon exposure to microbial legends, stem cells
change their differentiation to help the initial immune response [110]. Microbial ligands can
influence stem cell fate via pattern recognition receptors. Microbial ligands such as LPS and
lipoproteins can alter: proliferation, differentiation, migration and the function of stem cells.
In mice stem cell proliferation is stimulated by TLR activation, while in humans most TLR
activity does not seem to affect stem cell proliferation [110]. TLR activation alters stem cell
differentiation, cytokine production of stem cells and immunosuppressive functions of MSCs

183

184

Progress in Stem Cell Transplantation

[110]. However, cytokine production can also be influenced by microenvironment, costimulatory molecules as well as downstream signaling pathways [110]. The immunosup
pressive function of MSCs can be stimulated or inhibited by TLR activation depending on the
type of signaling pathways that are activated [110]. With the identification of innate immune
receptors on stem cells and the finding that microbial ligands can influence stem cell fate, a
new era of stem cell research has begun [110].

11. MSCs and HSCT


Recent studies revealed that, during pathogen exposure, hematopoiesis may yield progeny in
magnitudes that are different from those produced under routine or stable hemostatic
circumstances [111]. HSCs not only sustain blood cell formation following bleeding, BM
damage or chemotherapeutic ablation, but also respond directly to microbial products as well
as inflammatory cytokines thus permitting real-time alterations in the direction of hemato
poiesis in response to exposure to a certain burden of pathogenic organisms [111].
Various evidences from experimental models and clinical studies suggest the implication of
bacterial and fungal infections in the pathogenesis of acute GVHD [112]. Appropriate treat
ment or prophylaxis of bacterial infections during the early post-HSCT period might be
beneficial in reducing not only infection-related but also GVHD-related mortality [112]. To
eliminate the systemic proinflammatory cytokine surge induced by bacterial infection, the
following are needed: (1) specific antimicrobial strategies, (2) therapies targeting the pathways
of innate immunity, and (3) nutritional interventions that might help in reducing the risk of
acute GVHD. These issues should be evaluated prospectively in clinical trials[112]. In a
retrospective cohort study that evaluated the risk factors for pneumonia-related death
following HSCT and that included 691 patients, meta-analysis showed that the following were
the risk factors that contributed to death: (1) acute GVHD grades II - IV, (2) CMV infection,
and (3) receiving MSCs. Additionally, bacteremia and mold infections contributed to pneu
monia-related deaths [113].
MSC therapy in HSCT recipients has been found to have the following advantages: (1)
prevention and treatment of GVHD, (2) immune reconstitution, (3) induction of faster
engraftment, (4) healing of infections and inflammatory disorders, and (5) reduction in the
incidence of various infectious complications [92, 103, 104, 114, 115]. Studies have shown that
administration of human BM-derived MSCs given during allogeneic bone marrow transplan
tation or human umbilical cord blood-derived MSCs in the post-transplant period, in patients
with bone marrow failure, is safe and advantageous [92, 114]. In recipients of unrelated
allogeneic HSCT following non-myeloablative conditioning therapy, co-infusion of MSCs did
not show any pulmonary deterioration for up to 1 year posttransplant [115]. Additionally, in
recipients of haploidentical HSCT, infusion of umbilical cordderived MSCs did not increase
the incidence of pulmonary infections [116].

Mesenchymal Stem Cells Their Antimicrobial Effects and Their Promising Future Role as Novel Therapies
http://dx.doi.org/10.5772/60640

12. Nanotechnology in stem cell research and therapy


Stem cell tracking using modern imaging modalities offers new insights into understanding
the biology and achieving the full therapeutic potentials of stem cell therapies [117]. Currently
used standard methods for tracking stem cells in vivo include: (1) MRI, (2) bioluminescence
imaging, (3) positron emission tomography, (4) fluorescence imaging, (5) single-photon
emission tomography, (6) X-ray computed microtomography, (7) Raman or surface enhanced
Raman spectroscopy-based imaging, and (8) photoacoustic imaging [117-119]. The selection
of the imaging modality and stem cell tracer or label should take into consideration: the clinical
condition of the patient, the primary disease and the comorbid medical conditions [120].
Nanotechnology offers valuable information on migration, homing, survival, differentiation,
function and the engraftment of transplanted stem cells [117, 121, 122]. The delivery of
nanomaterials enables a personalized approach and individualized tailoring of nanotechnol
ogy and materials used to the specific needs of each patient [120]. To be of most use, tracking
methods should ideally be non-invasive, high resolution and allow tracking in three dimen
sions [121]. To identify transplanted stem cells from the host tissue, optically active probes are
usually used to label stem cells before their administration [117]. Nanofibers have recently
gained substantial interest for their potential application in tissue engineering [123]. Nanofib
ers accommodate: (1) the survival and proliferation of human MSCs, and (2) the continuous
differentiation of human MSCs into obsteoblasts and chondrocytes [123].

13. Homing and migration of MSCs


An important property of MSCs is their capacity for migration and homing in or around the
zones damaged by trauma, inflammation, ischemia or tumor infiltration [124]. Intravenous
administration of MSCs causes their migration, in substantial numbers, into areas of tissue
damage [124]. Therefore, it is essential to understand the mechanisms involved in the homing
and migration of MSCs. In addition, MSCs derived from various sources express different
patterns of chemokines and their receptors [124]. Hence, the possibility to modulate the
migration ability of MSCs opens a new era for the development of directed migration of greater
numbers of MSCs injected intravenously into the sites of injury [124].

