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Am J Physiol Heart Circ Physiol 288: H2557–H2567, 2005;
doi:10.1152/ajpheart.01215.2004.
Invited Review
Bone marrow stem cell transplantation for cardiac repair
Husnain Kh Haider and Muhammad Ashraf
Department of Pathology and Laboratory of Medicine, University of Cincinnati, Cincinnati, Ohio
myocardial infarction; cardiomyocyte; plasticity; transdifferentiation
in both small and large animal models
and phase 1 clinical studies in humans have shown the promise
of bone marrow and bone marrow-derived stem cells in the
treatment of diseased myocardium (111). The secret of this
promise lies in the remarkable potential of bone marrow stem
cells to undergo multilineage differentiation in general and
cardiomyogenic potential in particular (66, 108).
Bone marrow consists of a nonhomogeneous population of
cells composed of various lineages with differing abilities. The
hematopoietic stem cell (HSC) fraction of the bone marrow is
responsible for the production of ⬎95% of the body’s blood
cells. They have an extensive capacity of self-renewal. Recent
reports (27, 65) have shown that HSC may also have the
potential to differentiate into other lineages of cells, including
their competence to attain the cardiac phenotype. The work of
Matsuzaki and colleagues (81) suggests high-marrow seeding
efficiency as a specific characteristic of primitive HSC in
addition to their self-renewal and multipotent capacity. They
have demonstrated a high “homing to niche” capacity of these
cells. Over a long period of time, CD34, a cell surface molecule that is expressed on 1–3% of bone marrow cells, has been
used as a convenient positive selection marker for HSC (94).
However, several reports have raised serious questions about
CD34 expression on hematopoietic cells in the mouse (36).
Sato and colleagues (112) have shown that CD34 expression in
murine HSC reflects the activation state, and this may be so in
humans. Moreover, the presence of human CD34⫺ HSC has
been reported as being more immature than CD34⫹ stem cells
(15). Consequently, AC133 is being used as an alternative
selection marker to CD34 antigen. The rationale to use purified
THE RESULTS OF STUDIES
AC133⫹ cells is to avoid injection of a large number of
leukocytes and their progenitors, which have limited plasticity
and the presence of which in large numbers may give rise to an
unwanted inflammatory response at the site of the graft (152).
On the other hand, the non-HSC fraction is mainly composed of mesenchymal stem cells. They are clonogenic and
possess the potential to develop into mature cells that produce
fat, cartilage, bone, tendons, and muscle (108). They can be
isolated from bone marrow and can easily be expanded in an in
vitro cell culture without compromising their stem cell capabilities (86). Because of the ease of the method of their
purification and multipotent nature, they have been extensively
studied in both experimental and clinical settings. There is no
universal surface marker for the identification of mesenchymal
stem cells. They are negative for HSC markers CD31, CD34,
and CD45 and express on their surface CD44, CD90, CD105,
CD106, and CD166 (78). Besides, they have been reported to
express T cell receptor components that enable them to remain
in a state of readiness to enter various pathways of differentiation upon induction (158). Mesenchymal stem cells with
similar potential have also been isolated from tissues other than
bone marrow including peripheral blood and umbilical cord
blood (61). Kawada et al. (59) have recently shown that
CD34⫺ nonhematopoietic bone marrow mesenchymal stem
cells can differentiate into cardiomyocytes. The heterogeneous
mononuclear fraction of the bone marrow (BMMNC) is the
most promising and extensively studied stem cell population
for cellular cardiomyoplasty (24, 47, 54, 56). Besides, CD117
and Sca-1⫹ cells have also been focused to assess their cardiomyogenic potential (72, 73, 76, 80, 152).
MALLEABLE NATURE OF BONE MARROW STEM CELLS
Address for reprint requests and other correspondence: H. Kh Haider, Dept.
of Pathology and Laboratory of Medicine, 231-Albert Sabinway, Univ. of
Cincinnati, Cinncinati, OH 45267-0529 (E-mail: [email protected]).
