Stem Cell Reviews and Reports (2022) 18:23–36

https://doi.org/10.1007/s12015-021-10231-w

Clinical Trials Based on Mesenchymal Stromal Cells are Exponentially

Increasing: Where are We in Recent Years?
Umberto Galderisi1,2,3 · Gianfranco Peluso4 · Giovanni Di Bernardo1,2

Accepted: 29 July 2021 / Published online: 16 August 2021

© The Author(s) 2021

Abstract
Mesenchymal stromal cells (MSCs), present in the stromal component of several tissues, include multipotent stem cells,
progenitors, and differentiated cells. MSCs have quickly attracted considerable attention in the clinical field for their regen-
erative properties and their ability to promote tissue homeostasis following injury. In recent years, MSCs mainly isolated
from bone marrow, adipose tissue, and umbilical cord—have been utilized in hundreds of clinical trials for the treatment
of various diseases. However, in addition to some successes, MSC-based therapies have experienced several failures. The
number of new trials with MSCs is exponentially growing; still, complete results are only available for a limited number of
trials. This dearth does not help prevent potentially inefficacious and unnecessary clinical trials. Results from unsuccess-
ful studies may be useful in planning new therapeutic approaches to improve clinical outcomes. In order to bolster critical
analysis of trial results, we reviewed the state of art of MSC clinical trials that have been published in the last six years.
Most of the 416 published trials evaluated MSCs’ effectiveness in treating cardiovascular diseases, GvHD, and brain and
neurological disorders, although some trials sought to treat immune system diseases and wounds and to restore tissue. We
also report some unorthodox clinical trials that include unusual studies.

Keywords Mesenchymal stem cells · Stem cells · Clinical trials · Stromal cells

Introduction
Significance Statement In the past ten years, stem cell therapy
has represented a revolutionary tool for the treatment of several Mesenchymal stromal cells (MSCs), present in most stromal
diseases. The mesenchymal stromal cells (MSCs) are present in tissues, are a heterogeneous population containing multipo-
many tissues, they include multipotent stem cells, progenitors,
and differentiated cells. Several clinical trials are based on tent stem cells, progenitors, and differentiated cells [1, 2].
the use MSCs for treatment of cardiovascular, neurological, MSCs are able to differentiate into mesodermal progeny,
immunological, bone and cartilage diseases. MSCs provide such as osteocytes, chondrocytes, adipocytes, and muscle
significant benefits in tissue repair strategies thanks to secretion cells [3]. MSCs were first characterized in 1967 by Frieden-
of many bioactive molecules, such as growth factors and anti-
inflammatory proteins. stein, who separated adherent clonogenic fibroblast-like col-
We performed a critical analysis of MSC trial results to bolster onies (colony-forming unit fibroblasts, or CFU-F) from bone
reliable, reproducible, and effective therapies based on these cells. marrow (BM). The cells originating from CFU-F colonies
were distinct for their strong in vitro replication capacity and
* Giovanni Di Bernardo
gianni.dibernardo@unicampania.it their ability to differentiate into osteocytes, chondrocytes,
and adipocytes. In addition, when re-transplanted in vivo,
1
Department of Experimental Medicine, Luigi Vanvitelli CFU-F colonies were able to support bone marrow micro-
Campania University, Naples, Italy environments [4].
2
Center for Biotechnology, Sbarro Institute for Cancer In 1995, Hillard Lazarus performed a cell therapy with
Research and Molecular Medicine, Temple University, MSCs for the first time; since then, this approach has become
Philadelphia, PA, USA
one of the greatest clinically-experimental approaches in the
3
Genome and Stem Cell Center (GENKÖK), Erciyes world. Lazarus’s team reported a phase I trial evaluating
University, Kayseri, Turkey
the suitability of human bone marrow-derived progenitor
4
Research Institute On Ecosystems (IRET), CNR, Naples,
Italy

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24 Stem Cell Reviews and Reports (2022) 18:23–36