14. Banking of MSCs


MSCs hold great potential for developing effective cellular therapies and current trends
indicate that their clinical applications will continue to rise markedly [125]. There has been
considerable success in manufacturing and cryopreserving MSCs at laboratory level, but these
successes have not translated into technologies developed at industrial scale [125]. The
development of cost-effective and advanced technologies for the production and cryopreser
vation of MSCs is a crucial step in the process of successful clinical cell therapy [125]. Also, it

185

186

Progress in Stem Cell Transplantation

is essential to have simple and appropriate but validated protocols for cell and tissue proc
essing under good manufacturing conditions in order to develop a cost-effective banking of
MSCs such as those obtained from umbilical cord blood [126].

15. Conclusions and future directions


MSCs are heterogeneous progenitor cells that have the capacity of self-renewal and multilineage differentiation. Their distinguished immunomodulation and immunosuppressive
properties allowed MSCs to have several therapeutic applications. MSCs are essential constit
uents of the framework that supports organ integrity and tissue barriers. Suppression of both
T and B cells enables them to be major players in controlling inflammatory response and in
the innate response to bacterial infection. Human BM-MSCs possess direct antibacterial
activity against Gram-negative bacilli and they have been shown to improve survival and
reduce mortality in animal models having septic complications. Also, human BM-MSCs can
act as drug delivery vehicles, enhance the effectiveness of conventional antimicrobials and
may prevent the evolution of drugresistant microbes. MSCs contain a subset of IL-17+ that is
capable of inhibiting the growth of C. albicans. CD 271+ BM-MSCs may provide a long-term
protective intracellular niche in the host where M.TB organisms remain viable but in a dormant
state. Two recent clinical trials in humans have shown that autologous transplantation of MSCs
can successfully treat MDR strains of M.TB. Animal studies have demonstrated that MSCs
enhance host defenses against malaria. MSC therapy improves liver function and promotes
hepatocellular regeneration in patients with hepatic fibrosis caused by schistosomiasis.
Transplantation of MSCs has been shown to reverse right ventricular dilatation, cardiomyop
athy and advanced heart involvement in T. cruzi infection. Transfusion of MSCs can confer
resistance to HIV and may restore immune reconstitution in infected individuals. Autologous
MSC transfusion in patients having liver cirrhosis secondary to hepatitis B or C infection
improves liver function tests. MSCs improve murine models of acute myocarditis caused by
CVB3 infection. However, MSCs are not effective in the prevention or treatment of severe
Influenza virus infections. There is low risk of transmission of human herpes viruses by
transplantation of MSCs from healthy seropositive donors. CMV infection impairs the
immunosuppressive and antimicrobial effector functions of human MSCs, thus overt CMV
infection in recipients of HSCT may undermine the clinical efficacy of MSCs in treating GVHD.
MSC therapy in patients with severe GVHD is associated with increased mortality related to
Adenovirus infections. Therapeutic applications of BM-MSCs in recipients of HSCT include
prevention and treatment of GVHD, induction of faster engraftment, immune reconstitution,
healing of inflammation as well as treatment and prevention of various infectious complica
tions. Also, cultured or banked human BM-MSCs may be effective in treating sepsis in highrisk patients.
Taking into consideration the remarkable success in the utilization of MSCs in the treatment
of various infections in animal models and the few published clinical trials in humans with
MDR infections, such as those caused by M.TB, and with the advancements in technology and
medical care, it is reasonable to predict a similar success in the use of MSC therapy in humans

Mesenchymal Stem Cells Their Antimicrobial Effects and Their Promising Future Role as Novel Therapies
http://dx.doi.org/10.5772/60640

in the near future. However, complications of this form of cellular therapy should never be
underestimated. Also, it is essential to have banking facilities for these stem cells in addition
to guidelines and protocols for their use in high risk individuals, particularly those with HIV,
MDR-TB, hematological malignancy, recipients of SOT and HSCT as well as patients receiving
advanced level of care in ICUs.

Author details
K.A. Al-Anazi1* and A.M. Al-Jasser2
*Address all correspondence to: kaa_alanazi@yahoo.com
1 Department of Adult Hematology and Hematopoietic Stem Cell Transplantation, Cancer
Center, King Fahad Specialist Hospital, Dammam, Saudi Arabia
2 Riyadh Regional Laboratory, Ministry of Health, Riyadh, Saudi Arabia

References
[1] Wong RSY. Mesenchymal stem cells: angels or demons. J Biomed Biotechnol. 2011;
2011: 459510; 18.
[2] Ra JC, Shin IS, Kim SH, Kang SK, Kang BC, Lee HY, et al. Safety of intravenous infu
sion of human adipose tissue-derived mesenchymal stem cells in animals and hu
mans. Stem Cells Dev. 2011; 20 (8) 12971308.
[3] Herberts CA, Kwa MS, Hermsen HP. Risk factors in the development of stem cell
therapy. J Transl Med. 2011; 9 (29): 114.
[4] Wang Y, Han Z-b, Song Y-p, Han ZC. Safety of mesenchymal stem cells for clinical
application. Stem Cell Int. 2012; 2012: 652034; 14.
[5] Lalu MM, McIntyre L, Pugliese C, Fergusson D, Winston BW, Marshall JC, et al. for
the Canadian Trials Group. Safety of cell therapy with mesenchymal stromal cells
(SafeCell): a systematic review and a meta-analysis of clinical trials. PLoS One 2012; 7
(10): e47559.
[6] Cornlio DA, de Medeiros SRB. Genetic evaluation of mesenchymal stem cells. Rev
Bras Hematol Hemoter. 2014; 36(4): 238240.
[7] von Bahr L, Sundberg B, Lnnies L, Sander B, Karbach H, Ljungman P, et al. Longterm complications, immuonological effects, and role of passage for outcome in mes
enchymal stromal cell therapy. Biol Blood Marrow Transplant. 2012; 18 (4): 557564.

