Front. Med.

2011, 5(4): 372378

DOI 10.1007/s11684-011-0164-4

REVIEW

Mesenchymal stem cells hold promise for regenerative medicine

)

Shihua Wang, Xuebin Qu, Robert Chunhua Zhao (

Center of Excellence in Tissue Engineering, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union
Medical College, Beijing 100005, China

Higher Education Press and Springer-Verlag Berlin Heidelberg 2011

Abstract Regenerative medicine is an emerging interdisciplinary eld of research that uses several technological
approaches including stem cells to repair tissues. Mesenchymal stem cells (MSCs), a type of adult stem cell, have
generated a great amount of interest over the past decade in this eld. Numerous studies have explored the role of
MSCs in tissue repair and modulation of allogeneic immune responses. The mechanisms through which MSCs
exert their therapeutic potential rely on some key properties of the cells as follows: the capacity to differentiate into
osteoblasts, chondrocytes, adipocytes, cardiomyocytes, hepatocytes, endothelial, and neuronal cells; the ability to
secrete multiple bioactive molecules capable of stimulating the recovery of injured cells and inhibiting
inammation; the lack of immunogenicity; and the ability to perform immunomodulatory functions. In the
present review, we focus on these three aspects upon which the therapeutic effects of MSCs are mainly based.
Furthermore, some pathological conditions under which the application of MSCs should be done with caution are
also mentioned.
Keywords

mesenchymal stem cells; differentiation; immunomodulation; regenerative medicine

Introduction
Regenerative medicine is an emerging interdisciplinary eld
of research and clinical applications focused on the repair,
replacement, or regeneration of cells, tissues, or organs to
restore impaired function resulting from multiple causes,
including congenital defects, disease, and trauma. Regenerative medicine uses a combination of several technological
approaches that transcend beyond traditional transplantation
and replacement therapies. These approaches include, but are
not limited to, the use of stem cells [1]. Many different types
of stem cells can be used for regenerative medicine, including
the following: (1) Embryonic stem cells derived from the
inner cell mass of the blastocyst, and can produce the entire
repertoire of cells in the body. However, they form teratoma
when transplanted directly, and they are ethically controversial. (2) Adult stem cells, which are already somewhat
specialized and have limited differentiation potential. They
can be isolated from various tissues and are currently the most
commonly used seed cells in regenerative medicine. One
example is hematopoietic stem cells (HSCs), which sustain
blood formation throughout our entire lives and are restricted

Received August 12, 2011; accepted September 15, 2011

Correspondence: chunhuaz@public.tpt.tj.cn

in their developmental potential to generate only blood cell

lineages. Currently, HSC transplantation is a routine medical
procedure for several diseases. (3) Induced pluripotent stem
cells (iPS) are generated through nuclear reprogramming,
which resets the fate of somatic cells to an embryonic stem
cell-like state. iPS cells have normal karyotypes, express
genes typical of ES cells, and maintain the developmental
potential to differentiate into cells of all three germ layers. iPS
cells are a major breakthrough in regenerative biology.
In the present review, we focus on mesenchymal stem cells
(MSCs), a type of adult stem cell that has generated a great
amount of interest as a potential therapy for various diseases.
MSCs were rst discovered in 1968 by Friedenstein et al. [2]
as an adherent broblast-like population in the bone marrow
capable of differentiating into bone. Since then, a similar
population has been isolated from various tissues, such as
adipose tissue, peripheral blood, umbilical cord, and amniotic
uid. Given a lack of unique MSC surface markers, the
International Society of Cellular Therapy dened MSCs in
2006 based on three criteria as follows: (1) MSCs must be
adherent to plastic under standard tissue culture conditions;
(2) MSCs must express certain cell surface markers, such as
CD73, CD90, and CD105, and lack the expression of other
markers, including CD45, CD34, CD14, or CD11b, CD79alpha or CD19 and HLA-DR surface molecules; and (3) MSCs
must have the capacity to differentiate into osteoblasts,

Shihua Wang et al.

373

adipocytes, and chondroblasts under in vitro conditions [3].