stromal cells after ex vivo culture expansion and intravenous that of other tissues; thus, the term “mesenchymal stem cell”
infusion in 23 patients with hematological malignancies [5]. should be restricted to this population of mesenchymal cells
Until 2006, the lack of homogeneous criteria for isolating (Fig. 1) [10]. Additionally, the ISCT has suggested that the
and cultivating MSCs made it difficult to establish a reliable plastic-adherent cells fluently defined as mesenchymal stem
and reproducible application in the preclinical and clinical cells should be named ‘multi-potent mesenchymal stromal
fields. This issue led the International Society for Cellular cells’. This statement inspired the scientific community to
Therapy (ISCT) to recommend essential and objective cri- approve this nomenclature in all written documents and oral
teria that are useful in characterizing the unique population communications [11]. Although bone marrow represents the
of MSCs [6]: majority and primary origin of MSCs, several depots have
been identified as alternative MSC reservoirs, including adi-
• MSCs must be plastic-adherent when grown under stand- pose tissue [12], umbilical cord blood [13], placenta [14],
ard conditions. yellow ligament [15], and dental pulp [16].
• The majority of the MSC population (≥ 95%) must be In the human body, the impairment of MSC activities
positive by flow cytometry for CD105, CD73, and CD90; has huge repercussions on health, given their key role in
must express low levels of MHC class I; and must be tissue and organ homeostasis. These properties have been
negative for MHC class II, CD11b, CD34, CD14, CD45, exploited in MSC-based cell therapy. Transplanted MSCs
and CD31. can efficiently focus on injured tissues and actively par-
• MSCs must be able to differentiate in vitro in various ticipate in tissue repair by secreting cytokines and growth
tissues of mesodermal origin—such as osteocytes, adi- factors that can restore tissue homeostasis, reducing local
pocytes, and chondrocytes—under appropriate growth inflammation and differentiating into one or more of the
conditions. cell types’ residents in the injured tissues [17, 18]. Moreo-
ver, MSCs decrease inflammation and increase cell prolif-
eration during tissue regeneration via release of exosomes
Mesenchymal Stromal Cells or Mesenchymal containing a variety of cargo, including mRNAs, proteins,
Stem Cells? and microRNAs [19, 20]. MSCs exhibit immunoregulatory
properties by interacting with the innate immune system,
Over the years, the use of the acronym ‘MSC’ has caused showing both pro-inflammatory and anti-inflammatory
a great deal of confusion in the literature. The term “mes- activities. These unique properties make MSCs useful can-
enchymal stem cell” was introduced by Caplan in the early didates for the treatment of various congenital and acquired
1990s [7], indicating that MSCs provide a production source diseases [21]. Many clinical trials have been conducted to
of dermis, muscles, tendons, bones, cartilages, ligaments, evaluate the reliability and efficacy of cell therapy, and thou-
connective tissue, and adipocytes. However, definitive data sands of patients have received MSC transplants in order to
supporting the stemness of this heterogeneous cell popula- treat different diseases: graft-versus-host disease (GvHD),
tion were not provided [8, 9]. It has been hypothesized that malignant neoplasms, heart diseases, immune system dis-
a stromal stem cell population may be present in the stromal eases, and neurological disorders. An international panel
component of the bone marrow microenvironment and in of experts has established a reference plan to standardize

Fig. 1  The picture shows the

main components present in
stromal tissues. Different cell
phenotypes are intermingled
with blood vessels and extracel-
lular matrix (ECM) compo-
nents. The principal cell types
are: macrophages, fibroblasts,
pericytes, committed cells and
stem cells

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Stem Cell Reviews and Reports (2022) 18:23–36 25

MSC therapeutic treatments so as to avoid the spread of proliferation capacity, higher differentiation potential, and
dubious stem cell therapy centers and the uncontrolled use prolonged in vitro life span before onset of replicative senes-
and commercialization of unproven stem cell treatments. In cence [29].
this context, a methodological algorithm called DOSES has MSCs isolated from different adult tissues also showed
been proposed: D—Donor (i.e., autologous, allogeneic, or biological heterogeneity. In particular, MSCs extracted from
xenogeneic), O—Origin Tissue, S—Separation Method, E— umbilical cord blood were unable to differentiate in adipo-
Exhibited Characteristics (associated with cell behavior), cytes, while those originating from bone marrow showed
S—Site of Delivery [2, 22, 23]. This standard may improve a bias toward differentiation in osteocytes [30]. No clear
MSC treatments. correlations have been established between MSC properties
The current review describes the state of art of recent and gender/age of donors [31], although some investigations
MSC clinical trials from 2015 to the present and highlights have indicated a reduction in proliferation rate, life span,
the limits and potentialities of cell therapy [24]. and differentiation potential in MSCs obtained from elderly
donors [32]. These discrepancies suggest a probable envi-
ronmental niche memory, which could be useful in isolating
MSC Features the most suitable tissue source for a given clinical applica-
tion [30, 33].
The following paragraphs describe the main biological prop-
erties of MSCs, providing a better understanding of their
therapeutic potential (Fig. 2). Secretome of MSCs

The MSC secretome has been described as an elaborate

Population Heterogeneity blend of bioactive molecules containing both a free frac-
tion—composed mainly of growth factors, chemokines,
MSCs contain multipotent stem cell populations that can cytokines, lipid intermediary molecules, cellular adhesion
be committed to some specific cells lineages [25]. Several molecules, interleukins, and hormones—and a vesicular
findings have shown a heterogeneity in the differentiation encapsulated fraction—formed by exosomes and microvesi-
potential of these cells, as MSC cultures include stem cells cles that are engaged to carry a variety of cargos, including
with tri-, bi-, and uni-potential differentiation capabilities RNAs (e.g., microRNAs), lipids, proteins, and DNA [34,
[26] [27, 28]. 35]. These circulating factors are mainly involved in tis-
MSCs can be obtained from various fetal or adult tis- sue regeneration and repair through paracrine effects that
sues. In comparisons of MSCs isolated from adult sources mediate cell-to-cell signaling. This cross-talk communica-
with those from fetal tissues, the latter showed higher tion between the cells and the surrounding tissues plays a

Fig. 2  The summary of MSC

mechanisms in cell therapy

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26 Stem Cell Reviews and Reports (2022) 18:23–36