187

188

Progress in Stem Cell Transplantation

[8] Sundin M, Lindblom A, Orvell C, Barrett AJ, Sundberg B, Watz E, et al. Persistence of
human parvovirus B19 in multipotent mesenchymal stromal cells expressing the er
ythrocyte P antigen: implications for transplantation. Biol Blood Marrow Transplant.
2008; 14 (10): 11721179.
[9] Ning H, Yang F, Jiang M, Hu L, Feng K, Zhang J, et al. The correlation between co
transplantation of mesenchymal stem cells and higher recurrence rate in hematologic
malignancy patients: outcome of a pilot clinical study. Leukemia. 2008; 22 (3): 593
599.
[10] Leentjens J, Kox M, van der Hoven JG, Netea MG, Dickkers P. Immunotherapy for
the adjunctive treatment of sepsis: from immunosuppression to immunomodulation,
time for a paradigm change? Am J Respir Crit Care Med. 2013; 187 (12): 12871293.
[11] Elman JS, Li M, Wang F, Gimble JM, Parekkadan B. A comparison of adipose and
bone marrow-derived mesenchymal stromal cell secreted factors in the treatment of
systemic inflammation. J Inflamm (Lond). 2014; 11(1):1.
[12] Shin S, Kim Y, Jeong S, Hong S, Kim I, Lee W; et al. The therapeutic effect of human
adult stem cells derived from adipose tissue in endotoxemic rat model. Int J Med Sci.
2013; 10 (1): 818.
[13] Suen C, Cheung L. The world's first in-human stem cell trial for septic shock: a
bench-to-bedside journey in critical care from the perspective of Dr Lauralyn McIn
tyre. UOJM 2013; 3: 810.
[14] Gorbunov MV, Elliott TB, McDaniel DP, Lund K, Liao P-J, Zhai M, et al. Up-regula
tion of autophagy defence mechanisms in mouse mesenchymal stromal cells in re
sponse to ionizing irradiation followed by bacterial challenge. Edited by Yannik
Bailly; InTech; 2013; ISBN: 978-953-51-1062-0.
[15] Mai S, Khan M, Liaw P, Fox-Robichaud A, on behalf of the Canadadian Critical Care
Translational Biology Group (CCCTBG). Experimental Sepsis Models. Edited by Lu
ciano Azevedo; InTech; 2012. ISBN: 978-953-51-0780-4.
[16] Azevedo LCP. Microparticles and exosomes: are they part of important pathways in
sepsis pathophysiology? Severe sepsis and septic shock-understanding a serious kill
er. Edited by Dr Richardo Fernandez; InTech; 2012; ISBN: 978-953-307-950-9.
[17] Meisel R, Heseler K, Nau J, Schmidt SK, Leinewever M, Pudelko S, et al. Cytomega
lovirus infection impairs immunosuppressive and antimicrobial effector functions of
human multipotent mesenchymal stromal cells. Mediators Inflamm. 2014; 2014:
898630.
[18] Van Linthout S, Savvatis K, Miteva K, Peng T, Ringe J, Warstat K, et al. Mesenchymal
stem cells improve murine acute Coxsackivirus B3-induced myocarditis. Eur Heart J.
2011; 32: 21682178.

Mesenchymal Stem Cells Their Antimicrobial Effects and Their Promising Future Role as Novel Therapies
http://dx.doi.org/10.5772/60640

[19] Hall SR, Tsoyi K, Ith B, Padera RF Jr, Leaderer JA, Wang Z, et al. Mesenchymal stro
mal cells improve survival during sepsis in the absence of neutrophils. Stem Cells.
2013; 31 (2): 397-407.
[20] Mei SHJ, Haitsma JJ, Dos Santos CC, Deng Y, Lai PFH, Slutsky AS, et al. Mesenchy
mal stem cells reduce inflammation while enhancing bacterial clearance and improv
ing survival in sepsis. Am J Respir Crit Care Med. 2010; 182 (8):10471057.
[21] Luo C-J, Zhang F-j, Zhang L, Geng Y-q, Li Q-g, Hong Q, et al. Mesenchymal stem
cells ameliorate sepsis-associated acute kidney injury in mice. Shock. 2014; 41 (2),
123129.
[22] Gupta N, Krasnodembskaya A, Kapetanaki M, Mouded M, Tan X, Serikov V, et al.
Mesenchymal stem cells enhance survival and bacterial clearance in murine Escheri
chia coli pneumonia. Thorax 2012; 67 (6): 533539.
[23] Nemeth K, Leelahavanichkul A, Yuen PST, Mayer B, Parmelee A, Doi K, et al. Bone
marrow stromal cells attenuate sepsis via prostaglandin E2- dependent reprogram
ming of host macrophages to increase their interleukin-10 production. Nat Med.
2009; 15 (1): 4249.
[24] Gonzalez-Ray E, Gonzalez MA, Rico L, Buscher D, Delgado M. Human adult stem
cells derived from adipose tissue protect against experimental colitis and sepsis. Gut
2009; 58 (7): 929939.
[25] Chang C-L, Leu S, Sung H-C, Zhen Y-Y, Cho C-L, Chen A, et al. Impact of apoptotic
adipose-derived mesenchymal stem cells on attenuating organ damage and reducing
mortality in rat sepsis syndrome induced by cecal puncture and ligation. J Transl
Med. 2012; 10: 244.
[26] Yang R, Liu Y, Kelk P, Qu C, Akiyama K, Chen C, et al. A subset of IL-17+ mesenchy
mal stem cells possesses anti-Candida albicans effect. Cell Res 2013; 23 (1):107121.
[27] Sung P-H, Chang C-L, Tsai T-H, Chang L-T, Leu S, Chen Y-L, et al. Apoptotic adi
pose-derived mesenchymal stem cell therapy protects against lung and kidney injury
in sepsis syndrome caused by cecal ligation puncture in rats. Stem Cell Res Ther.
2013; 4 (6): 155.
[28] Meisel R, Brookers S, Heseler K, Degistirici ; Blle H, Woite C, et al. Human but not
murine multipotent mesenchymal stromal cells exhibit broad-spectrum antimicrobial
effector function mediated by indoleamine 2, 3-dioxygenase. Leukemia 2011; 25: 648
654.
[29] Krasnodesmbskaya A, Song Y, Fang X, Gupta N, Serikov V, Lee J-W, et al. Antibacte
rial effect of human mesenchymal stem cells is mediated in part from secretion of the
antimicrobial peptide LL-37. Stem Cells 2010; 28 (12): 22292238.
[30] Krasnodesmbskaya A, Samarani G, Song Y, Zhuo H, Su X, Lee J-W, et al. Human
mesenchymal stem cells reduce mortality and bacteremia in Gram-negative sepsis in