http://www.ajpheart.org
Intravenous administration of bone marrow-derived mesenchymal stem cells leads to their preferential migration to the
0363-6135/05 $8.00 Copyright © 2005 the American Physiological Society
H2557
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Haider, Kh Husnain, and Muhammad Ashraf. Bone marrow stem cell
transplantation for cardiac repair. Am J Physiol Heart Circ Physiol 288: H2557–
H2567, 2005; doi:10.1152/ajpheart.01215.2004.—Cardiomyocytes respond to
physiological or pathological stress only by hypertrophy and not by an increase in
the number of functioning cardiomyocytes. However, recent evidence suggests that
adult cardiomyocytes have the ability, albeit limited, to divide to compensate for
the cardiomyocyte loss in the event of myocardial injury. Similarly, the presence of
stem cells in the myocardium is a good omen. Their activation to participate in the
repair process is, however, hindered by some as-yet-undetermined biological
impediments. The rationale behind the use of adult stem cell transplantation is to
supplement the inadequacies of the intrinsic repair mechanism of the heart and
compensate for the cardiomyocyte loss in the event of injury. Various cell types
including embryonic, fetal, and adult cardiomyocytes, smooth muscle cells, and
stable cell lines have been used to augment the declining cardiomyocyte number
and cardiac function. More recently, the focus has been shifted to the use of
autologous skeletal myoblasts and bone marrow-derived stem cells. This review is
a synopsis of some interesting aspects of the fast-emerging field of bone marrowderived stem cell therapy for cardiac repair.
Invited Review
H2558
BONE MARROW STEM CELLS FOR HEART
mechanisms, the consensus is on transdifferentiation of bone
marrow cells into cardiomyocytes and endothelial cell phenotypes and angiogenesis (Tables 1–3).
The ability of bone marrow-derived stem cells to break the
barriers of lineage restriction and transdifferentiate to form
different tissue cells are being extensively investigated (6, 37,
46, 53, 133, 135). A series of recent experiments have challenged the long-standing dogma of lineage restriction. The
multipotential nature of bone marrow stem cells to transdifferentiate into various lineages has been shown in vitro (18, 21,
98, 137, 148, 151). Similar results have also been corroborated
in vivo (9, 69, 95, 157). The underlying principle to these
observations is that stem cells form the tissue in which they
reside. Hence, it is thought that bone marrow stem cells under
the influence of the new microenvironment after transplantation start to adopt the new phenotype and produce cells of the
resident tissue (39, 52). However, these findings have been
challenged by several research groups that have independently
advocated the possibility of fusion between donor bone marrow cells with host cells to adopt the phenotype of the host
tissue (134, 153). Recent publications from Alvarez and colleagues (5) have shown fusion between donor bone marrow
cells and Purkinje fibers, cardiomyocytes, and hepatocytes.
Thus there is a prevailing notion that fusion between donor
stem cells and host tissue cells might be misleading the
researchers to conclude that stem cells can cross the boundaries
of lineage restriction.
Back-to-back recent reports from Balsam et al. (11) and Murry
et al. (91) have clearly depicted a lack of ability of donor bone
marrow cells to undergo differentiation into cardiomyocytes after
transplantation. They have shown little evidence for transplanted
bone marrow cells to form cardiomyocytes at the site of the graft
posttransplantation. Similar concern has been shown by earlier
researchers when isolated unfractionated bone marrow cells were
found to be unable to differentiate into cardiomyocytes (13).
These results are presenting a serious challenge to the findings that
have been documented by Orlic and colleagues (101) and thus
require an in-depth assessment of whether bone marrow stem cells
have the required plasticity to transdifferentiate into cardiomyocytes posttransplantation.
CARDIOMYOGENIC TRANSDIFFERENTIATION OF BONE
MARROW STEM CELLS IN VITRO
Cardiomyogenic differentiation of stem cells has been vastly
reported (60, 102, 138). The cells undergoing cardiomyogenic
Table 1. In vitro studies on BMC transdifferentiation into cardiovascular-related lineages
References
Cells
Makino et al. (77)
Fukuda et al. (32)
Fuchs et al. (30)
Toma et al. (137)
Terada et al. (134)
Eisenberg et al. (27)
Fukuhara et al. (33)
Oswald et al. (103)
BMSC
BMSC
BMC
hBMMSC
BMMNC
HPC
BMSC
hBMMSC
Coculture
Pretreatment
No
ESC
Chick embryo heart tissue
Cardiomyocytes
5-Aza
5-Aza
Yes
MyoD transduction
IL-3 for 7 days
RA and ECGS PGE2 and IL-2
VEGF
Differentiation
Myocytes
Myocytes
Myocytes
Myocytes
Myocytes
Myocytes
Endothelial cells
BMC, bone marrow cells; BMSC, bone marrow stromal cells; 5-Aza, 5-azacytidine; hBMMSC, human bone marrow mesenchymal stem cells; BMMNC, bone
marrow mononuclear cells; ESC, embryonic stem cells; IL, interleukin; HPC, hemapoietic progenitor cells; RA retinoic acid; ECGS, endothelial cell growth
supplement.