key role in immunomodulation, angiogenesis, anti-cancer, the innate immune system [51]; in the inflammation area,
and tissue protection [36]. In the past decade researchers MSCs control the polarization of macrophages in activated
have turned a spotlight onto the importance of the MSC M2 macrophages, through the production of cyclooxygenase
secretome both in cell transplant treatments and in cell-free 2 and the expression of indolamine 2,3-dioxygenase [52]. In
therapies [37]. the absence of IL-6, MSCs polarize monocytes in activated
M1 macrophages that, unlike M2, increment local inflam-
mation by secreting pro-inflammatory cytokines (IFN-γ and
Secretome Immunomodulatory Properties TNF-α). Therefore, the interactions between MSCs and the
innate immune system to balance pro- and anti-inflammatory
MSC activities can modulate both adaptive and innate responses are important to preserving tissue functionality
immune responses [38, 39]. For this reason, MSCs exhibit and integrity.
therapeutic potential in the treatment of immune system dis-
orders [40, 41].
The inflammatory response acts through Toll-like recep- Secretome Angiogenic, Pro‑survival,
tors, which are activated following noxious stimuli; their and Tissue Regeneration Properties
activation counteracts pathogenic agents or stimuli from
damaged tissues [42]. The activation of Toll-like path- The paracrine function of MSCs represents one of the pri-
ways triggers immune responses based on the secretion of mary mechanisms supporting the effectiveness of MSC-
inflammatory molecules and phagocytosis. MSCs and stro- based cell therapy. After transplantation, the great majority
mal components are also activated to complete the immune of MSCs persist in recipients’ organs for a short period of
response, characterized by high levels of TNF-α and IFN-γ time (around 48 h) [53], and thus their beneficial effects
[42, 43]. In particular, MSCs show two different polarization cannot be ascribed to differentiation processes that replace
phenotypes, pro-inflammatory (MSC1) or anti-inflammatory damaged cells. Indeed, transplanted MSCs release a plethora
(MSC2), that depend on Toll-like receptor (TLR3, TLR4) of growth factors, chemokines, and cytokines able to per-
signaling. form angiogenic, immunomodulatory, antioxidative, and
The short-term stimulation of TLR4 on MSCs and the antiapoptotic effects during the initial days following MSC
low levels of TNF-α and IFN-γ supports the establishment infusion [54, 55].
of a pro-inflammatory MSC1 phenotype, which increases T Various studies have demonstrated the role of MSCs
cell reactions via chemokines secretion, such as RANTES, in angiogenesis and arteriogenesis, useful in improving
MIP-1α MIP-1β, CXCL9, and CXCL10. These factors are coronary heart disease, skin wound healing, and hindlimb
registered in an inflammation area [44]. A sustained TLR3 ischemia [56–58]. Acting as intermediary of angiogenesis,
stimulation of MSCs, associated with high levels of TNF-α MSCs release various growth factors, such as vascular
and IFN-γ, triggers the MSC2 anti-inflammatory phenotype, endothelial growth factor (VEGF), fibroblast growth fac-
which promotes the release of effector molecules that are tors (FGFs), hepatocyte growth factor (HGF), stromal cell-
capable of inhibiting cell-mediated and humoral activities of derived factor 1 (SDF-1), and angiopoietin-1 (ANG-1). All
the immune system [45]. The anti-inflammatory properties these molecules are fundamental to endothelial cell growth
of MSCs have been thoroughly investigated. For example, and vascularization [59, 60]. MSCs are also involved in
recent studies have indicated that MSCs, via soluble factors direct inhibiting apoptosis and promoting tissue regenera-
(IL-10, prostaglandin E2, IL-6, and TGF-β), are able to pre- tion by secreting insulin-like growth factor-I (IGFI), stan-
vent dendritic cell-induced T cell activation and growth, thus niocalcin-1 (STC1), B-cell lymphoma 2 (BCL-2), survivin,
blocking innate immune response and sustaining immune and granulocyte–macrophage colony-stimulating factor
tolerance [46]. Other studies have proven that MSC-derived (GM-CSF). In a recent study, a mouse model of a chem-
extracellular vesicles are able to modulate B lymphocytes’ ically-injured cornea was used to demonstrate change in
proliferation and to promote the activity of regulatory B the expression of genes (Bcl-2, Bax, P53) associated with
cells, which possess IL-10-associated immunosuppressive apoptosis. Transplantation of MSCs was able to mitigate the
capacity [47]. Similarly, clinical applications and experi- changes attenuating apoptosis [61].
mental models have demonstrated the immunosuppres- Many pathological conditions (e.g., inflammation, cel-
sive role of MSCs in modulating natural killer (NK) cell lular damage, and metabolism disorders) are associated
responses [48]. MSCs significantly decreased IL-2/15-in- with oxidative stress events that promote the formation of
duced proliferation of NK cells, their cytotoxicity, and the damaging reactive oxygen species. Different animal mod-
production of IFN-γ [49]. All these features are very impor- els have indicated a therapeutic antioxidant property of
tant in improving the engraftment of bone marrow trans- MSCs via free radicals scavenging, stimulation of physi-
plantation [50]. Macrophage activation is another aspect of ological antioxidant defenses, modification of mitochondrial

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Stem Cell Reviews and Reports (2022) 18:23–36 27

bioenergetics, and mitochondria transferring to injured cells of several diseases, providing significant benefits in tis-
through tunneling nanotubes [62–65]. Several studies have sue repair strategies thanks to various advantages such as
demonstrated that MSCs are also highly resistant to oxi- autologous transplantation, safety around cellular division,
dative stress induced by ionizing radiation [66]. Globally and lack of teratoma onset [67–69].
speaking, MSCs can modulate their cytoprotective and anti‐ From 2015 to present, 416 clinical trials based on
inflammatory features by setting the redox environment and the use of MSCs have been implemented to treat vari-
oxidative stress. ous pathologies, according to the US National Institute of
Health–ClinicalTrials database (http://​clini​caltr​ials.​gov).
At present, of these trials, 55 are Active non-recruiting,
MSC‑based Therapy: A Recent Overview 233 studies are Recruiting, 117 are Completed, and 11 tri-
of Clinical Trials als are Terminated (ended prematurely) (Fig. 3). The great
majority of trials have been carried out in the U.S.A. and
In the past ten years, stem cell therapy has represented a China, but several investigations have been performed in
revolutionary tool for regenerative medicine, and MSCs other countries too (Fig. 4).
have been a valuable therapeutic approach in the treatment