189

190

Progress in Stem Cell Transplantation

mice in part by enhancing the phagocytic activity of blood monocytes. Am J Physiol


Lung Cell Mol Physiol. 2012; 302 (10): L1003L1013.
[31] Kim ES, Chang YS, Choi SJ, Kim TK, Yoo HS, Ahn SY, et al. Intratracheal transplanta
tion of human umbilical cord blood-derived mesenchymal stem cells attenuates Es
cherichia coli-induced acute lung injury in mice. Respir Res. 2011; 12 (108): 1-11.
[32] Cassatella MA, Mosna F, Micheletti A, Lisi V, Tamassia N, Cont C, et al. Toll-like re
ceptor-3-activated human mesenchymal stromal cells significantly prolong the sur
vival and function of neutrophils. Stem Cells 2011; 29: 10011011.
[33] Maqbool M, Vidyadaran S, George E, Ramasamy R. Human mesenchymal stem cells
protect neutrophils from serum-deprived cell death. Cell Biol Int. 2011; 35: 1247
1251.
[34] Raffaghello L, Bianchi G, Bertolotto M, Montecucco F, Busca A, Dallegri F, et al.. Hu
man mesenchuymal stem cells inhibit neutrophil apoptosis: a model for neutrophil
preseveation in the bone marrow niche. Stem Cells 2008; 26: 151162.
[35] Lee JW, Krasnodembskaya A, McKenna DH, Song Y, Abbott J, Matthay MA. Thera
peutic effects of human mesenchymal stem cells in ex vivo human lungs injured with
live bacteria. Am J Respir Crit Care Med. 2013; 187 (7): 751760.
[36] Kusadasi N, Groeneveld AB. A perspective on mesenchymal stromal cell transplan
tation in the treatment of sepsis. Shock 2013; 40 (5): 352357.
[37] Yuan Y, Lin S, Guo N, Zhao C, Shen S, Bu X, et al. Marrow mesenchymal stromal
cells reduce methicillin-resistant Staphylococcus aureus infection in rat models. Cyto
therapy 2014; 16 (1): 5663.
[38] Kim H, Darwish I, Monroy M-F, Prockop DJ, Liles WC, Kain KC. Mesenchymal stro
mal (stem) cells suppress pro-inflammatory cytokine production but fail to improve
survival in experimental Staphylococcal toxic shock syndrome. BMC Immunol. 2014;
15:1.
[39] Johnson V, Webb T, Dow S. Activated mesenchymal stem cells amplify antibiotic ac
tivity against chronic Staphylococcus aureus infection (P2056). J Immunol. 2013; 190:
180, 11.
[40] Dow S, Johnson V. Activated mesenchymal stem cells enhance antibiotic treatment of
bacterial infections. Colorado State University Ventures, Inc. Posted by Sarah Belford
on 14/11/2013; file No.: 12-060.
[41] Weil BR, Herrmann JL, Abarbancell AM, Manukyan MC, Poynter JA, Meldrum DR.
Intravenous infusion of mesenchymal stem cells is associated with improved myo
cardial function during endotoxemia. Shock 2011; 36 (3): 235241.