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infracted myocardium (92), and tissue injury is considered as
one important factor that influences the transdifferentiation of
bone marrow cells to other lineages (1). BMMNCs taken from
myocardial infarction patients have been found to show tropism for damaged cardiac tissue (10a). Similarly, there is a
significant debate over the presence of stem cells from extracardiac origin in the myocardium (12, 110). Despite these
interesting findings, the underlying mechanism as to how the
donor bone marrow stem cells home into the damaged myocardium and contribute toward improved cardiac function remains highly debatable (97, 118). However, it is considered to
be the resultant effect of more than one mechanism. First, bone
marrow cells undergo differentiation into cardiomyocytes, either due to preprogramming or under the influence of signals
from myocardial microenvironment (64, 100, 121, 140). Second, they contribute toward improved wall thickness and a
reduction in the infarct size. Bone marrow stem cells have been
shown to express angiogenic growth factors in a paracrine way
to stimulate neovascularization at the site of the cell graft and
undergo transdifferentiation into endothelial cells to participate
in angiogenesis, thus alleviating myocardial ischemia (42, 132,
139). The paracrine effect may not be the effect of individual
cytokines themselves. Rather, this may be related with their
synergistic interaction that may lead to the beneficial outcome
in terms of neovascularization. Kinnaird and colleagues (62)
have reported a full spectrum of arteriogenic cytokines released
from bone marrow stromal cells. The expression of these
growth factors gets accentuated under stressful hypoxic conditions (8). Mesenchymal stem cells grown under hypoxic
conditions migrated and formed three-dimensional capillarylike structures on a Matrigel matrix. They also showed these
effects when triggered by conditioned media taken from mesenchymal stem cells grown under hypoxic stress. These observations clearly depict the involvement of both paracrine as well
as autocrine mechanisms. The role of paracrine signaling
pathways as a mediator of bone marrow cell therapy has also
been highlighted in vivo in the treatment of tissue ischemia,
which clearly depicts that donor cell incorporation into vessels
is not a prerequisite for their effects in angiogenesis (63).
An interesting study from Pak et al. (104) showed that bone
marrow cell transplantation induces cardiac nerve sprouting
and sympathetic hyperinnervation. Another proposed mechanism is the fusion of donor bone marrow cells with host
cardiomyocytes to adopt their phenotype (123). The donor cell
genes may supplement for the lost genetic material from the
host nucleus during the ischemic injury. Out of all these
Invited Review
H2559
BONE MARROW STEM CELLS FOR HEART
Table 2. Small animal model studies used for BMC transplantation for cardiac repair
Model
Rat
Tomita et al. (138)
Wang et al. (143)
Wang et al. (144)
Davani et al. (24)
Cells
Pretreatment
Angiogenesis
BMC
BMSC
BMSC
BMMPC
5-Aza
No
No
No
CAL
CAL
CAL
Doxorubicin
CAL
CAL
BM-MSC
BMSC
BMC ⫹ myoblasts
BMMNC
BMMSC
BMMNC
HGF transduction
5-Aza
No
No
No
No
CAL
CAL
Lin⫺ ckit⫹
SP
No
Yes
Yes
Saito et al. (114)
CAL
BMSC
No
Yes
Toma et al. (137)
Agbulut et al. (3)
Kudo et al. (68)
Hiasa et al. (47)
Murry et al. (91)
Balsam et al. (11)
Normal
Doxorubicin
CAL
CAL
Normal/CAL
CAL
hBMMSC
BMC
Lin⫺ ckit⫹
BMMNC
Lin⫺ ckit⫹
Lin⫺ ckit⫹ and Lin⫺
ckit⫹ Thy1.1loSca⫹
No
No
No
No
No
No
Yes
No
No
No
Duan et al. (26)
Saito et al. (115)
Sakaghuchi et al. (116)
Ishida et al. (54)
Tang et al. (132)
Zhang et al. (156)
Mouse
Orlic et al. (102)
Jackson et al. (55)
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Myocytes
Myocytes
Myocytes
Smooth muscle and
endothelial
phenotype
Myocyte-like cells
Myocytes
Endothelial cells
Endothelial cells
Myocytes
Myocytes and
endothelial cells
Vascular smooth
muscle cells and
myocytes
Myocytes
Myocytes
Myocytes
No
No
No
CAL, coronary artery ligation; HGF, hepatocyte growth factor; SP, side population.