Fig. 3  MSC clinical trials clas-

sified by disease categories were
also subdivided by progress
status: in green, “Recruiting
Status”; in red, “Completed”; in
yellow, “Active not recruiting”;
in magenta, “Terminated”. The
22 shown categories account
for > 90% of the trials reported
on clinicaltrials.gov from 2015
to present

Fig. 4  Geographic distribu-

tion of MSC clinical trials in
the world. The world map was
obtained from clinicaltrials.gov

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The following sections describe the most significant received 100 million allo-MSCs; the remaining 30 patients
trials, grouped by type of target diseases. We focused our will be randomized 1:1 to receive allo-MSCs or vehicle via
attention on completed trials, primarily Phase II–III trials. 20 transendocardial injections. All endpoints are/will be
In the text, the studies are reported with the corresponding assessed at 6- and 12-months post-treatment. The approach
clinicaltrials.gov identifier (NCT). of the SENECA study represents the first clinical trial for
As a reminder for readers, clinical trials are divided in treating AIC through direct cardiac injection of cells. Pre-
four phases. liminary results and further investigations have been pub-
Phase I: A small group of healthy volunteers (20–100 lished [75] [76]. The researchers involved in this trial con-
individuals) undergoes treatment for several months to test cluded that transendocardial cell administration appears safe
the safety and dosage of an experimental procedure. and feasible, although the phase I study was small and not
Phase II: A higher number of enrolled patients is required powered or designed to assess efficacy; larger phase II and
(up to several hundred) to evaluate efficacy and side effects III trials aimed at assessing efficacy are needed.
of the treatment. In another clinical trial (NCT02501811), the same
Phase III: Effectiveness and safety are further evaluated, research group proposed an investigation named CON-
sometimes in combination with other well-known pharma- CERT-HF (Combination of Mesenchymal and c-kit+ Car-
ceutical treatments. Regulatory medical agencies approve diac Stem Cells As Regenerative Therapy for Heart Fail-
the treatment if safety, efficacy, and reduced adverse reac- ure). This trial aimed to evaluate the feasibility, safety, and
tions of the treatment are proven during this phase. efficacy of transendocardial administration of autologous
Phase IV: With large and multiple populations, the treat- MSCs (target dose: 150 million) and cardiac stem cells
ment is monitored for a long time period. The analysis of (c-kit +) (target dose: 5 million), alone and in combination,
treatment continues after its release on the market to check in patients with heart failure caused by chronic ischemic
safety and efficacy. cardiomyopathy. CONCERT-HF was designed as a rand-
omized, double-blind, placebo-controlled trial and enrolled
162 patients—18 in a safety lead-in phase (Phase I) and
Cardiovascular Diseases 144 in the main trial (Phase II). Phase I is completed, and
Phase II is currently randomizing patients from 7 centers
According to the World Health Organization, cardiovascular across the United States. Each participant will have regu-
disease is a group of disorders of heart and blood vessels lar follow-up visits after one day, one week, one month,
including hypertension, coronary heart disease, peripheral three months, six months, and 12 months. CONCERT-HF
vascular disease, and myocardial infarction. Cardiovascu- will examine whether the cell administration alleviates left
lar diseases represent one of the primary causes of death ventricular remodeling and dysfunction, reduces scar size,
and disability. After myocardial infarction, cardiomyocytes improves quality of life, or augments functional capacity in
die and their function is lost with subsequent ventricular this population sample. Preliminary data encourage the use
remodeling, inflammatory response, and fibrous scar forma- of CONCERT-HF for its potential therapeutic utility [77].
tion that lead to heart failure [70]. In addition to drug treat- Final results are still not available.
ments and heart transplantation [71, 72], the use of MSCs The remaining clinical trials for cardiovascular disease
has appeared as an encouraging cell therapy for heart disease in recruiting status (Phase I or Phase II) offer some other
in the past decade [18, 73, 74]. options: PERISCOPE (Pericardial Matrix With Mesenchy-
An interesting completed study in phase I mal Stem Cells for the Treatment of Patients With Infarcted
(NCT02509156) sought to evaluate the safety and feasibil- Myocardial Tissue–NCT03798353), MESAMI2 (Adminis-
ity of transendocardial injection of bone marrow allogenic tration of Mesenchymal Stem Cells in Patients With Chronic
MSCs (allo-MSCs) in cancer survivors with anthracycline- Ischemic Cardiomyopathy–NCT02462330), and AMAS-
induced cardiomyopathy (AIC). The secondary objectives CIS-02 (Allogeneic Adipose Tissue-derived Mesenchymal
were to determine the effects of allo-MSCs’ administration Stem Cells in Ischemic Stroke–NCT04280003). These trials
on left ventricular function and functional status from base- use MSCs isolated from allogenic umbilical cord, Wharton’s
line to 6 months and from baseline to 12 months after treat- jelly, or autologous bone marrow to validate the safety and
ment. In this study, 37 patients met the eligibility criteria, potential benefits of cell therapy performed with intramyo-
one of which was that patients must be clinically free of cardial or intravenous injections.
cancer for at least two years with a ≤ 30% estimated five- In another trial (NCT02635464), human umbilical cord-
year risk of recurrence. This study, named SENECA (StEm derived MSCs were loaded into a collagen scaffold and
cell iNjECtion in cAncer survivors), offers a promising new injected into the infarct region to determine whether cell-
approach to repairing damaged myocardium. The first six laden hydrogel treatment is safe and feasible for patients
subjects participated in an open-label, lead-in phase trial and with chronic ischemic cardiomyopathy. Among 115 eligible