Mesenchymal Stem Cells Their Antimicrobial Effects and Their Promising Future Role as Novel Therapies
http://dx.doi.org/10.5772/60640

[42] Sisto F, Bonomi A, Cavicchini L, Cocce V, Scaltrito MM, Bondiolotti G, et al. Human
mesenchymal stromal cells can uptake and release ciprofloxacin, acquiring in vitro
anti-bacterial activity. Cytotherapy 2014; 16 (2): 181190.
[43] Todd GP, LeRoux MA, Danilkovitch-Miagkova A. Mesenchymal stem cells as vehi
cles for targeted therapies. Drug discovery and development-present and future.
Edited by Dr Izet Kapetanovic; InTech; 2011. ISBN: 978-953-307-615-7.
[44] Avanzi S, Leoni V, Rotola A, Alviano F, Solimando L, Lanzoni G, et al. Susceptibility
of human placenta derived mesenchymal stromal/stem cells to human herpesviruses
infection. PLoS One. 2013; 8 (8): e71412.
[45] Wei G, Lin M, Cai Z, Huang H. Cytomegalovirus infection in mesenchymal stem
cells and their activation could be enhanced by nuclear factor-kB inhibitor pyrroli
dindithiocarbamate in vitro. Transplant Proc. 2011; 43 (5): 19441949.
[46] Smirnov SV, Harbacheuski R, Lewis-Antes A, Zhu H, Rameshwar P, Kotenko SV.
Bone marrow-derived mesenchymal stem cells as a target for cytomegalovirus infec
tion: implications for hematopoiesis, self-renewal and differentiation potential. Virol
ogy 2007; 360 (1): 616.
[47] Cotter EJ, Maughan RT, Doran PP. Role of mesenchymal stem cells (MSC) in HIV-1
associated bone and lipid toxicities. Stem cells and cancer stem cells. Edited by M.A.
Hayat; Springer; 2012; 8: 7990.
[48] Zhang Z, Fu J, Xu X, Wang S, Xu R, Zhao M. Safety and immunological responses to
human mesenchymal stem cell therapy in difficult-to-treat HIV-1-infected patients.
AIDS. 2013; 27 (8): 12831293.
[49] Allam O, Samarani S, Ahmad A. Mesenchymal stem cell therapy in HIV-infected
HAART-treated nonimmune responders restores immune competence. AIDS. 2013;
27 (8): 13491352.
[50] Rodrigues ES, do Carmo Favarin M, de Macedo MD, Otaguiri KK, Orellana MD, Ta
kayanagui OM. HTLV-1 infection in bone marrow mesenchymal stem cells isolated
from HTLV-1 individuals. Retrovirology. 2014; 11 (Suppl l): P106.
[51] Darwish I, Banner D, Mubareka S, Kim H, Besla R, Kelvin DJ, et al. Mesenchymal
stromal (stem) cell therapy fails to improve outcomes in experimental severe influen
za. PLoS One. 2013; 8: e71761.
[52] Zhao C, Wu N, Deng F, Zhang H, Wang N, Zhang W. Adenovirus-medicated gene
transfer in mesenchymal stem cells can be significantly enhanced by the cationic pol
ymer polybrene. PLoS One. 2014; 9 (3): e92908.
[53] Ma R, Xing Q, Shao L, Wang D, Hao Q, Li X. Hepatitis B virus infection and replica
tion in human bone marrow mesenchymal stem cells. Virology J. 2011; 8 (486): 18.

191

192

Progress in Stem Cell Transplantation

[54] Zhang Y. Persisters, persistent infections and Yin-Yang model. Emerg Microbes In
fect. 2014; 3 (1): e3.
[55] Sikri K, Tyagi JS. The evolution of Mycobacterium tuberculosis dormacy models. Cur
rent Science. 2013; 105 (5): 607616.
[56] Raghuvanshi S, Sharma P, Singh S, Kaer LV, Das G. Mycobacterium tuberculosis
evades host immunity by recruiting mesenchymal stem cells. Proc Natl Acad Sci U S
A. 2010; 107 (50): 2165321658.
[57] Al-Anazi KA, Al-Jasser AM, Alsaleh K. Infections caused by Mycobacterium tuberculo
sis in recipients of hematopoietic stem cell transplantation. Front Oncol. 2014; 4: 231.
[58] Kelly DM, ten Bokum AMC, OLeary SM, OSullivan MP, Keane J. Bystander macro
phage apoptosis after Mycobacterium tuberculosis H37 Ra infection. Infect Immun.
2008; 76 (1): 351360.
[59] Tousif S, Singh DK, Ahmad S, Moodley P, Bhattacharyya M, Van Kaer L, et al. Iso
niazid induces apoptosis of activated CD4+ T cells: implications for post-therapy tu
berculosis reactivation and reinfection. J Biol Chem. 2014; 289 (44): 3019030195.
[60] Das B, Kashino SS, Pulu I, Kalita D, Swamy V, Yeger H, et al. CD271+ bone marrow
mesenchymal stem cells may provide a niche for dormant Mycobacterium tuberculosis.
Sci Transl Med. 2013; 5 (170): 170 ra13.
[61] Beamer G, Major S, Das B, Campos-Neto A. Bone marrow mesenchymal stem cells
provide an antibiotic-protective niche for persistent viable Mycobacterium tuberculosis
that survive antibiotic treatment. Am J Pathol. 2014; 184 (12): 31703175.
[62] Erokhin VV, Vasileva IA, Konopoliannikov AG, Chukanov VI, Tsyb AF, Bogdasari
an TR. Systemic transplantation of autologous mesenchymal stem cells of the bone
marrow in the treatment of patients with multidrug-resistant pulmonary tuberculo
sis. Probl Tuberk Bolezn Leak. 2008; 10: 36.
[63] Skrahin A, Ahmed RK, Ferrata G, Rane L, Poiret T, Isaikina Y, et al. Autologous mes
enchymal stromal cell infusion as part of adjunct treatment in patients with multi
drug and extensively drug-resistant tuberculosis: an open-label phase 1 safety trial.
Lancet Respir Med 2014; 2 (2): 108122.
[64] Thakur RS, Tousif S, Awasthi V, Sanyal A, Atul PK, Punia P, et al. Mesenchymal
stem cells play an important role in host protective immune responses against malar
ia by modulating regulatory T cells. Eur J Immunol. 2013; 43: 20702077.
[65] Sinha S, Medhi B, Sehgal R. Challenges of drug-resistant malaria. Parasite 2014;
21(61): 1-15.
[66] Allahverdiyev A, Bagirova M, Elcicek S, Koc RC, Baydar SY, Findikli N, et al. Adi
pose tissue-derived mesenchymal stem cells as a new host cell in latent leishmania
sis. Am J Trop Med Hyg. 2011; 85 (3): 535539.

