tmp980C TMP
tmp980C TMP
tmp980C TMP
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
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
1- Bone marrow
2- Peripheral blood
differentiating into:
host disease
4- Placenta
osteoblasts, adipocytes
- Enhancement of engraftment
4- Amniotic fluid
and chondrocytes
5- Synovial fluid
- Myocardial infarction
7- Palatal tonsil
- CD 105
- Dilated cardiomyopathy
8- Fallopian tubes
- CD 73
- CD 90
- CD 45
- CD 34
7- Liver injury
- CD 14
8- Regenerative medicine
- CD 11
9- Osteogenesis imperfecta
- CD 19
- CD 79
- HLA - DR
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168
Study and
year of
administration of MSCs
mechanism(s) of action
publication
Hau SR et al
2013
- Intravenous injection of
of mice
- CLP, in vivo method
- Polymicrobial sepsis
Mei SHJ et al
- Bone Marrow-MSCs
2010
- Intravenous administration
- CLP
- In vivo method
Luo CT et al
- Bone marrow-MSCs
2014
- Intravenous administration
- CLP
- Polymicrobial sepsis
Gupta N et al
2012
- Intratracheal injection
- E. Coli pneumonia
- In vitro study
Nemeth K et al
2009
- Activated MSCs
- CLP
- In vivo study
Gonzalez-
Rey et al
adipose tissue-MSCs
2008
- Intraperitoneal injection
amelioration of severity
Et al
- Rat model
2012
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
year of
administration of MSCs
mechanism(s) of action
publication
Yang R et al
- CLP
injury
2013
Sung P-H
- Rat model
et al
2013
- CLP
of publication
Meisel
- Human MSCs
R et al
2011
- In vitro study
Krasnodembskaya - Human BM-MSCs murine model - Increased antimicrobial activity and decreased bacterial
A et al
2010
MSCs
aureus pneumonia
bacterial clearance.
A et al
- Intravenous administration
from circulation.
2012
- Murine Gram-negative
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
MSCs
169
170
of publication
2011
- Intrathecal administration
- 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
2011
- In vitro study
Maqbool M et al
- Human MSCs
2011
- In vitro study
Rafaghello L et al
2008
neutrophils
media
apoptosis
2013
E. coli delivery
lung injury
* IV or intrabronchial injection
of MSCs
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
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172
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
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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].
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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
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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].
Mesenchymal Stem Cells Their Antimicrobial Effects and Their Promising Future Role as Novel Therapies
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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].
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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
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fraction, use of purified stem cell population has the potential to significantly increase the
therapeutic benefit of cell therapy in chagasic CMP [89].
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enhance closure of enterocutaneous fistula and aided in the recovery and healing of wounds
in a rat model [97].
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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].
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Phase
damage signals
response
Elimination of pathogens
Induction of proinflammatory
gradients
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
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[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].
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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].
Mesenchymal Stem Cells Their Antimicrobial Effects and Their Promising Future Role as Novel Therapies
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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
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