plemented with retinoic acid, DMSO, and 5-azacytidine (5-Aza)
(45). Cardiomyogenic differentiation of bone marrow in vitro has
specifically been achieved using the demethylating agent 5-Aza
(Table 1). Makino et al. (77) reported 5-Aza-induced differentiation of mice bone marrow stromal cells into cardiac-like cells. At
a concentration of 3 ␮mol/l for 1 wk, 5-Aza induced bone marrow
cells into cardiomyogenic cells. These cells stained positive for
myosin, actin, and desmin and showed spontaneous beating at 3
wk after treatment. Electron microscopy revealed a cardiomyocyte-like ultrastructure, such as the presence of sarcomeres, centrally positioned nuclei, and atrial granules.
Coculture of bone marrow stem cells with cardiomyocytes
has been shown to preprogram these cells to adopt a cardiac
phenotype. Our research group (147) has recently shown that
differentiation achieve the cardiomyocyte phenotype through
the expression of specific genes encoding various transcription
factors and structural and regulatory proteins (105). Among
these are included GATA-4, Nkx 2.5, MEF2, and HAND.
However, the exact role of these genes, the timing of their
activation, and the signaling pathways involved in mediating
cardiomyogenic differentiation remain unknown. Besides
these, a recent report (41) has shown that they also express
functional adrenergic and muscrinic receptors that modulate
their function.
Various strategies have been adopted for directed differentiation of stem cells into cardiomyocytes (45). The induction of
cardiomyogenic differentiation of stem cells has been achieved by
culturing bone marrow cells in vitro using culture medium supTable 3. Large animal studies using BMC for cardiac repair
Pig
Kamihata et al. (56)
Fuchs et al. (30)
Shake et al. (121)
Tomita et al. (139)
Min et al. (84)
Pak et al. (104)
Yau et al. (150)
Dog
Hamano et al. (42)
Sheep
Bel et al. (13)
Airey et al. (4)
Model
Cells
Pretreatment
Angiogenesis
LAD ligation
Ameroid ring
60-min LAD occlusion
LAD occlusion
LAD branch ligation
LAD microcoil
embolization
Coil occlusion
Differentiation
BMMNC
BMC
BMMSC
BMSC
hMSC⫹ hFC
BMMSC
No
No
No
5-Aza
No
No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Nerve sprouting
BMSC
No
Yes
Yes
LAD ligation
Fresh BMC
No
Yes
Yes
LCx ligation
In utero injection
Fresh BMC
hMSC
No
No
Yes
No
Pukinje fibers
LAD, left anterior descending coronary artery; hMSC, human mesenchymal stem cells; hFC, human fetal cardiomyocytes; LCx, left circumflex coronary
artery.
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Cryoinjury
Normal heart
CAL
CAL
Differentiation
Invited Review
H2560
BONE MARROW STEM CELLS FOR HEART
cell-to-cell contact during coculture of bone marrow cells with
cardiomyocytes is imperative to trigger their cardiomyogenic
transformation.
TRANSDIFFERENTIATION OF BONE MARROW STEM CELLS
IN VIVO
AJP-Heart Circ Physiol • VOL
CLINICAL STUDIES
Since the first human autologous skeletal myoblasts transplantation (82), more research groups have been involved in
phase 1 safety and feasibility studies using adult stem cell
transplantation for cardiac repair, including bone marrow cells.
The underlying principle is to take advantage of the plastic
nature of bone marrow stem cells, which enables them to cross
the lineage restriction and participate in the reparative process
by attaining the cardiac phenotype.