Mesenchymal Stem Cells Their Antimicrobial Effects and Their Promising Future Role as Novel Therapies
http://dx.doi.org/10.5772/60640

[67] Bodgan C, Donhauser N, Dring R, Rllinghoff M, Diefenbach A, Ritting MG. Fibro


blasts as host cells in latent leishmaniasis. J Exp Med. 2000; 191 (12): 21212129.
[68] Xu H, Qian H, Zhu W, Zhang X, Yan Y, Mao F. et al. Mesenchymal stem cells relieve
fibrosis of Schistosoma japonicum-induced mouse liver injury. Exp Biol Med. 2012; 237
(5): 585592.
[69] Zhang Y, Mi JY, Rui YJ, Xu YL, Wang W. Stem cell therapy for the treatment of para
sitic infections: is it far away? Parasitol Res. 2014; 113 (2): 607612.
[70] Abdul Aziz MT, Atta HM, Roshdy NK, Rashed LA, Sabry D, Hassouna AA, et al.
Amelioration of murine Schistosoma mansoni induced liver fibrosis by mesenchymal
stem cells. J Stem Cell Reg Med. 2012; 8 (1): 2834.
[71] Spekker K, Leineweber M. Antimicrobial effects of murine mesenchymal stromal
cells directed against Toxoplasma gondii and Neospora caninum: role of immunity-relat
ed GTPases (IRGs) and guanylate-binding proteins (GBPs). Med Microbiol Immunol.
2013; 202 (3): 197206.
[72] de Carvalho AC, Carvalho AB, Mello DB, Goldenberg RC. Bone marrow-derived cell
therapy in chagasic cardiac disease: a review of pre-clinical and clinical results. Car
diovasc Diagn Ther. 2012; 2 (3): 213219.
[73] Muratore CA, Baranchuk A. Current and emerging therapeutic options for the treat
ment of chronic chagasic cardiomyopathy. Vasc Health Risk Manag 2010; 6: 593601.
[74] Makino S, Fukuda K, Miyoshi S, Konishi F, Kodama H, Pan J, et al. Cardiomyocytes
can be generated from bone marrow stromal cells in vitro. J Clin Invest. 1999; 103 (5):
697705.
[75] Tomita, S, Li R-K, Weisel RD, Mickle DA, Kim E-J, Sakai T, et al. Autologous trans
plantation of bone marrow cells improves damaged heart function. Circulation 1999;
100 (Suppl II): II-247II-256.
[76] Orlic D, Kajstura J, Chimenti S, Jakonluk I, Anderson SM, Li B, Plckel J, et al. Bone
Marrow cells regenerate infarcted myocardium. Nature 2001; 410: 701705.
[77] Silva JD, Souza MC, Antunes MA, Xisto DG, Padua TN, Abreu TP, et al. Effects of
bone marrow derived mesenchymal stromal cells on lung and distal organ damage
in experimental malaria. Am J Respir Crit Care Med. 2014; 189(1): A5249.
[78] Guarita-Souza LC, Carvalho KA, Woituwicz V, Rebelatto C, Senegaglia A, Hansen P,
et al. Simultaneous autologous transplantation of cocultured mesenchymal stem cells
and skeletal myoblasts improves ventricular function in a murine model of Chagas
disease. Circulation 2006; 114 (Suppl I): I-120I-124.
[79] Larocca TF, de Freitas Souza BS, Silva CA, Kaneto CM, de Alcantara AC, Azevedo CM, et al. Transplantation of adipose-derived stem cells in experimental chronic cha
gasic cardiopathy. Arq Bras Cardiol. 2013; 100 (5): 460468.

