Copyright © 2012 Cognizant Communication Corporation
DOI: 10.3727/096368912X655172
CT-2435 Accepted for publication PPSSCR Issue of “Cell Transplantation”
Mesenchymal Stem Cell Insights: Prospects in Hematologic Transplantation
Shiu-Huey Chou1, Shinn-Zong Lin2, Cecilia Hsuan Day3, Wei-Wen Kuo4, Chia-Yao
Shen3, Dennis Jine-Yuan Hsieh5, Jing-Ying Lin6, Fuu-Jen Tsai7, Chang-Hai Tsai8,
Chih-Yang Huang7,9,10,*
1
Department of Life Science, Fu-Jen Catholic University, Xinzhuang Dist., New
Taipei City, Taiwan, 2Graduate Institute of Immunology, China Medical University,
3
Taichung, Taiwan, Department of Nursing, MeiHo University, Pingtung, Taiwan,
4
Department of Biological Science and Technology, China Medical College,
Taichung, Taiwan, 5 School of Medical Technology, Chung Shan Medical University,
Taichung, Taiwan, 6Department of Nursing, Central Taiwan University of Science
and Technology, Taichung, Taiwan, 7Graduate Institute of Chinese Medical Science,
China
Medical
University,
Taichung,
Taiwan,
8
Department of
Healthcare
9
Administration, Asia University, Taichung, Taiwan. Graduate Institute of Basic
Medical Science, China Medical University, Taichung, Taiwan,
10
Department of
Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan
Running head: Mesenchymal stem cell insights
*Corresponding author
Chih-Yang Huang, PhD
Graduate Institute of Basic Medical Science
China Medical University and Hospital
No.91 Hsueh-Shih Rd., Taichung, Taiwan 40402, R.O.C
Tel：+886-4-22053366ext3313, Fax：+886-4-22333641
Email: cyhuang@mail.cmu.edu.tw
Conflict of interest statement: The authors declare not to have any conflict of interest
related to the work presented in this publication.
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Abstract
Adult stem cells have been proven to possess tremendous potential in the treatment of
hematological disorders, possibly in transplantation. Mesenchymal stem cells (MSCs)
are a heterogeneous group of cells in culture, with hypo-immunogenic character to
avoid alloreactive T cell recognition as well as inhibition of T cell proliferation.
Numerous experimental findings have shown that MSCs also possess the ability to
promote engraftment of donor cells and to accelerate the speed of hematological
recovery. Despite that the exact mechanism remains unclear, the therapeutic ability of
MSCs on hematologic transplantation have been tested in pre-clinical trials. Based on
encouraging preliminary findings, MSCs might become a potentially efficacious tool
in the therapeutic options available to treat and cure hematological malignancies and
non-malignant disorders. The molecular mechanisms behind the real efficacy of
MSCs on promoting engraftment and accelerating hematological recovery are
awaiting clarification. It is hypothesized that direct cell-to-cell contact, paracrine
factors, extracellular matrix scaffold, BM homing capability, and endogenous
metabolites of immunologic and non-immunologic elements are involved in the
interactions between MSCs and HSCs. This review focuses on recent experimental
and clinical findings related to MSCs, highlighting their roles in promoting
engraftment, hematopoietic recovery, and GvHD/graft rejection prevention after
HSCT, discussing the potential clinical applications of MSC-based treatment
strategies in the context of hematologic transplantation.
Key words: mesenchymal stem cells, hematopoietic niche, hematopoiesis,
hematopoietic stem cells, bone marrow
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INTRODUCTION
Hematopoiesis is a physiological activity maintained by hematopoietic stem cells
(HSCs) and hematopoietic progenitors (HPs) which possess the ability to self-renew
and sustain long-term generations of all lineages of blood cells (45,50). The use of
stem cells in hematologic therapeutic areas has gathered tremendous momentum over
the last two to three decades. The development of hematologic malignant and nonmalignant disorders is frequently accompanied by various hematopoietic lineage
failures. Therefore, hematopoietic stem cell transplantation (HSCT) has become a
well established treatment for hematological malignancies and non-malignant
disorders. Despite advances in human leukocyte antigen (HLA) typing, supportive
care, and treatment of graft versus host disease (GvHD), the transplant related
mortality and long-term morbidity from allogeneic hematopoietic stem cell
transplantation (ASCT) remains significant for non-malignant diseases. The damaged
microenvironment after myeloablative therapy and rejection associated with
autologous recovery are two major causes for the delay in engraftment, limited
number of grafts, or failure of allogeneic transplantation for many of the hematologic
disorders. Therefore, ways to improve clinical outcome of autologous and allogeneic
HSC transplantation have become a crucial issue in current hematologic
transplantation.