Whereas some of these studies have been carried out as the
sole-therapy procedure using a bone marrow cell implantation
approach (10a, 14, 31, 106, 141), others have been performed
as an adjunct to either coronary artery bypass grafting (34, 109,
126, 127, 154) or percutaneous revascularization (10, 19, 22,
125, 129, 145). The small number of the patients in each study
(without a blinded control group) and their performance as an
adjunct procedure make it difficult to assess and attribute the
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Encouraged by the results from in vitro studies, both small
and large animal studies have been carried out to show that the
whole bone marrow and its subpopulations potentially repopulate the injured myocardium and undergo milieu-dependent
differentiation to form endothelial cells and cells with a cardiomyocyte-like phenotype (Tables 2 and 3). It has been
hypothesized that preprogramming donor bone marrow cells to
adopt a cardiomyogenic differentiation pathway before their
transplantation in animal models may have better chances of
their transdifferentiation into cardiomyocytes than transplantation of uncommitted bone marrow cells (16, 138). The heart
function of the 5-Aza-treated bone marrow cell transplanted
group was better than that of other groups. Liechty et al. (74)
demonstrated in vivo site-specific differentiation of human
bone marrow into cardiomyocytes. The cells were directly
injected into the fetal sheep peritoneal cavity. Lin⫺ ckit⫹ bone
marrow cells developed into fetal and neonatal myocytes in
infarcted mice hearts (101). They were positive for cardiac
myosin, GATA-4, MEF2, and Csx/Nkx 2.5. The cells were
also positive for connexin43, indicating intercellular communication between the grafted cells and host tissue. A highly
enriched hematopoietic CD34⫺ “side population” of bone
marrow cells was transplanted into lethally irradiated C57BL/
6-Ly-5.1 mice (55). The engrafted side population bone marrow cells differentiated into cardiomyocytes and endothelial
cells. The derived cardiomyocytes were found primarily in the
peri-infarct region. These studies suggested that signals originating from the cytokine-rich microenvironment of the injured
myocardium and the direct cell-cell interaction between donor
bone marrow cells and host cardiomyocytes triggered their
myogenic differentiation. The injured heart is a more efficient
inducer of bone marrow cells differentiation into cardiomyocytes (64). Shintani et al. (124) demonstrated that endothelial
progenitor cells were mobilized into the peripheral blood and
contributed to neovascularization in the heart during an acute
infarction event in humans. These studies suggested that inflammatory cytokines and factors released by the infarcted
heart into the peripheral blood may have the potential to trigger
circulating bone marrow cells to differentiate into specific cell
lineages. Condorelli et al. (23) observed that the majority of
endothelial cells injected into infarcted mice differentiated into
myosin-positive cells with a cardiomyocytes-like morphology,
whereas only a very few of them differentiated into cardiomyocytes after injection into the normal mice heart. Our research
group (68) has previously shown that transplantation of bone
marrow-derived Lin⫺ ckit⫹ cells significantly reduced infarction and fibrosis in an ischemic mouse heart. The donor bone
marrow cells differentiated into cardiomyocytes and endothelial cells in the ischemically damaged murine heart. Transplantation of bone marrow stromal cells has also been shown to
improve the functioning of the healed infarcted rat heart
through myogenesis and angiogenesis (99). The angiogenic
potential of bone marrow cells posttransplantation may be
enhanced by subjecting the cells to ischemic stress before
transplantation (75). In recent study (117), granulocyte colonystimulating factor (G-CSF)-mobilized human bone marrow
CD34⫹ and CD34⫺ cells were delivered intravenously into an
infracted nude rat heart model of myocardial infarction. The
cells were found to migrate and repopulate the ischemic myocardium and induce neovascularization. There was a resultantly improved cardiac function and reduced remodeling.
To achieve controlled delivery of the transplanted bone
marrow cells, Liu et al. (75) used a novel fibrin patch-based
delivery of cells. A fibrin patch coated with autologous bone
marrow cells was placed on the infarct site. The results revealed that the transplanted cells differentiated into cardiomyocyte-like cells and participated in the angiogenic process
and became part of the capillary network.
Taken together, these data suggest that the injured heart
might have a greater contribution to the milieu-dependent
cardiomyocyte differentiation of bone marrow cells. However,
the information on the signaling molecules and responding
molecular mechanisms that recruit bone marrow cells to the
injured heart and transdifferentiation into cardiomyocytes is
still unclear. Myocardial infarction can mobilize bone marrow
cells and recruit them to injured myocardium where they get
stimulated for transformation into new cardiomyocytes.