193

194

Progress in Stem Cell Transplantation

[80] Vilas-Boas F, Feitosa GS, Soares MB, Mota A, Pinho-Filho JA, Almeida AJ, et al. Early
results of bone marrow cell transplantation to the myocardium of patients with heart
failure due to Chagas disease. Arq Bras Cardiol. 2006; 87 (2): 17.
[81] Macambira SG, Vasconcelos JF, Costa CR, Klein W, Lima RS, Guimares P, et al.
Granulocyte colony-stimulating factor treatment in chronic Chagas disease: preserva
tion and improvement of cardiac structure and function. FASEB J. 2009; 23 (11):
38433850.
[82] Ribeiro Dos Santos RR, Rassi S, Feitosa G, Grecco OT, Rassi A Jr, da Cunha A, et al.
Cell therapy in Chagas cardiomyopathy (Chagas arm of the multicenter randomized
trial of cell therapy in cardiopathies study): a multicenter randomized trial. Circula
tion 2012; 125 (20): 24542461.
[83] Soares MB, Lima RS, Rocha LL, Takyia CM, Pontes-de-Carvalho L, de Carvalho AC,
et al. Transplanted bone marrow cells repair heart tissue and reduce myocarditis in
chronic chagasic mice. Am J pathol. 2004; 164 (2): 441447.
[84] Goldenberg RC, Jelicks LA, Fortes FS, Weis LM, Rocha LL, Zhao D, et al. Bone mar
row cell therapy ameliorates and reverses chagasic cardiomyopathy in a mouse mod
el. J Infect Dis. 2008; 197 (4): 544547.
[85] Soares MB, Lima RS, Souza BS, Vasconcelos JF, Rocha LL, Dos Santos RR, et al. Re
version of gene expression alterations in hearts of mice with chronic chagasic cardio
myopathy after transplantation of bone marrow cells. Cell Cycle 2011; 10 (9): 1448
1455.
[86] Teixeira AR, Gomes C, Nitz N, Sousa AO, Alves RM, Guimaro MC, et al. Trypanoso
ma cruzi in the chicken model: chagas-like heart disease in the absence of parasitism.
PLoS One Negl Trop Dis. 2011; 5 (3): e1000.
[87] Mukherjee S, Nagajyothi F, Mukhopadhyay A, Machado FS, Belbin TJ, , de Carvalho
AC, et al. Alterations in myocardial gene expression associated with experimental
Trypanosoma cruzi infection. Genomics 2008; 91: 423432.
[88] de Calvalho KA, Abdelwahid E, Ferreira RJ, Irioda AC, Guarita-Souza LC. Preclinical
stem cell therapy in Chagas disease: perspectives for future research. World J
Transpl. 2013; 3 (4): 119126.
[89] de Carvalho AC, Goldenberg RC, Jelicks LA, Soares MB, Dos Santos RR, Spray DC,
et al. Cell therapy in Chagas disease. Interdiscip Perspect Infect Dis. 2009; 2009:
484358.
[90] Lehrnbecher T, Kalkum M, Champer J, Tramsen L, Schmidt S, Klingebiel T. Immuno
therapy in invasive fungal infectionfocus on invasive aspergillosis. Curr Pharm Des.
2013; 19 (20): 36893712.

Mesenchymal Stem Cells Their Antimicrobial Effects and Their Promising Future Role as Novel Therapies
http://dx.doi.org/10.5772/60640

[91] Lehrnbecher T, Tramsen L, Koehl U, Schmidt S, Bochennek K, Klingbiel T. Immuno


therapy against invasive fungal diseases in stem cell transplant recipients. Immunol
Invest. 2011; 40 (7-8): 839852.
[92] zdoul H, Yeral M, Boa C, Kozanolu I. Use of mesenchymal cells to modulate
immune suppression and immune reconstruction in a patient with aplastic anemia
complicated by invasive sino-orbital aspergillosis. Turk J Hematol. 2014; 31: 181183.
[93] Wong JH, Ng TB, Legowska A, Rolka K, Hui M, Cho CH. Antifungal action of hu
man cathelicidin fragment (LL13-37) on Candida albicans. Peptides 2011; 32 (10): 1996
2002.
[94] Lathrop MJ, Brooks EM, Bonenfant NR, Sokocevic D, Borg ZD, Goodwin M, et al.
Mesenchymal stromal cells mediate Aspergillus hyphal extract-induced allergic air
way inflammation by inhibition of the Th17 signaling pathway. Stem Cells Transl
Med. 2014; 3: 194205.
[95] Smith AA, Bellows CF. The use of paracrine factors from reprogrammed mesenchy
mal stem cells to treat biofilm-infected wound in vivo. Basic Science, Clinical Con
gress. October 2013, Washington, DC.
[96] Chen AF, Tuan RS. In vitro testing of adult mesenchymal stem cells as an adjunct
therapy for treating periposthetic joint infections. Poster No. 0918. ORS 2012 Annual
Meeting.
[97] Volpe BB, Santos Duarte Ads, Ribeiro TB, Atocchero I, Kharmandayan P, Olalla Saad
ST, et al. Mesenchymal stromal cells from adipose tissue attached to suture material
enhance the closure of enterocutaneous fistulas in a rat model. Cytotherapy 2014; 16
(12): 17091719.
[98] Chen H-H, Chang, C-L, Lin K-C, Sung P-S, Chaig H-T, Zhen Y-Y. Melatonin aug
ments apoptotic adipose-derived mesenchymal stem cell treatment against sepsis-in
duced acute lung injury. Am J Transl Res. 2014; 6 (5): 439458.
[99] Xia P, Peng X. Study on MSCs transplantation in respiratory diseases. J Chem Pham
Res. 2014; 6 (4): 447449.
[100] Chen X, Liang H, Lian J, Lu Y, Li X, Zhi S. The protective effect of bone marrow mes
enchymal stem cell on lung injury induced by Vibrio vulnificus sepsis. Zhonghua Wei
Zhong Bing Ji Jiu Yi Xue. 2014; 26 (11): 821826.
[101] Pelosi P, Suthersan Y. Bone marrow-derived monocuclear cell therapy in sepsis-in
duced acute respiratory distress syndrome: different insults, different effects! Stem
Cell Res Ther. 2013; 4 (143): 13.
[102] Walter J, Ware LB, Matthay MA. Mesenchymal stem cells: mechanisms of potential
therapeutic benefit in ARDS and sepsis. Lancet respir Med. 2014; 2 (12): 10161026.