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patients with chronic ischemic heart disease, 50 patients thus could be also investigated in relation to other inflam-
with left ventricular ejection fraction of 45% or less were matory and immune-mediated diseases.
selected to receive elective coronary artery bypass grafting Kurtzberg et al. described a phase III prospective study
and were additionally randomized to cell-plus-collagen treat- (NCT02336230) to treat 54 pediatric subjects (male and
ment (collagen/cell group), cell treatment alone (cell group), female) between the ages of 2 months and 17 years who were
or a control group. Sixty-five patients were excluded due to suffering from corticosteroid-resistant aGvHD. Patients were
severe comorbidities or unwillingness to participate. Forty- treated with an intravenous MSC injection (Remestemcel-
five participants (88%) completed the study; the last patient L) at a dose of 2 × ­106 MSCs/kg twice per week for 4 con-
completed their 12-month follow-up in August 2019. The secutive weeks. The treatment significantly boosted overall
encouraging data provides the first step to supporting clini- response rate (OR) by day 28 compared to the control. The
cal use of collagen hydrogel as support for cell delivery [78]. statistically significant OR (70.4%) persisted through day
100 and included an enhancement in complete response
from 29.6% at day 28 to 44.4% at day 100. Overall survival
Graft Versus Host Disease was 74.1% at day 100 and 68.5% at day 180 [87].The authors
state that Remestemcel-L therapy is tolerated, safe, and non-
Allogeneic hematopoietic stem cell transplantation appears toxic, representing a valid treatment for pediatric patients
to be the most successful strategy to treat hematological and suffering from steroid-resistant aGvHD.
autoimmune diseases [79, 80]. Nevertheless, graft versus
host disease (GvHD) represents one of the major elements
limiting the success of this therapeutic approach, influencing Brain and Neurological Disorders
the survival percentage of grafted patients [81]. GvHD is
also frequent after host tissue and solid organ transplantation MSC-based therapies also appear as a promising new treat-
(lung, skin, liver, and digestive tract) [82, 83]. According to ment for several brain and neurological diseases. The neuro-
different pathologic parameters, GvHD has been clinically trophic, migratory, immunosuppressive, and tissue-regener-
classified as acute (aGvHD) or chronic (cGvHD). aGvHD ative properties of MSCs could be useful for treating neural
is identified by T helper cells 1 activation, while cGvHD is injuries and neuropathologies with an inflammatory etiol-
principally attributed to the T helper cells 2 response [80]. ogy [88–90]. In recent years, various clinical investigations
Steroid therapy is an early approach for treating aGvHD have reported the therapeutic advantages of MSC-based cell
[84]; nevertheless, in many cases (30–50%), aGvHD is not therapy in treating stroke (NCT02378974, NCT03371329),
controlled with steroid treatment and requires additional multi-system atrophy (NCT03265444), multiple sclerosis
therapeutic strategies [85]. In this context, MSCs, with their (NCT02495766, NCT02403947), amyotrophic lateral scle-
immunomodulation abilities, can play a pivotal role in the rosis (NCT03280056), Parkinson’s disease (NCT02611167,
therapeutic approach to counteracting aGvHD that is resist- NCT03684122), Alzheimer’s Disease (NCT03117738), and
ant to steroid treatments. chronic spinal cord injury (NCT02152657, NCT02981576,
Bloor et al. enrolled sixteen patients with steroid-resistant NCT02570932).
aGvHD (SR-aGvHD) in a phase I, open-label clinical trial Petrou et al. described in their study (NCT02166021) the
(NCT02923375).The subjects were divided in two groups health effects of autologous MSC transplantation in multi-
(cohort A and cohort B) and received intravenous admin- ple sclerosis patients. They evaluated the optimal procedure
istration of iPSC-derived MSCs on days 0 and 7. Cohort A of MSC administration, its safety, and its clinical efficacy
received a dose of 1 million cells/kg, up to a maximum of [91]. Between 2015 and 2018, 48 patients with active and
100 million cells, while cohort B received a dose of 2 million progressive multiple sclerosis were enrolled. Patients were
cells/kg, up to a maximum of 200 million cells. The iPSCs randomized into 3 different groups: intrathecal, intravenous
derived from patients’ fibroblasts offered a great advantage, (in both cases using 1 × ­106/kg autologous MSCs), and
as they accelerate the production of a fruitfully unlimited sham injections. Six months later, half of the patients that
amount of MSCs from a single blood donation, overcoming had received MSCs via intrathecal and intravenous injec-
the limits associated with production of donor-originated tion were submitted to a second cell treatment, while the
MSCs. The principal aim of Bloor et al.’s investigation was remaining half received a placebo. The authors claim that
to estimate the safety and tolerability of the approach and the cell treatments were well tolerated and enabled short-
to assess its efficacy by evaluating the percentage of candi- term healthy effects concerning the primary end points, par-
dates that displayed a complete response (53.3%), an overall ticularly in patients with active disease. Furthermore, in an
response (86.7%), and overall survival (86.7%) by day 100 evaluation of different disease parameters, intrathecal injec-
[86]. As described by the authors, the procedures are safe tion was more efficacious than intravenous administration,
and well-tolerated, without significant adverse events, and although a phase III trial is needed to confirm these results.