One important consideration, however, is that the plastic and
malleable nature of unselected multipotent bone marrow may
be disadvantageous and results in unwarranted and unwanted
outcomes. The presence of cells with osteogenic potential or a
multipotent stem cell population together with local milieu of
the cytokine-rich infarcted myocardium may favor osteogenic
differentiation of bone marrow cells and enhance calcium
deposition with an as-yet-undefined regulatory mechanism. It
has been shown that transplantation of unselected bone marrow
cells into the acutely infarcted myocardium may cause significant intramyocardial calcification, thus leading to contractile
dysfunction or arrhythmias (155). The calcification in the bone
marrow cell-transplanted hearts was identified in the periinfarct area or normal myocardium, where the myocardial
structure was relatively well preserved. Similarly, transplantation of undifferentiated mesenchymal stem cells has been
shown to develop into fibroblastic scar tissue (144). These
results underscore the importance of regulating cellular differentiation of adult stem cells in therapeutic applications.
Invited Review
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BONE MARROW STEM CELLS FOR HEART
Table 4. Randomized clinical studies with control groups using BMC
Patients
Study
Control
With cells
Cell type
Assumus (10)
09
20
BMMNC
Chen (22)
35
34
BMMNC
Wollert (145)
30
30
CD34⫹
Composition
7.35 ⫾ 7.31 ⫻ 106
CD34/CD45-positive
cells
Delivery
Mode
Adjunct
Procedure
IC/CPC
PCI
IC
PCI
IC
PCI
24.6 ⫾ 9.4 ⫻ 108
nucleated cells, 9.5 ⫾
6.3 ⫻ 106 CD34⫹
cells, and 3.6 ⫾ 3.4 ⫻
106 hemopoietic
colony-forming cells
Result Summary
Improved regional wall motion in the
infarct area, enhanced LVEF,
profoundly reduced LVESV,
enhanced viability in the infarcted
one by DS-echocardiography, and
quantitative PET scan
Improved wall velocity in the
infracted segments, reduction in
perfusion defects, improved LVEF,
and significantly reduced LVESV
by echocardiography, NOGA
EMM, and PET scanning
Improved LVEF 24-h Holter
monitoring and functional MRI
IC, intracoronary; CPC, circulating progenitor cells; PCI, percutaneous coronary intervention; LVEF, left ventricular ejection fraction; LVESV, left ventricular
end-systolic volume; DS, dobutamine stress; PET, positron emission tomography; NOGA, EMM, electromechanical mapping system.
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sure (129). The control group patients received 6 ml of normal
saline solution without cells using the same method. The
patients underwent [18F]fluorodeoxyglucose PET scanning and
echocardiography on the day of cell transplantation and were
followed up at 3 and 6 mo. The follow-up results were
encouraging and showed significant differences between the
two groups of patients. The percentage of hypokinetic, akinetic, and dyskinetic areas in the left myocardium significantly
decreased (from 32 ⫾ 5% to 13 ⫾ 11%), whereas wall motion
velocity (from 2.17 ⫾ 1.3 to 4.2 ⫾ 2.5 cm/s) and left ventricular ejection fraction (LVEF; from 49 ⫾ 9% to 67 ⫾ 11%)
registered significant increases in the cell transplanted patients
together with significantly decreased perfusion defects as detected by PET. The most encouraging finding of the study was
that the indicators of improvement in cardiac performance
were maintained unruffled until 6 mo of observation.
The Bone Marrow Transfer to Enhance S-T Elevation Infarct Regeneration study, a recent randomized controlled clinical trial involving 60 patients, was reported by Wollert and
colleagues (145). The patients were randomized to receive
optimum medical treatment and PCI together with autologous
bone marrow cell transplantation (n ⫽ 30) or without cell
transplantation as the control group (n ⫽ 30). A total of 24.6 ⫻
108 freshly isolated CD34⫹ cells were transplanted by intracoronary infusion using a balloon catheter in the infarct related
artery. Mean global LVEF showed a 7% increase in the stem
cell transfer group compared with 0.7% in the medical therapy
group (P ⫽ 0.0026). Study limitations included a lack of
sham-operated control subjects and an inability to determine
the mechanisms of action of bone marrow cells.