These cells possess the following advantages: (1) they are
easy to obtain and are highly proliferative under ex vivo
culture conditions and (2) neither autologous nor allogeneic
MSCs induce any immunoreactivity in the host upon local
transplantation or systemic administration [4,5]. Our laboratory has been studying the biologic characteristics of MSCs,
their therapeutic effects, and the underlying mechanisms for
over a decade. We believe that the current enthusiasm
surrounding the potential application of MSCs for therapeutic
purposes is based on their multilineage differentiation
capacity, their immunomodulatory properties, and their
ability to secrete bioactive molecules. We illustrate these
three aspects in detail, based on the experimental results
obtained in the present review.

Therapeutic effect based on multilineage

differentiation capacity
MSCs have the capacity to differentiate into mesenchymal
lineages including osteoblasts, adipocytes, and chondroblasts
under in vitro conditions [6]. We isolated MSC from a human
fetal bone marrow, called Flk1+CD31CD34 stem cells, and
found that they could differentiate into the above mentioned
lineages, and also into cells of the three germ layers, such as
endothelial, hepatocyte-like, neural, and erythroid cells at the
single-cell level [7,8]. Based on this nding, we hypothesized
that post-embryonic subtotipotent stem cells exist [9], and this
hypothesis was later conrmed by other scientists (Table 1).
MSCs have great differentiation potential, so they can be
used to treat various diseases by replacing damaged cells. In
our laboratory, we proved this application with a series of
animal disease models. In a C57BL/6 mouse model of
ischemia-reperfusion kidney, transplanted human adipose
tissue-derived MSCs were able to differentiate toward renal

Table 1

tubular epithelium at an early stage of injury. The differentiated donor cells replaced the vacant space left by the
dead cells, thereby contributing to the maintenance of
structural integrity and proceeding to a subsequent tissuerepair process [17]. In Wistar rat models of diabetic
retinopathy, transplanted MSCs differentiated into photoreceptor and glial-like cells in the retina, which improved the
integrity of the blood-retinal barrier in diabetic rats [18]. In
mdx mice, AD-MSCs homed on the injured muscle tissues
and differentiated into myotubes and endothelial cells, as well
as muscle satellite cells [19]. Other examples of the use of
MSC to treat diseases through differentiation are shown in
Table 2.

Therapeutic effect based on secretion of

multiple bioactive molecules
MSCs do more than respond to stimuli and differentiate.
Proteomic analyses of MSC-conditioned medium indicate
that MSCs secrete many known growth factors, cytokines,
and chemokines, which have profound effects on local
cellular dynamics. Table 3 shows some important soluble
factors secreted by MSC. Both in vitro and in vivo studies
indicate that many cell types are responsive to MSC paracrine
signaling. The effects of MSC-secreted bioactive molecules
can be either direct or indirect or even both: direct by causing
intracellular signaling or indirect by causing another cell in
the microenvironment to secrete functionally active agent.
The secretion of soluble factors is the mechanism underlying
the therapeutic effect of MSC in many disease models.
Cerebral ischemia is a prime clinical neurologic disorder,
and MSC transplantation in ischemic tissues could improve
the neurologic functions by increasing interleukin-10 (IL-10)
expression. IL-10 is a well-known anti-inammatory cytokine with neuroprotective effects [35]. Previous studies

Studies conrming the subtotipotent stem cell hypothesis

Tissue
Term placental membranes

Cell types produced

All embryonic germ layers, including alveolar type II cells

Reference
[10]

Wharton's jelly of umbilical cord

Ectoderm-, mesoderm-, and endoderm-derived cells, including insulin-producing cells

[11]

Amniotic uid

All embryonic germ layers, including neuronal lineage cells secreting the neurotransmitter L-glutamate or
expressing G-protein-gated inwardly rectifying potassium channels, hepatic lineage cells producing urea,
and osteogenic lineage cells forming tissue-engineered bone

[12]

Placenta and bone marrow

Adipocytes and osteoblast-like cells (mesoderm), glucagon and insulin expressing pancreatic-like cells
(endoderm), as well as cells expressing the neuronal markers neuron-specic enolase, glutamic acid
decarboxylase-67 (GAD), or class III beta-tubulin, and the astrocyte marker glial brillary acidic protein
(ectoderm)

[13]

Human term placenta

All three germ layersendoderm (liver, pancreas), mesoderm (cardiomyocyte), and ectoderm (neural
cells) in vitro

[14]