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In a similar investigation, a clinical trial is being per- Lung and Bronchial Diseases
formed to explore the efficacy and safety of MSC-based
therapy for treating multiple sclerosis (NCT02239393). Pawel and Silvestri used P ­ NEUMOSTEM® as a cellular
The study, named MESEMS (MEsenchymal StEm cells for therapy product for the prevention of bronchopulmonary
Multiple Sclerosis), has been planned to connect partially dysplasia in premature infants at high risk of death. The
independent clinical trials, follow uniformed protocols, and study (NCT02381366) is an open-label, single-center, dose
share some key centralized procedures, such as data analysis escalation investigation, consisting of patient injection
and collection [92]. The data are still being evaluated. with ex vivo cultured allogeneic, unrelated, human umbili-
cal cord blood-derived MSCs. The experimental procedure
consisted of two cellular doses: 6 of 12 patients received
dose A (­ 106cells/kg), while the remaining received dose B
Muscle, Bone, and Cartilage Diseases ­(206cells/kg) by intratracheal administration. All patients
tolerated the administration, with no toxicities during the
The ability of MSCs to differentiate into osteocytes, chon- first monitoring period (72 h) and no side effects during
drocytes, adipocytes, muscle cells, and other tissues of the 84 subsequent days [96]. However, the cohort was too
mesenchymal origin makes them an ideal candidate in the small to evaluate real benefit; a larger randomized study is
treatment of bone and cartilage diseases. Osteoarthritis is necessary to establish the effectiveness of such a therapy.
the most common form of knee arthritis; it is a degenerative Pneumoconiosis is a lung disease that occurs due to the
disease that occurs mainly in individuals older than 50 years, inhalation of fine particles, such as silica. (For this reason,
although it may be also present in young people. In knee the disease is commonly called silicosis.) Currently, there
osteoarthritis, cartilage articulation a slow, progressive ero- is no effective drug treatment improving respiratory func-
sion, causing bone rub and promoting painful bone spurs tion and reversing the progression of pulmonary fibrosis.
[93]. For these reasons, knee osteoarthritis is one of the most At present, one trial (NCT02668068) analyzes and evalu-
investigated bone and cartilage disorders in MSC-based clin- ates the safety and effectiveness of clinical-grade umbilical
ical studies (NCT02580695, NCT04326985, NCT02351011, cord MSC transplantation for pneumoconiosis treatment
NCT03337243, NCT02958267, NCT03509025, in combination with whole-lung lavage, a conventional
NCT04037345, NCT02674399, NCT03000712, therapy. Eighty participants have been enrolled, who
NCT03990805, NCT01879046). will receive 1­ 06cells/kg/person that will be injected after
JOINTSTEM (NCT02658344) is a clinical trial using whole-lung lavage. The trial is still ongoing.
autologous adipose-derived MSCs. The aim of this study
was to promote cartilage growth and regeneration within six
months in knees of patients with osteoarthritis. The study
was a phase IIb prospective, double-blinded, randomized Wounds and Restorations
trial. The MSCs (1 × ­108 cells in 3 mL of saline solution)
were intra-articularly injected in 12 patients, and outcomes Foot ulcers are a common consequence in diabetic patients
were compared with 12 other patients (control group) as a result of skin breakdown. Infected ulcers could cause
who were administered a saline solution. According to the limb amputation if they are neglected. A non-healing
authors, the intra‐articular injection of autologous adipose minor amputation frequently precedes a major amputation
MSCs provided functional progress and pain reduction in that will have a huge impact on the function and quality of
treated patients, without side effects [94]. Nevertheless, life of the patient.
long‐term studies should be carried, as 6 months is a short Lonardi et al. evaluated the healthy benefits of autolo-
time period for evaluating clinical efficacy and structural gous adipose MSC injection at the amputation stump of
outcomes. Moreover, large sample cohorts are necessary. diabetic patients who had minor lower limb amputation.
In another trial, Zhao et al. used allogeneic adipose- In this randomized controlled trial (NCT03276312), 114
derived MSCs in knee osteoarthritis patients. Eight- patients undergoing a minor lower limb amputation were
een patients participated a phase I/IIa clinical trial randomized to standard care or to cell treatment, called
(NCT02641860). All individuals were randomized into three Lipogems®. This latter treatment is based on a minimum
groups (six patients each) and received a low-dose (1.0 × ­107 quantity of autologous lipoaspirates that were used, with a
cells), mid-dose (2.0 × ­107), or high-dose (5.0 × ­107) intra- minimal manipulation, for patient injection. The rationale
articular injections of cells [95]. Preliminary data showed behind this procedure is the presence of unpurified MSCs
functional progress and pain reduction in treated patients. in lipoaspirates. By evaluating the healing rate and the
Here, too, larger patient cohorts and long-term follow-up time after the minor amputation, the authors found that
are required.

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Stem Cell Reviews and Reports (2022) 18:23–36 31