Zeiher’s group, in Germany, has documented preliminary
results of the Transfer of Progenitor Cells and Regeneration
Enhancement in Acute Myocardial Infarction study. The randomized study, which previously reported 20 patients, included
8 more patients to the cohort (10, 19). Interestingly, the study
involves a comparison between BMMNC and circulating progenitor cells (CPC) in blood for cardiac repair together with an
internal reference group of 11 patients who were included as a
real benefit and improvement in cardiac function to bone
marrow cell transplantation. Invariably, all the studies have
used autologous bone marrow cell transplantation. However,
they differ in the processing, culture, and selection of the
subpopulation before transplantation. For example, unlike
Galinanes et al. (34), who used unmanipulated autologous bone
marrow (34), and Tse et al. (141), who used unselected
BMMNC for transplantation, others have tried to purify a
subpopulation of BMMNC (106, 126, 129, 145). NOGA has
been used for electromechanical mapping to discriminate between the ischemic and viable regions and for targeted delivery
of cells (106, 141). The methods for the end-point measurement have been variable and include treadmill exercise duration, consumption of nitroglycerine, single photon emission
computed tomography (SPECT) perfusion imaging, electromechanical mapping system (NOGA, EMM), echocardiography,
[18F]fluorodeoxyglucose positron emission tomography (PET),
and magnetic resonance imaging. In most cases, the cell
transplantation procedure was uneventful, and the patients
recovered well without any postprocedural complications. No
arrhythmic changes have been reported on Holter monitoring
during any study. Only two deaths, one each in the experimental and control groups, were reported by Perin et al. (106).
However, both these deaths were unrelated to the cell transplantation procedure. Despite their observational status and
design limitations, their outcome reveals the safety and feasibility of the approach. Taken together, the results of the phase
1 studies have been encouraging. Table 4 summarizes the bone
marrow cell transplantation reports with the largest number of
patients published in refereed journals.
The largest study, with 78 patients, was reported by Chen et
al. (22). The patients were randomized to receive bone marrow
cells (n ⫽ 34) and only percutaneous coronary intervention
(n ⫽ 35) as the control group. After being cultured for 10 days
in vitro, 8 –10 ⫻ 109 cells/ml of autologous bone marrow cells
were resuspended in 6 ml of heparinized saline solution and
transfused into the infarct related target coronary artery
through an inflated over-the-balloon catheter with high pres-
Invited Review
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BONE MARROW STEM CELLS FOR HEART
BONE MARROW STEM CELL MOBILIZATION
BMMNC taken from myocardial infarction patients have
been found to show tropism for damaged cardiac tissue in vitro
(28). Moreover, there is evidence that repair of cardiac and
vascular tissue by bone marrow stem cells are naturally occurring processes after injury (35, 124). Besides tissue-specific
resident stem cells, a very low level of progenitor cells move
from their bone marrow niche into peripheral blood under
physiological conditions as a part of the homeostatic mechanism. However, in patients with acute myocardial infarction,
circulating mononuclear cells are significantly increased (124).
It is thought that tissue ischemia mobilizes mononuclear cells
from the bone marrow to the peripheral blood, and the mobilized mononuclear cells home specifically to participate in
neovascularization and differentiate into mature endothelial
cells (130). It has been demonstrated that after myocardial
infarction, mesenchymal stem cells are recruited to the injured
heart, where they undergo milieu-dependent differentiation and
may participate in the pathophysiological mechanisms of
postinfarct remodeling, angiogenesis, and maturation of the
scar (17). However, the process is far from being adequate to
compensate for the massive loss of cardiomyocytes and needs
to be supported for its inadequacy from an outside intervention.
Attempts are being made to pharmacologically augment the
process of mobilization of progenitor cells from the bone
marrow niche for their homing into the infarcted myocardium
(96).
Stem cell mobilization using various cytokines and growth
factors is routinely practiced in hematological procedures. The
use of cytokines for induction of endogenous bone marrow
stem cells to home into the infarcted myocardium is gaining
popularity. It is less invasive and obviates the use of cells from
nonautologous sources and hence the risk of transmission of
infectious agents and immunological rejection of the cell graft.