Placental cord blood

In vitroosteoblasts, chondroblasts, adipocytes, and hematopoietic and neural cells including astrocytes
and neurons that express neurolament, sodium channel protein, and various neurotransmitter phenotypes.
In vivomesodermal and endodermal lineages demonstrated in animal models

[15]

Adult bone marrow

Cells with visceral mesoderm, neuroectoderm, and endoderm characteristics in vitro

[16]

374
Table 2

Mesenchymal stem cells in regenerative medicine

Examples of MSCs used to treat diseases through differentiation

Disease model
Lung injurythe thoraxes of C57BL/6 mice
were exposed to 1 400 cGy

Detailed information
Reference
MSCs injected immediately after injury were shown to differentiate into functional lung cells,
[20]
such as epithelial and endothelial cells

Hindlimb ischemia mouse model

MSCs differentiated in response to local cues into endothelial cells and contributed to
neoangiogenesis

[21]

Fibrosis formation induced by carbon

tetrachloride (CCl4)

MSCs engrafted into host liver, had epithelium-like morphology, and expressed albumin,
although at a low frequency

[22]

Lethally irradiated C57BL/6

mice

Fluorescence-labeled Flk + MSC of BALB/c mice (H-2Kd, white) were transplanted into lethally
irradiated C57BL/6 mice (H-2Kb, black); donor cells could migrate and take residency at the
skin. The recipient mice grew white hairs after approximately 40 days. Immunochemistry
staining and RT-PCR demonstrated that skin tissue within the white hair regions was largely
composed of donor-derived H-2Kd cells, including stem cells and committed cells. Furthermore,
most skin cells cultured from white hair skin originated from the donor. Thus, these ndings
provide direct evidence that bone marrow-derived cells can give rise to functional skin cells and
regenerate skin tissue

[23]

Table 3

Bioactive molecules secreted by MSCs and their functions

Bioactive molecules
Prostaglandin E2

Functions
Anti-proliferative mediators

Interleukin-10

Anti-inammatory

Transforming growth factor -1, hepatocyte growth factor

Suppress T-lymphocyte proliferation

[27]

Interleukin-1 receptor antagonist

Anti-inammatory

[28]

Human leukocyte antigen G isoform

Anti-proliferative for naive T cells

LL-37

Anti-microbial peptide and reduce inammation

[31,32]

Endothelial growth factor, basic broblast growth factor,

placental growth factor, and monocyte chemoattractant protein-1

Enhance proliferation of endothelial cells and smooth muscle cells

[33,34]

suggest that MSCs have the ability to protect cultured neurons

from excitotoxicity-induced apoptosis. We proved that MSC
could be protective against glutamate-induced injury in PC12
cells, and this effect is mediated by secreted neurotrophic
factors, including endothelial growth factor, hepatocyte
growth factor, brain-derived neurotrophic factor, and nerve
growth factor [36].

Therapeutic effect based on

immunomodulatory functions of MSCs
MSCs lack immunogenicity because they express low levels
of major histocompatibility complex-I (MHC-I) molecules
and they do not express MHC-II molecules and costimulatory
molecules, such as CD80, CD86, or CD40 [37]. This unique
property allows for the transplantation of allogeneic MSCs.
MSCs can also modulate the functions of the immune system
by interacting with a wide range of immune cells, including T
lymphocytes, B lymphocytes, natural killer cells, and
dendritic cells. MSCs regulate the proliferation, activation,
and maturation of T and B lymphocytes in vitro in a dosedependent and time-limited manner [38,39], and they can
facilitate the immunosuppressive effect of cyclosporin A on T
lymphocytes through Jagged-1-mediated inhibition of NF-B
signaling [40]. We rst reported that MSCs could inhibit the

Reference
[24]
[25,26]

[29,30]

upregulation of CD1a, CD40, CD80, CD86, and HLA-DR

during DC differentiation and prevent an increase of CD40,
CD86, and CD83 expression during DC maturation [41]. We
also demonstrated that in the presence of MSCs, the
percentage of cells with cDC phenotype is signicantly
reduced, whereas the percentage of pDC increases, further
suggesting that MSCs can signicantly inuence DC
development [42]. MSCs could drive maDCs to differentiate
into a novel Jagged-2-dependent regulatory DC population
and escape their apoptotic fate, providing more evidence to
support the role of MSCs in rejection prevention during organ
transplantation and treatment of autoimmune disease [43]. We
rst reported the immunomodulatory effects of MSCs on the
abnormal immune system of BXSB mice which were born
with immunologic deciency and developed lupus naturally.
MSCs can signicantly downregulate Th2 cells in pathological conditions and further inhibit the abnormal activation of
humoral immunity to maintain the original balance [44].
MSCs lack immunogenicity and can modulate the immune
system simultaneously. These two properties make them great
candidates for applications in both the induction of tolerance
in transplantation and in the treatment of autoimmune
diseases. A report showed that cotransplantation of MSCs
prevents death from graft-versus-host disease (GVHD) without abrogating the graft-versus-tumor effects after HLA-