Lipogems® improved the healing rate of treated feet. The improvement after injections. In some cases, transient mild
approach was safe, and technical success was obtained in side effects were observed, including increased body temper-
all cases. Additionally, skin tropism and pain scale were ature, pain due to liposuction, and slight growth of epileptic
improved [97]. episodes. After treatment, patients showed improved social
Moon et al. examined the potential of allogenic adi- functioning and intellectual performance [100].
pose-derived MSCs in treating diabetic foot ulcers. Fifty- Systemic lupus erythematosus is an autoimmune disease
nine patients were randomized into two groups (n = 30 characterized by the production of auto-antibodies against
and n = 29) for MSC administration or polyurethane film cellular nucleus. Although approximately 50% of lupus
(control), respectively. The cells embedded within the patients have lupus nephritis, there is no therapy for this
film or the film alone were applied on diabetic wounds complication. For lupus treatment, three different studies
weekly (NCT02619877), and these wounds were assessed are included on the clinical trials website as evaluating the
for 12 weeks. At two months, entire wound closure was safety and effectiveness of MSCs obtained from umbilical
obtained in 73% of patients in the treatment group and in cords (NCT03171194), olfactory mucosa (NCT04184258),
47% of patients in the control group; at three months, total and allogenic bone marrow (NCT03174587). As yet, no
wound closure was 82% in the treatment group and 53% in study results have been published.
the control group [98]. No serious collateral effects were
found to be associated with cell therapy. Thus, allogeneic
MSCs might be a valid and safe approach to treat diabetic Unorthodox Clinical Trials
foot ulcers.
A Phase I study (NCT02589119) with 15 adult patients The versatility of MSC-based therapy has paved the way to
aged 18 years and over with cryptoglandular fistulas and their application in odd trials, some of which completely
used a single dose of 20 million MSC-coated fistula plugs lack scientific meaning. Others may have therapeutic effec-
(Gore Fistula Plug). Patients first underwent standard adju- tiveness, even if the rationale behind them is not completely
vant therapy, which included drainage of the infection and understood.
placement of a draining seton. A month and a half later, the Mattei et al. proposed a clinical trial (NCT02622464)
seton was replaced with an MSC-coated fistula plug. The to treat patients suffering from scarred vocal folds. Scarred
subjects were subsequently followed up with for 24 months vocal folds are characterized by anomalous scar tissue pre-
for response and closure of the fistula. As yet, no study sent in the vibrating layer of the vocal folds, causing voice
results have been published. problems. The study considered autologous adipose tissue-
derived stromal vascular fraction (by lipoaspirates) as a
therapeutic candidate for treating scarred vocal folds, given
Immune System Diseases the angiogenic, immunomodulatory, anti-inflammatory, and
regenerative properties of stromal cells. This study, named
Systemic sclerosis is a progressive autoimmune disease CELLCORDES, was a prospective, open-label, single-
that results in disability due to diffuse fibrosis and vascular arm, single-center, nonrandomized controlled trial. Eight
abnormalities in the skin, joints, and internal organs. patients with severe dysphonia due to vocal fold scarring
Park et al. performed an open-label study in early phase were treated with stromal vascular fraction in situ (into 1
I (NCT03060551) to investigate the efficacy and safety of or 2 vocal folds) during laryngoscopy. The results indicate
an autologous fat tissue-derived stromal vascular fraction feasibility and tolerability of cell injection, but further stud-
injected into systemic sclerosis patients. Twenty patients ies using randomized clinical trials with an adequate number
with hand disability received an average of 3.61 × ­106 MSCs of patients are needed to evaluate the treatment effectiveness
in each finger. A 24-month follow-up had been planned for [101].
every patient. According to the results, autologous adipose Jieming et al. at Ruijin Hospital in Shanghai, China, set
tissue-derived MSC injection into patients is well tolerated. up a clinical study (NCT04213248) to evaluate the safety
The trial indicated clinical efficacies of the proposed treat- and tolerance of aerosol inhalation of the exosomes derived
ment, as it promoted improvement of skin fibrosis, quality from allogenic adipose MSCs in the treatment of severe
of life, and attenuation of digital ulcers [99]. lung diseases (including severe lung infection, acute respira-
Autologous adipose-derived MSCs were also used to treat tory distress syndrome, and chronic obstructive pulmonary
autoimmune refractory epilepsy. The study was registered disease). Their experimental plan is based on studies that
with trial identifier NCT03676569. In six patients, intrath- have demonstrated the ability of MSCs and exosomes to
ecal injection of autologous MSCs was repeated 3 times significantly reduce lung inflammation and other lung inju-
every 3 months. All parameters and antiepileptic effects ries. Consequently, they argue that exosomes (containing
were monitored for 12 months. All patients showed clinical cytokines, growth factors, signaling lipids, mRNAs, and

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32 Stem Cell Reviews and Reports (2022) 18:23–36