Currently, it is a well-accepted concept that the developmental potential of HSCs is
greatly affected by stromal microenvironments, termed niches, and the development
of HSCs could be reprogrammed by changing their niche. In adults, HSC and HP
niches are located in the bone marrow; however, how HSCs interact with their niche
cells, and the identity of the niche cells for hematopoietic maintenance, remains
unclear. Numerous reports have demonstrated the role of bone marrow stromal cells
(BMSCs) acting as niche cells for maintenance of hematopoietic development
(14,17,72,80). In 1968, a non-hematopoietic stem cell with multiple mesoderm
differentiation potential within the bone marrow (BM) was first described by
Friendensten and his colleagues (16). Mesenchymal stem cells (MSCs) are a rare but
unique population which have self-renewal and differentiation abilities and are able
to replenish a variety of specific cell types. Evidence is emerging that MSCs can
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escape recognition by alloreactive T cells and exert hypo-immunogenic characters
(5,15,36,66). In addition, MSCs may act as the precursor cells for stromal tissues
supporting hematopoiesis (25). For many years, MSCs have been considered as
merely a component of marrow stroma without specific functions. Recently, it was
shown
that
MSCs
provide
an
enabling
environment
for
HSC-mediated
hematopoiesis, and have a crucial role in the development and differentiation of
various hematopoietic lineages through cell-to-cell interactions and by producing a
number of growth factors and regulatory cytokines (69,71). However, the molecular
mechanism of HSC-MSC interaction has been barely unraveled and requires so
further research.
More recently, experimental findings and clinical trials have focused on the
therapeutic ability of MSCs on cellular therapy, transplantation, and regenerative
medicine. The immunomodulatory activity and engraftment-promoting properties of
MSCs have been tested in a variety of animal models and human clinical trials. Based
on the encouraging preliminary findings, MSCs might become a potentially
efficacious tool as a therapeutic option available to treat and cure serious illnesses.
This review focuses on recent experimental and clinical findings related to MSCs,
highlighting their roles in promoting engraftment, hematopoietic recovery, and
GvHD/graft rejection prevention after HSCT, discussing the potential clinical
applications of MSC-based treatment strategies in the context of hematologic
transplantation.
CHARACTERISTICS OF MSCs
MSCs are stromal cells that have been isolated from most species so far investigated
including mice, rat, human, cat, dog, rabbit, pig, and baboons.. The sources for
isolation of MSCs include adult bone marrow, adipose tissue, cord blood, umbilical
cord, amniotic fluid, placenta, fetal liver, and other fetal tissues. It is well accepted
that morphologic, phenotypic, and in vitro tri-differentiation potential and expansion
capacity are the major criteria to be used for identification of MSCs. The physical
property of MSCs is plastic adherence and its presence in low numbers in the bone
marrow (1 of 104-105 mononuclear cells) (53). MSCs in culture are morphologically
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heterogeneous, containing cells ranging from narrow spindle shaped to large
polygonal and slightly cuboidal cells (16,53). Figure 1A shows the morphology of
MSCs derived from mouse placenta decidua in a phase contrast image.
Phenotypically, there are no specific markers for MSCs individually or in
combination. It is generally accepted that human MSCs do not express markers of
hematopoietic lineages such as cluster of differentiation 34 (CD34), CD45,
glycophorin A, T cell, B cell, HLA-DR, CD11a, CD14, and markers of endothelial
including CD11b and CD31. MSCs often express CD44, CD49e, CD62, CD73,
CD90, CD105 (endoglin), CD117, CD140b, CD271, and STRO-1 (for general review
see ref. (7)).