Shihua Wang et al.

mismatched
allogeneic
transplantation
following
nonmyeloablative conditioning [45]. We explored the
efcacy and safety for treating chronic graft-versus-host
disease (cGVHD), particularly sclerotic skin manifestations
of cGVHD (ScGVHD) by MSC transplantation. Patients with
ScGVHD had improved symptoms after receiving MSC
expanded ex vivo from unrelated donors by intra-BM
injection [46]. Based on studies in our laboratory, we drew
a schematic picture of the immunomodulatory effects of
MSCs both in vitro and in vivo (Fig. 1).

Possible side effects related to the

application of MSCs

375

growth, as well as cancer metastases. We cultured two cancer

cell lines (MDA-MB-435S and MCF7) with human adiposederived MSCs, and found that the invasive capacity and
migration ability of the two cancer cell lines post-coculture
were signicantly enhanced (unpublished data). To date,
various reports emphasized the pro-tumor growth role of
MSCs. In addition, MSCs could aggravate arthritis in a
collagen-induced arthritis model by at least upregulating the
secretion of IL-6, which favors Th17 differentiation [48].
These studies remind us that we should be cautious about
subjects with some pathological conditions when using MSCs
for patients.

Conclusions and future prospects

From the literature, MSCs possess a vast therapeutic capacity
that assists in the treatment of various diseases. However, side
effects related to MSC transplantation have also been
reported. Karnoub et al. [47] co-injected bone marrowderived human MSCs with green uorescent protein-labeled
human breast cancer cells MCF/Ras into immunocompromised mice, and found that MSCs accelerate breast tumor

MSCs hold promise to fulll unmet needs in regenerative

medicine, and have recently emerged as great candidates for
cell-based therapy because they can differentiate into a wide
range of cells; produce a series of growth factors, cytokines,
and signal molecules; as well as modulate the immune
responses in various ways. Although we divided the effects of

Fig. 1 The immunomodulatory effects of MSCs both in vitro and in vivo.

376

MSC into these three aspects for better description in the

present review, in reality, these three aspects are combined
and overlapped. For example, MSCs exert their immunomodulatory effect by secreting bioactive factors, such as IL-10.
MSCs can differentiate into specic cell types and secret new
bioactive factors in accordance with the microenviroment.
Thus, these effects are not separated; instead, they interconnect with each other.
Although tremendous progress has been achieved by
scientists and clinicians, future research in this eld should
continue and focus on elucidating some main issues. The rst
issue concerns the mechanisms underlying MSC multilineage
differentiation. Lineage specication of MSCs is tightly
controlled by both genetic and epigenetic factors. Recently,
microRNAs, a class of non-coding RNA that regulates gene
expression at the post-transcriptional level, have been
demonstrated to play an important role in MSC differentiation. We found that microRNA-138 could inhibit adipogenic
differentiation of human MSCs through EID-1 [49]. Genetic
and epigenetic factors intertwine, further complicating the
mechanisms governing MSC differentiation. The second
issue concerns how MSCs react to the environment and
secrete bioactive molecules accordingly. The third involves
the mechanism underlying MSC immunomodulatory function. The last issue entails determining possible adverse
effects and complications that might arise from MSC
transplantation. We believe that eventually, a novel and safe
therapy with MSCs can emerge and revolutionize treatment
and therapies for patients with severe diseases.

Acknowledgements
This work was supported by grants from the 863 Projects of
Ministry of Science and Technology of P. R. China (No.
2011AA020100), the National Natural Science Foundation of
China (Grant No. 30830052), the National Key Scientic Program
of China (No. 2011CB964901), and the Program for Changjiang
Scholars and Innovative Research Team in University (PCSIRT)
(No. IRT0909).

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