These advantages of cytokine-induced mobilization of endogenous bone marrow stem cells make it a superior choice for
regenerating infarcted myocardium. Various cytokines and
growth factors either alone or in combination together can
release HSC from the bone marrow into the peripheral blood
(7, 85, 90, 100, 119, 149). G-CSF is currently the most
commonly used agent for HSC mobilization (131). This is
AJP-Heart Circ Physiol • VOL
based on the fact that G-CSF is an effective chemoattractant for
bone marrow stem cells and enhances the infiltration of the side
population after myocardial infarction in mice (2). The outcome of the mobilization protocol is significantly influenced by
the dose and route of G-CSF administration. Similarly, a
comparative study (113) between continuous administration
and bolus administration of G-CSF has shown that the former
mode of administration reduced activation of polymorphonuclear cells. Treatment with G-CSF also induces an angiogenic
response (120). Despite its effectiveness in translocation of
bone marrow cells from their niche, the high dose of G-CSF
that is required to achieve bone marrow cell mobilization is not
without side effects (49, 58, 79). To overcome this problem, a
combination of G-CSF with stem cell factor-1 (SCF-1) has
been used (146). SCF is expressed constitutively in bone
marrow stromal cells, fibroblasts, and endothelial cells and is
essential to the survival, proliferation, adhesion/migration, and
differentiation of HSC (20, 43). The synergistic interaction
between G-CSF and other cytokines in mobilizing progenitor
cells from the bone marrow has been demonstrated by multiple
studies in animals and humans (38, 70, 89). Recent studies
support the ability of HSC induced by cytokine(s) to transdifferentiate into cardiomyocytes; however, nothing is actually
known regarding the process of transendothelial migration of
HSC to the myocardium. In the hematopoietic microenvironment, bone marrow-derived endothelial cells may play an
important role in the trafficking and maintenance of progenitor
and stem cells due to adhesive interactions and paracrine
secretion of hematopoietic growth factors.
It is hypothesized that bone marrow cells are integrated in
their bone marrow niche with the bone marrow stroma. For the
translocation of cells from their bone marrow niche under the
influence of various cytokines, it is imperative to break these
cytoadhesive interactions before they are blood borne (67).
Besides others, CXCR-4 is a cell surface antigen expressed on
hematopoietic progenitor cells including the primitive, pluripotent CD34⫹ subpopulation and is related to efficient SDF1-induced migration in vitro (88, 107). Stromal cell derived
factor-1 (SDF-1), through its receptor CXCR-4, is believed to
be superior in stem cell mobilization, angiogenesis, and cell
survival. Besides, G-CSF-induced HSC mobilization may also
involve the SDF-1/CXCR-4 axis (107). Homing in of the
mobilized stem cells to the injured myocardium is milieu
dependent. Ischemia enhances the homing-in process. A multitude of local and systemic factors influence the homing-in of
stem cells, including VEGF and its receptor-2, c-kit, and stem
cell factors (93).
FUTURE DIRECTIONS
Stem cell therapy in general (44, 50, 51) and therapy based
on bone marrow-derived stem cells in particular (31, 105, 127)
is quickly emerging as an alternative strategy in cardiovascular
therapeutics. Proof-of-concept animal studies and phase 1
clinical trials have already shown the safety and feasibility of
this approach. However, there are some fundamental issues
that need to be resolved to streamline research in this area. The
ability of bone marrow cells to transdifferentiate into cardiomyocytes and integrate into the host tissue is being questioned.
The proponents of fusion as the mechanism for the survival of
donor cells posttransplantation are arguing for the development
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control for comparison of results. BMMNC (CD34⫹/CD45⫹)
were purified from autologous bone marrow aspirates of each
patient undergoing BMMNC transplantation, and CPC were
purified and expanded ex vivo for 3 days for each patient
undergoing CPC transplantation from 250 ml venous blood.
Except for one patient who suffered anterior wall infarction 3
days after cell transplantation, the whole exercise was without
any problem. A 4 mo follow-up revealed improvement in
global cardiac function; however, it did not differ between
patients receiving BMMNC or CPC. The control group patients without cell therapy revealed no significant changes in
the respective parameters of observation. The study results
highlight the safety and efficacy of the procedure, like many of
the previously reported studies. Moreover, it also showed that
transplantation of CPC, the collection and availability of which
is relatively easy and less invasive compared with BMMNC, is
as effective as BMMNC in improving contractile function of
the heart and coronary artery flow reserve.
Invited Review
BONE MARROW STEM CELLS FOR HEART
AJP-Heart Circ Physiol • VOL
provide an alternative option with superior attributes in cell
therapy for cardiac repair.
The results of the phase 1 clinical studies have been encouraging. However, in the absence of a blinded control group, and
with a small number of patients involved in most of these
studies, it is difficult to assert the beneficial effects of stem cell
therapy. Furthermore, it is important to define the patient
population that can benefit from cell therapy. For this purpose,
a more concerted effort between the various research groups
involved is needed.
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of hybrid cells as a result of fusion between donor cells and
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