195

196

Progress in Stem Cell Transplantation

[103] Brandau S, Jakob M, Brukere KK, Bootz F, Giebel B, Radtke S. Mesenchymal stem
cells augment the anti-bacterial activity of neutrophil granulocytes. PLoS One. 2014;
9 (9): e106903.
[104] Jacobs SA, Roobrouck VD, Verfaillie CM, Van Gool SV. Immunological characteris
tics of human mesenchymal stem cells and multipotent adult progenitor cells. Immu
nol Cell Biol. 2013; 91: 3239.
[105] Brown KA, Treacher DF. Neutrophils as potential therapeutic targets in sepsis. Dis
cov Med. 2009; 6 (33): 118122.
[106] Auletta JJ, Deans RJ, Bartholomew AM. Emerging roles of multipotent, bone mar
row-derived stromal cells in host defense. Blood 2012; 119 (8): 18011809.
[107] Krasnodembskaya A, Song Y, Lee J-W, Matthay MA. Human mesenchymal stem
cells exert antimicrobial activity in vitro and in vivo in part through the secretion of
the antimicrobial peptide LL-37. Meeting Abstract: 183, 1: A 1246, 2011.
[108] Rai RC, Battacharya D, Das G. Stem cells in infectious diseases. Insight and control of
infectious disease in global scenario. Edited by Dr Roy Priti; InTech 2012; ISBN:
978-953-51-0319-6.
[109] Cullen TW, Schofield WB, Barry NA, Putnam EF, Rundell EA, Trent MS, et al. Anti
microbial peptide resistance mediates resilience of prominent gut commensals dur
ing inflammation. Science 2015; 347: 170175.
[110] Bouwman LI. Microbial ligands alter the fate of stem cells. TLR activation influences
survival, proliferation, differentiation and function of stem cells. Universiteit Ulrecht,
2009; 128.
[111] Boika JR, Borghesi L. Hematopoiesis sculpted by pathogens: Toll-like receptors and
inflammatory mediators directly activate stem cells. Cytokine. 2012; 57: 18.
[112] Fuji S, Kapp M, Einsele H. Possible implications of bacterial infections in acute graftversus-host disease after allogeneic hematopoietic stem cell transplantation. Front
Oncol. 2014; 4 (89): 17.
[113] Forslow U, Blennow O, Le Blanc K, Ringden, O, Gustafsson T, Mattson T, et al. Treat
ment with mesenchymal stromal cells is a risk factor for pneumonia-related death af
ter allogeneic hematopoietic stem cell transplantation. Eur J Haematol. 2012; 89 (3):
220227.
[114] Si Y, Yang K, Qin M, Zhang C, Du Z, Zhang X, et al. Efficacy and safety of human
umbilical cord derived mesenchymal stem cell therapy in children with severe aplas
tic anemia following allogeneic hematopoietic stem cell transplantation: a retrospec
tive case series of 37 patients. Pediatr Hematol Oncol. 2014; 31(1): 3949.
[115] Moermans C, Lechanteur C, Boudoux E, Giet O, Henket M, Seidel L, et al. Impact of
cotransplantation of mesenchymal stem cells on lung function after unrelated alloge

Mesenchymal Stem Cells Their Antimicrobial Effects and Their Promising Future Role as Novel Therapies
http://dx.doi.org/10.5772/60640

neic hematopoietic stem cell transplantation following non-myeloablative condition


ing. Transplantation 2014; 98 (3): 348353.
[116] Han DM, Wang ZD, Ding L, Zheng XL, Yan HM, Xue M. Effect of umbilical cord
MSC infusion on the pulmonary infection in haploidentical hematopoietic stem cell
transplantation. Zhongguo Shi Yan Xue Ye Xue Xa Zhi 2014; 22 (4): 10841088.
[117] Gao Y, Cui Y, Chan JK, Xu C. Stem cell tracking with optically active nanoparticles.
Am J Nucl Med Imaging. 2013; 3 (3): 232246.
[118] Li SC, Tachili LM, Luo J, Dethlefs DA, Chen Z, Loudon WG. A biological global posi
tioning system: considerations for tracking stem cell behaviors in the whole body.
Stem Cell Rev. 2010; 6 (2): 317333.
[119] Villa C, Erratico S, Razini P, Fiori F, Rustichelli F, Torrente Y, et al. Stem cell tracking
by nanotechnologies. Int J Mol Sci. 2010; 11: 10701081.
[120] Janowski M, Bulte JW, Walczak P. Personalized nanomedicine advancements for
stem cell tracking. Adv Drug Deliv Rev. 2012; 64 (13): 1488-1507.
[121] Edmundson M, Thanh NT, Song B. Nanoparticles based stem cell tracking in regen
erative medicine. Theranostics 2013; 3 (8): 573582.
[122] Wang Y, Xu C, Ow H. Commercial nanoparticles for stem cell labelling and tracking.
Theranostics 2013; 3 (8): 544560.
[123] Xin X, Hussain M, Mao JJ. Continuing differentiation of human mesenchymal stem
cells and induced chondrogenic and osteogenic lineages in electrospun PLGA nano
fiber scaffold. Biomaterials 2007; 28 (2): 316325.
[124] Kholodenko IV, Konieva AA, Kholodenko RV, Yarygin KN. Molecular mechanisms
of migration and homing of intravenously transplanted mesenchymal stem cells. J
Regen Med Tissue Eng 2013; 2 (4): 111.
[125] Thirumala S, Goebel WS, Woods EJ. Manufacturing and banking of mesenchymal
stem cells. Expert Opin Biol Ther. 2013; 13 (5): 673691.
[126] Cooper K, Viswanathan C. Establishment of a mesenchymal stem cell bank. Stem
Cells Int. 2011; 2011: 905621.

197

You might also like