It is important to emphasize that the MSC population in culture conditions is
heterogeneous. Hence, morphologic or phenotypic criteria cannot be used for the
unique identification of MSCs. Perhaps evaluating the function of MSCs is therefore
the most useful approach for MSC identification. It is broadly accepted that the
capacity for induced in vitro differentiation of MSCs to bone, fat, and cartilage is the
major critical requirement to identify putative MSC populations (53). There are also
generally only a few clones capable of extensive expansion. Thus, a hierarchical
model is applied on MSC cultures in which multi-potency is lost following repeated
passaging, with the majority of cells being transitional cells with specified lineage
potential. According to data, the International Society for Cellular Therapy has
provided the minimum criteria for defining multipotent human MSCs (25). The in
vitro characterization
morphology,
characteristics,
of MSCs includes
colony-forming
and
unit-fibroblast
tri-differentiation
plastic adherence,
(CFU-F)
potential
under
fibroblast-like
content,
appropriate
phenotypic
inductive
conditions. The expression of marker genes and surface antigens of lineage
differentiation in culture does not fully represent the functionality of these cells.
Furthermore, in vitro differentiation of MSCs is highly influenced by culture
conditions. Hence, the physiological roles of MSCs need to be determined by in vivo
assay systems. However, there is little information on the in vivo behavior of MSCs
(37). Clinical studies indicated that site-directed administration of MSCs can result in
successful engraftment under injury conditions, such as brain ischemia, brain injury,
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lung fibrosis, and osteogenesis imperfect. Furthermore, the evidence indicated that
the number of MSCs in engraftment areas is very small in various tissues (49,51,79).
IMMUNOMODULATORY PROPERTIES OF MSCs
There is an emerging amount of data to suggest that autologous or allogeneic MSCs
possess broad immunomodulatory properties that make MSCs influence the activities
of all cells involved in the immune responses. This makes them potentially useful for
various transplantation and immune-related disease treatment purposes. In more than
95% of MSCs, the immune phenotypes are expressed at low levels of major
histocompatibility complex (MHC) class I, but no MHC class II. MSCs lack surface
expression of Fas-ligand or costimulatory molecules, such as B7-1 (CD80), B7-2
(CD86), CD40 or CD40L. In addition, they do express adhesion molecules involved
in T cell interaction, including vascular cell adhesion molecule-1 (VCAM-1),
intracellular adhesion molecule (ICAM), and lymphocyte function-associated antigen
3 (LFA-3; CD58) (41). In the absence of costimulation, T-cell and MSC engagement
can result in anergy.
In vitro studies have shown that MSCs suppress lymphocyte proliferation in mixed
lymphocyte culture, induced by alloantigens or mitogens such as Phytohemagglutinin
(PHA), Concanavalin A (Con A), tuberculin, as well as activation of T cell by CD3
and CD28 antibodies (5,15,36,40,66). The degree of MSC suppression is dosedependent and T cells do not become apoptotic or anergic, because they can be restimulated by MSC removal (15,40). It seems that MSCs inhibit T cell proliferation
by mechanisms which do not require antigen presenting cells (APCs). However,
MSCs did affect the maturation or functional operation of APCs. Zhang et al. (78)
showed that MSCs inhibit up-regulation of CD1a, CD40, B7-1, B7-2, and HLA-DR
during dendritic cell (DC) maturation. In addition, MSCs decrease the interferon
(IFN)-γ, interleukin (IL)-12 and tumor necrosis factor (TNF)-α production after being
co-cultured with monocytes (8). Several studies have shown a suppressive effect of
MSCs on immune cytotoxicity. MSCs can function as “veto cells” to inhibit lysis
when MSCs are added to the lysis assay (54). MSCs inhibited the formation of
cytotoxic T lymphocytes (CTLs) but did not abrogate cytotoxic T lymphocyte- or
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natural killer cell-induced lysis. This effect appears to be mediated by soluble factors
(59). MSCs can also modulate B cell proliferation and antibody production (2,11).