regulatory miRNAs) may exhibit therapeutic effect compa- transfusion was found to significantly reduce the proportions
rable to MSC-based cell therapy. Results are still lacking. of solid component lesion volume at day 28. The adverse
In the clinical trial registered as NCT02742857, inves- effects were similar in the two experimental groups. Accord-
tigators aimed to establish a reversal of brain death using ing to the authors, the results suggest that MSCs represent
intrathecal injection of bioactive peptides and MSCs asso- a therapeutic approach that is safe and potentially effective
ciated with laser stimulation of transcranial IV and median for COVID-19 patients with lung damage [102]. Therefore,
nerve. The research, which enrolled 20 patients, is com- the authors are looking to perform a phase III trial to esti-
pleted, but no results have been provided. mate the positive effects in terms of reducing mortality and
One more unusual study (NCT04213248) is ongoing at preventing long-term pulmonary disability.
the Zhongshan Ophthalmic Center at Sun Yat-sen Univer-
sity in China. The investigators seek to determine whether
umbilical MSC-derived exosomes could alleviate dry eye
Conclusions
symptoms in patients with cGvHD, as 60–90% of such
patients are affected by dry eye symptoms, which may seri-
We reviewed the state of art of MSC clinical trials—with
ously affect their life quality. The effectiveness of exosome
MSCs isolated from bone marrow, umbilical cord, and adi-
treatment will be evaluated by measuring the ocular surface
pose depots—conducted in the last six years (2015 to pre-
index score. Other analyses will measure the tear secretion
sent). Most of these studies have analyzed the effectiveness
amount, the tear break time, the ocular redness, the tear
of such cell therapies for the treatment of cardiovascular
meniscus, and the visual acuity. Approximately 27 subjects
diseases, GvHD, and brain and neurological disorders, but
will be recruited. The treatment group will receive artifi-
there are also trials analyzing its use in treatment of immune
cial tears for 2 weeks to normalize the baseline, followed
system diseases and wounds and tissue restoration.
by administration of exosomes at 10ug/drop, four times a
Although the number of new trials is exponentially grow-
day, for 14 days. The follow-up visit will be at 12 weeks
ing, the results (positive or negative) are only published in
post-treatment, where the progression of dry eye will be
a few completed clinical trials. This deficiency should be
evaluated.
addressed, since lack of data cannot help prevent poten-
tially inefficacious pleonastic clinical trials. Moreover, data
on unsuccessful studies could pave the way to setting up
COVID‑19 new therapeutic strategies to improve clinical outcomes.
Negative results may also derive from clinical trials with a
On March 1st, 2020, the World Health Organization
very limited number of enrolled patients; thus, this approach
declared COVID-19 a pandemic infectious disease, given
should be highly discouraged. Some indications about how
the thousands of coronavirus cases in over 110 countries
to standardize trials using MSCs were published several
and territories around the world. In recent months, more
years ago, but these recommendations are still disregarded
different scientific approaches have been proposed for
[103]. Donor variance, in vitro expansion, immunogenic-
treating coronavirus-affected patients. A growing num-
ity, senescence, and cryopreservation are key factors that
ber of MSC-based cellular therapies for the treatment of
can negatively affect the validity of MSC-based therapy.
COVID-19 (NCT04491240, NCT04492501, NCT04573270,
All these issues should be carefully addressed in order to
NCT04535856, NCT04355728, NCT04276987,
provide reliable, reproducible, and effective therapies based
NCT04713878) is seen on the clinical trials website. The
on MSCs.
rationale behind this choice is to exploit the anti-inflamma-
tory and immunomodulatory properties of MSCs in order to
reduce the damage caused by cytokine storm to tissues and Authors' Contributions U.G., G.D.B., and G.P.: collection and/or
organs, which are responsible for the onset of pneumonia, assembly of data, data analysis and interpretation; U.G. and G.D.B.:
acute respiratory distress syndrome, and multi-organ failure. manuscript writing, final approval of manuscript.
In the general hospital of Wuhan, China, where the pandemic
Funding Open access funding provided by Università degli Studi della
started, Shi et al. performed a phase II trial (NCT04288102)
Campania Luigi Vanvitelli within the CRUI-CARE Agreement. There
to ascertain the efficacy and safety of human umbilical cord were no funds for this research.
MSCs in treating severe COVID-19 patients with impair-
ment of lung functions. The trial, which was randomized, Data availability N/A
double-blind, and placebo-controlled, recruited 101 patients
with lung damage. Each of them received either MSCs Code availability N/A
(4 × ­107 cells per infusion) or a placebo on days 0, 3, and
6. Compared to the placebo, MSC injection by intravenous

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Stem Cell Reviews and Reports (2022) 18:23–36 33

Declarations Keating, A., & T International Society for Cellular. (2005). Clari-
fication of the nomenclature for MSC: The international society
for cellular therapy position statement. Cytotherapy, 7, 393–395.
Ethics approval N/A
12. Heidari, B., Shirazi, A., Akhondi, M. M., Hassanpour, H.,
Behzadi, B., Naderi, M. M., Sarvari, A., & Borjian, S. (2013).
Consent to participate N/A
Comparison of proliferative and multilineage differentiation
potential of sheep mesenchymal stem cells derived from bone
Consent for publication N/A
marrow, liver, and adipose tissue. Avicenna Journal of Medical
Biotechnology, 5, 104–117.
Conflict of interest None to disclose. 13. Romanov, Y. A., Svintsitskaya, V. A., & Smirnov, V. N. (2003).
Searching for alternative sources of postnatal human mesenchy-
Open Access This article is licensed under a Creative Commons Attri- mal stem cells: Candidate MSC-like cells from umbilical cord.
bution 4.0 International License, which permits use, sharing, adapta- Stem Cells, 21, 105–110.
tion, distribution and reproduction in any medium or format, as long 14. Papait, A., Vertua, E., Magatti, M., Ceccariglia, S., De Munari,
as you give appropriate credit to the original author(s) and the source, S., Silini, A. R., Sheleg, M., Ofir, R., & Parolini, O. (2020). Mes-
provide a link to the Creative Commons licence, and indicate if changes enchymal stromal cells from fetal and maternal placenta possess
were made. The images or other third party material in this article are key similarities and differences: Potential implications for their
included in the article's Creative Commons licence, unless indicated applications in regenerative medicine. Cells, 9, 127.
otherwise in a credit line to the material. If material is not included in 15. Chen, Y. T., Wei, J. D., Wang, J. P., Lee, H. H., Chiang, E. R.,
the article's Creative Commons licence and your intended use is not Lai, H. C., Chen, L. L., Lee, Y. T., Tsai, C. C., Liu, C. L., &
permitted by statutory regulation or exceeds the permitted use, you will Hung, S. C. (2011). Isolation of mesenchymal stem cells from
need to obtain permission directly from the copyright holder. To view a human ligamentum flavum implicating etiology of ligamentum
copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. flavum hypertrophy. Spine, 36, E1193–E1200.
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