The immunomodulatory effects of MSCs may make them useful for
immunotherapy. However, the exact mechanisms involved in the immunomodulatory
effects of MSCs remain unclear. Several mechanisms have been proposed. First,
regulatory T cells are thought to have a critical role in the suppression of immune
responses. Recent data suggests that MSCs increased the number of regulatory
CD4+CD25+ T cells in mixed lymphocyte culture or IL-2 stimulated peripheral blood
mononuclear cells (PBMCs) cocultured with MSCs (1,38). Second, cell-to-cell
contact molecules are considered to be involved in MSC-mediated immune
suppression. However, the immunomodulatory molecules are limited in their
expression on the MSC surface except for MHC I molecules. MSCs can express
certain immune regulatory molecules on the surface under certain conditions or
following differentiation. After differentiation of MSCs into bone, cartilage, or
adipose tissues, MSCs continue to express MHC class I, but not class II (36).
Furthermore, up-regulation of HLA class II by IFN-γ still did not elicit a proliferative
response (29,31,54). In addition, it has been recently reported that lack of costimulation is not the reason for MSC-induced T cell unresponsiveness because
retroviral transduction of MSCs with B7 molecules did not result in increased T cell
proliferation (29). This suggests that deficiency in MHC expression and costimulation by MSCs are not major reasons for immune escape and immune
suppression. In contrast, MSCs did down-regulate the costimulatory molecule
expressing profiles on APCs (78). Furthermore, programmed cell death-1 PD1/Programmed cell death ligand 1,2 (PD-L1,2) pathway may be responsible for MSCinduced suppression via cell-cell contact (3). Third, suppression seems to be mediated
by a soluble factor or factors produced by MSCs, because suppression still occurs if
MSCs and lymphocytes are separated in a transwell system (66). It has reported that
nitric oxide (NO), prostaglandin E2 (PGE2), IL-10, transforming growth factor-β1
(TGF-β1), hepatocyte growth factor (HGF), indoleamine 2,3-doxygenase (IDO),
parathyroid hormone (PTH), bone morphogenetic protein (BMP), and IFN-γmay be
involved (for reviews see refs. (61,67)).
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MSCs are also sensitive to inflammatory signals such as microbial compounds.
Recently, receptors to innate immune cells on MSCs were intensive studied. Toll-like
receptor (TLR) is a family of germ line-encoded pattern-recognition receptors (PRRs)
that have evolved to detect different components of foreign pathogens. It has been
reported that TLR2, TLR3, TLR4, TLR7, and TLR9 are expressed by MSCs and may
play a deleterious role in MSC-mediated protection (52,58). In addition, a family of
β-galactoside binding proteins, galectin, was discovered in MSCs. MSCs
constitutively express galectins-1, -3 and -8 at both the mRNA and protein levels. In
contrast to galectin-8, galectins-1 and -3 are secreted and found on the cell surface.
The single or double knockdown of galectin-1 or/and galectin-3 almost abolished the
immunosuppressive capacity of MSCs (19,62). However, the data available are
largely restricted to in vitro studies. In vivo biological evidence still needs to be
clearly elucidated.
MSCs ACT AS HSC NICHE CELLS
In adults, HSCs are located mainly in the bone marrow where HSCs interact
within a specific microenvironment, called the stem cell niche. Within these niches,
self-renewal, proliferation, and differentiation of HSCs are sophisticatedly regulated
by various intrinsic programs and an orchestral pathway. The nature and function of
these niches remains unclear. The HSCs located in bone marrow are previously
thought to reside in the trabecular endostream (also called the osteoblastic niche)
(64). However, recent studies indicated that HSCs also favor residence in the vascular
niche, reticular niche, or nestin expressing niche, depending on the state of
proliferation and undifferentiated state of the HSCs. The bone marrow vascular niche
is contributed to by endothelial cells (27). The reticular niche is created by a small
+
population of VCAM-1 reticular cells, termed chemokine (C-X-C motif) ligand 12
(CXCL12; stromal cell derived factor-1 [SDF-1])-abundant reticular (CAR) cells
(63). The nestin expressing niche is created by a population of cells which positively
express nestin, the endothelial and neural specific regulatory element, on the surface
of membranes (44). Within these niches, various niche cells act as supportive feeder
layers to attract and to anchor HSCs and HPs. In addition, niche cells also mediate
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HSC differentiation via secretion of various soluble factors and extracellular matrix
interactions.
MSCs resemble plastic-adherent cell preparations isolated from bone marrow
or other tissues that are very heterogeneous, comprising of only a small subset of
stem cells. Since MSCs can generate several types of stromal cells that constitute the
marrow niche, MSCs are considered as a niche feeder layer for hematopoiesis
supportive function. By using a HSC-MSC co-culture system, hematopoietic cells
were found in the supernatant and primary cobblestones areas have been formed
(Figure 1B). Interaction of HSCs and MSCs provides contact signals to trigger
hematopoiesis. Moreover, MSCs have been examined to generate several cytokines in
cultures, such as fetal liver tyrosine kinase-3 ligand (FLT3-L), stem cell factor (SCF),
IL-3 and thrombopoietin (TPO) which are essential cytokines for hematopoiesis
(22,68). Results from an in vitro MSC-HSC co-culture study indicated that MSCs
could provide an excellent surrogate in vitro model to understand the relative roles of
various homing and adhesion pathways in hematopoiesis (21,71).
MSCs IN EXPERIMENTAL AND CLINICAL HSCT
Promising therapeutic effect(s) of stem cell transplantation is(are) dependent
on their capacity to engraft and survive in the target tissue. However, transplantation
of large amounts of donor cells into chemo-radiotherapy recipients yielded only
marginal improvement in bone marrow transplantation. This is possibly in part due to
poor donor-cell engraftment, loss of engraftment or increased immunogenicity of the
transplanted cells in an unhealthy marrow environment. Therefore, strategies to
enhance repair cells implanted into the bone marrow and to decrease immune
rejection of transplanted cells by the recipients‟ immune system are key to successful
HSCT treatment. Several animal studies have demonstrated that administration of
donor MSCs can prolong allograft or xenograft survival after HSCT in fetal sheep,
mouse, and monkey. The outcome of graft enhancement and graft rejection or GvHD
prevention are summarized in Table 1 (43). In our studies, human bone marrow
derived mesenchymal stem cells have been transplanted into fetal mouse and showed
persistence for at least 4 months with multi-lineage differentiation potential (10).
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However, in several murine bone marrow transplant (BMT) studies, MSCs coinfusion has failed to suppress donor anti-host allo-responses in vivo or reduce
GvHD. Possible mechanisms were associated with homing failure of MSCs to
secondary lymphoid tissues or the generation of memory T cells after a repeated
challenge experiment (23,76). Thus, anti-GvHD potency or hematopoietic support of
MSCs may be critically determined by several factors including timing of MSC
infusion, context of the MSC‟s residing microenvironment, location of MSCs, and
persistence in the site of GvHD.
There is an urgent need for a better treatment and prevention of GvHD after
ASCT. Therefore, the clinical experience and safety of MSCs arouse great interest.
The immuno-modulatory effects of MSCs have offered greater possibilities of MSCs
in the management of GvHD, and protective effect of MSCs on GvHD is being tested
in a prospective, randomized trial. Several clinical experiences with MSC infusion on
HSCT are summarized in Table 2. The first clinical trial using MSCs was a safety
trial in which autologous mesenchymal progenitor cells were given (33). Subsequent
trials on the use of autologous MSCs for accelerating hematological recovery were
performed in breast cancer patients given autologous transplantation of peripheral
blood hematopoietic cells. Rapid hematopoietic recovery was noted (30). Afterwards,
several phase I/II trials aimed at evaluating the safety of MSC infusion was
conducted in hematological malignant patients receiving allogeneic HCT from an
human leukocyte antigen-identical sibling or haploidentical peripheral blood (PB).
HC-MSC co-infusion was not associated with adverse events, GvHD was prevented,
and hematopoietic recovery was prompt for most patients (4,34). One successful
treatment case of severe acute GvHD with third party haploidentical MSCs has been
reported by the Le Blanc group (35). MSCs have been employed in patients
transplanted with umbilical cord blood (UCB) cells. In these patients, MSCs were
administered without clinical adverse effects (28). Later, with MSCs used in pediatric
patients including phase I–II clinical trial, infusion of MSCs was proven to be safe,
prevented GvHD, and with prompt hematopoietic recovery (6,39). In one of the cases
of adult patients receiving UCB transplantation with co-infusion of third-party donormobilized HSCs, MSC administration at the time of transplantation had no effect on
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the kinetics of UCB cell engraftment, or on GvHD prevention (20). Altogether, these
data indicated that co-transplantation of HSCs and MSCs is safe. MSCs are believed
to modulate the immune system and may have application in the induction of
tolerance in transplantation. However, concerns over the MSCs‟ usefulness in human
subjects is still open to debate (65).
THE
MECHANISMS
OF
ACTION
FOR
MSCs
TO
PROMOTE
HEMATOPOIETIC ENGRAFTMENT
Owing to their property of immune-modulation, MSCs are being considered
as a double-edged sword which can not only bring about tissue repair but also
alleviate adverse inflammatory reactions such as those seen in autoimmune disorders
and after allogeneic haematopoietic stem cell transplantation. There is considerable
evidence that MSCs exert a hypo-immunogenic character. Experimental findings and
clinical trials have demonstrated that MSCs maintain the stem cell function of HSCs,
but there is still uncertainty about the real efficacy of MSCs on promoting the
engraftment of donor cells and accelerating the speed of hematological recovery.
However, the molecular mechanism of this interaction in vivo is hardly certified. Two
possible mechanisms are contributed by HSCT failure: immune rejection and
damaged hematopoiesis niche. In order to avoid tissue damage, the recipient usually
receives minimal toxic condition therapy before HSCT. However, the frequency of
rejection is associated with improved autologous recovery, causing allogeneic
transplantation
failure.
Therefore,
host
and
graft
alloreactivity
mediated
immunological responses is usually a major cause of graft failure. To this end, with
hypo-immunogenic character, MSC co-infusion may attenuate host alloreactivity and
promote graft residence time in the host. However, it cannot be excluded that MSCs
favor the donor HSC engraftment through non-immunological mechanisms. Damage
to the recipient‟s marrow microenvironment by chemo-radiotherapy before HSCT is
usually unavoidable, which might contribute to the delay in engraftment or limited
numbers of grafts. MSCs may create and support a better engraftment environment
for donor hematopoiesis. In hypothesis, five potential mechanisms might be involved
in the hematopoietic promoting function: (1) direct cell-to-cell contact can be
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established between MSCs and HSCs; (2) paracrine factors are secreted by MSCs; (3)
extracellular matrix components secreted by MSCs build a scaffold for HSCs; (4) BM
homing activity; (5) small molecules and metabolites. Most likely, all of these
mechanisms work together in an orchestra of factors to regulate stem cell function
(Figure 2).
Cell-cell interaction
MSCs exert supportive activity for hematopoiesis. In order to lead to efficient
hematopoiesis, a specific junctional complex has to be formed between HSCs and
MSCs. HSCs with higher self-renewal capacity demonstrated significantly higher
adhesion to human MSCs (70). Studies on interactions between human HSCs and the
niche of the same species are rare. Human MSCs provide a suitable model system for
such studies. The globule gene expression profiles of HSCs as well as MSCs have
been analyzed. Several genes and molecules up-regulated on both sides of the
HSC/MSC interaction included cadherin-11, N-cadherin, integrin alpha-1 (ITGA1),
alpha-5 (ITGA5, CD49e) and beta-1 (ITGB1, CD29), VCAM1, neural cell adhesion
molecule 1 (NCAM1), and thrombospondin 1 (THBS1) (69,70). These results imply
that molecular mechanisms essential in the maintenance of „stemness‟ are mediated
by a combination of cell-cell junction proteins. However, further studies are
necessary to determine the relative significance of these cell adhesion proteins.
Paracrine soluble factors
To date, various growth factor combinations for HSC cultures have been
analyzed. SCF, Flt-3 ligand (FL), and TPO seem to play a central role, and are often
added to co-cultures with stromal cells (75). MSCs secrete a variety of cytokines and
growth factors that have both paracrine and autocrine activities (9). Secreted
molecules might act via direct effects on the MSCs themselves, or indirectly by
inducing other cells nearby, followed by alteration in their biological properties and
functions. Chemokine secretion of the stromal feeder layer cells might also account
for the hematopoiesis supportive effect of MSCs. The Wagner group (69) have
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colony stimulating factor (GCSF), melanoma growth-stimulating activity protein
(GRO; CXCL1), Tissue inhibitor of metalloproteinase-1 (TIMP-1), and TIMP-2 were
highly expressed in MSCs from bone marrow, cord blood, and adipose tissue. They
also found that neither insulin-like growth factor binding protein-1 (IGFBP-1),
IGFBP-2, nor IGFBP-3 had an effect on the proliferation or maintenance of a
primitive immunophenotype of HPs. Many groups have demonstrated that HSCs
cannot be maintained in conditioned culture medium of feeder layer cells under noncontact conditions (21,42,57). There is evidence that soluble molecules alone are not
enough to maintain long-term repopulating potential. However, a reliable culture
platform for maintenance or expansion of HSCs without stromal cell support still
needs to be well defined.
Extracellular matrix scaffold and bone marrow homing
MSCs secrete extracellular matrix proteins that form a scaffold with a
potential pivotal role in HSC differentiation. Fibronectin (12), Laminin (60), sulfate
glycosaminoglycans (56) and various proteoglycans which reside in the bone marrow
have been demonstrated to support maintenance of primitive HPs. These extracellular
matrix components are also secreted by MSC feeder layer cells. It has been
demonstrated that blocking of binding function of extracellular matrix proteins
between HSCs and MSCs induce a significant hematopoietic supportive function
impairment (70,71).
Metabolites and Small molecules
It has been reported that serotonin, glucose and its metabolite concentrations
have been implicated in maintenance and regulation of HSC function (74).
Furthermore, low oxygen partial pressure within the bone marrow has been
demonstrated to enhance HP colony-forming cell expansion and maintenance of
hematopoietic repopulating cells (26). However, the influence of MSCs on the
composition of metabolites in their local microenvironment remains unclear. Further
research is necessary to elucidate the role of hormones, small molecules, or
metabolites in the regulation of stem cell function.
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Bone marrow homing capability
Despite scientific evidence indicating that MSCs possess the ability to
promote engraftment, homing of MSCs to the BM and sustained engraftment also
play a key role. Studies from functional experiments have been described for
adhesion proteins such as N-cadherin and extracellular matrix proteins such as
collagen types I, IV, and fibronectin play a potential pivotal role in homing of HSCs
to the bone marrow niche in animal models (47,55,77). Gene marking or
radiolabeling animal experiments have shown that MSCs are capable of homing to
the BM following systemic administration. In addition, most MSCs favor the lung
and secondarily the liver and other organs (13,18). Other authors have shown that
active homing of MSCs into the BM depends on SDF-1, which interacts with CXCR4
on the MSC surface (73). Conversely, it cannot be excluded that the engraftmentpromoting effect is obtained by the secretion of paracrine growth factors from MSCs
to promote the creation of a favorable microenvironment for the survival,
proliferation and engraftment of HPs.
CONCLUSIONS
To date, little is known about the anatomical location, architecture and cellular
composition of the hematopoietic niche. It is well accepted that self-renewal and
differentiation of HSCs have to be tightly regulated by the appropriate stem cell niche
via cell-to-cell contact or paracrine growth factors secreted by niche cells. Within the
bone marrow, HSCs lie in close proximity to the bone endosteal surface directly in
contact with endothelial cells, osteoblasts, CAR cells, nestin positive cells, and other
stromal cells. Experimental findings and clinical trials have proved that MSCs
maintain stem cell function of HSCs, but there is still uncertainty about a real efficacy
of MSCs on promoting engraftment of donor cells and accelerating the speed of
hematological recovery. The mechanisms and molecules involved in MSC functions
is still remain unconfirmed. Current data suggest that MSCs exhibit two key features
that could have a profound impact on their clinical use. First, MSCs can maintain
immune cells in an "anergy" state through immune-related mechanisms to allogeneic
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antigen challenge. Second, MSCs could create an accessible microenvironment to
repair the damaged marrow and provide trophic factors to support the survival of
donor HSCs and HPs, and this largely recapitulates their physiological effect in the
niche. Thus, MSCs have been employed in the clinical setting in phase I/II clinical
trials. Indeed, to date no adverse effects have been reported after MSC
administration. However, longer follow-up is necessary to draw definitive
conclusions on potential late adverse events.
ACKNOWLEDGEMENTS
The authors acknowledge financial support from Taiwan Department of Health
Clinical Trial and Research Center of Excellence (DOH100-TD-B-111-004), National
Science Council (NSC 98-2314-B-030-003) and Fu-Jen Catholic University [109(57)31040990-1].
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Table 1 Animal experiments of MSC co-injection on HSCT
MSC source
Human BM MSC
Fetal lung-derived MSC
Placenta MSC
Monkey BM MSC
BM MSC (CD271+)
Allogeneic MSC
Syngeneic MSC
Source of HSC
Human HSC
Human UCB-derived HSC
Human UCB HSC
Monkey BM-derived CD34+ HSC
Human CD133+ HSC
Murine BM-derived HSC
Murine BM-derived HSC
Animal model
Human → sheep
Human → NOD-SCID mouse
Human → NOD-SCID mouse
monkey → non-human primate
Human → NOD-SCID mouse
Mouse → mouse
Mouse → mouse
Outcome
Enhance engraftment
Enhance engraftment
Enhance engraftment
Enhance engraftment
Enhance engraftment
Promote graft-rejection
Induce engraftment
Ref. no.
36
48
24
43
32
46
46
Abbreviations: BM = bone marrow; HSCT = hematopoietic stem cell transplantation; HSC = hematopoietic stem cell; MSC = mesenchymal
stem cells; NOS-SCID = non-obese diabetic severe combined immunodeficient mice; Ref. no. = reference number; UCB = umbilical cord blood
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Table 2 Clinical trials of MSC infusion for enhancement of HSCT engraftment
BMT type
Disease
HSC Source MSC Source
Outcome
Ref. no.
Autologous MPC
Autologous HSCT
Allogeneic HSCT
Allogeneic HSCT
Double UCBT
UCBT
UCBT
Hematological malignancy
Breast cancer (PI-II)
Hematological malignancy (PI-II)
Hematological disorders (PI-II)
Hematological disorders
Hematological disorders (PI-II)
Hematological disorders (PI-II)
BM
PB
BM
PB
UCB
UCB
UCB
BM
BM
BM
BM
BM
BM
BM
UCBT + third-party
donor HSC
Hematological disorders (PI-II)
UCB + PB
BM
No adverse events
Enhance hematopoietic recovery
Prevent GvHD
Prevent graft rejection
No adverse effects
Enhance hematopoietic recovery
No effect on engraftment; GvHD
prevention
No effect on engraftment and GvHD
33
30
34
4
28
39
6
20
Abbreviations: BM = bone marrow; BMT = bone marrow transplant; GvHD = graft versus host disease; HSCT = hematopoietic stem cell
transplantation; HSC = hematopoietic stem cell; MSC = mesenchymal stem cells; MPC = mesenchymal progenitor cells; NOS-SCID = nonobese diabetic severe combined immunodeficient mice; PB = peripheral blood; P = phase of study; Ref. no. = reference number; UCB =
umbilical cord blood; UCBT = umbilical cord blood transplantation.
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FIGURE LEGENDS
Figure 1. Phase-contrast photographs and hematopoietic differentiation of
murine placenta-derived stem cells (PDSCs).
(A) PDSCs show a fibroblast-like morphology in culture (20X objective). (B)
Induction of cobblestone formation illustrate the hematopoietic differentiation of
murine hematopoietic stem cells (HSCs) after coculture on PDSC feeder layer. Phase
contrast microscopic analysis demonstrates that from the HSCs in direct cell-cell
contact with the PDSC layer cells, a dull cobblestone-like area was formed. Black
arrow head indicates cobblestone area (20X objective).
Figure 2. The proposed dual mechanisms have illustrated that MSCs could be
niche cells to maintain HSCs function via immunomodulatory or hematopoietic
mediated mechanism.
Through direct cell-cell contact, paracrine factors, extracellular matrix scaffold, BM
homing capability, and endogenous metabolites, MSCs can escape alloreactive
immune cell recognition, enhance engraftment, and to accelerate hematopoietic
recovery. Abbreviations: MSCs = mesenchymal stromal cells; HSCs = hematopoietic
stem cells; NKs = natural killer cells; ECM = extracellular matrix.
CT-2435 Cell Transplantation Epub
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Figure 1
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Figure 2
CT-2435 Cell Transplantation Epub 1