Despite the recent advances in percutaneous inter ven-
tion, drug and device therapy, patients with acute myo-
cardial infarction (AMI) and resulting left ventricular
impairment have 13% mortality at 1 year . Following
the loss of over one billion cardiomyocytes in a func-
tionally signifi cant MI, the overloaded surviving cardio-
myocytes undergo abnormal remodelling, eventually
leading to heart failure. Th is condition, a leading cause of
death and disability in the developed world, is associated
with 5-year mortality rates of up to 70% in symptomatic
patients . Current conventional therapies do not correct
underlying defects in cardiac muscle cell number .
Th e only therapeutic option that currently addresses
cardiomyocyte loss is heart transplantation. However,
due to stringent selection criteria and chronic shortage of
donor hearts, the vast majority of patients are deemed
unsuitable or never receive a transplant. Th erefore,
preventing this progression post-MI is a major challenge
requiring novel therapeutic strategies such as stem cell
transplantation to improve the prognosis and quality of
life for these patients.
Th e traditional view that the heart is a terminally
diff erentiated organ has been challenged by the discovery
of diff erentiation of stem cells into cardiomyocytes in
animal and human hearts [4-7]. Th is in turn has led to
the exciting possibility for regenerative therapy for
cardio myocyte loss after a MI. Th e demonstration of
functional recovery of myocardium through cardiomyo-
genesis and neoangiogenesis in AMI in murine models
by Orlic and colleagues  generated tremendous interest
in the potential of bone marrow-derived stem cells. Since
then, the cardiomyogenic ability of these cells has been
challenged. However, studies continue to demon strate
improvement in cardiac function and reduction in infarct
size. It should be noted that progenitor cells also
contribute to cardiac repair by mechanisms beyond the
growth of new cardiomyocytes and as such may off er an
‘indirect’ benefi t.
Animal and human trials
Th e most promising and obvious cell type for the growth
of new cardiomyocytes is the embryonic stem cell;
however, considerable technical and ethical issues exist
with these cells, which must be overcome before their
successful use in humans. Adult stem cells are an
attractive option to explore for transplantation as they
are autologous, but their diff erentiation potential is more
restricted than embryonic stem cells. Currently, the
major sources of adult cells used for basic research and in
clinical trials originate from the bone marrow. Th e bone
marrow mononuclear subset is heterogeneous and com-
prises mesenchymal stem cells, haematopoietic progenitor
cells and endothelial progenitor cells. Th e diff erentiation
capacity of diff erent populations of bone marrow-derived
stem cells into cardiomyocytes has been studied
intensively. Th e results are rather confusing and diffi cult
to compare, since diff erent isolation and identifi cation
Stem cell transplantation is emerging as a potential
therapy to treat heart diseases. Promising results
from early animal studies led to an explosion of
small, non-controlled clinical trials that created
even further excitement by showing that stem cell
transplantation improved left ventricular systolic
function and enhanced remodelling. However, the
specifi c mechanisms by which these cells improve
heart function remain largely unknown. A large variety
of cell types have been considered to possess the
regenerative ability needed to repair the damaged
heart. One of the most studied cell types is the bone
marrow-derived mononuclear cells and these form
the focus of this review. This review article aims to
provide an overview of their use in the setting of acute
myocardial infarction, the challenges it faces and the
future of stem cell therapy in heart disease.
© 2010 BioMed Central Ltd
Bone marrow mononuclear cells and acute
Samer Arnous1, Abdul Mozid1, John Martin1 and Anthony Mathur2*
2Department of Cardiology, London Chest Hospital, Queen Mary University of
London, Barts and the London NHS Trust, Bonner Road, London E2 9JX, UK
Full list of author information is available at the end of the article
Arnous et al. Stem Cell Research & Therapy 2012, 3:2
© 2012 BioMed Central Ltd
methods have been used to determine the cell population
studied. To date, only mesenchymal stem cells seem to
form cardiomyocytes, and only a small percentage of this
population will do so in vitro or in vivo. Pragmatically,
the translation of the basic science into clinical research
has followed a common pathway: injection of bone
marrow-derived mononuclear cells (BMMNCs) as a
source of stem cells into the heart. Table 1 provides a
summary of clinical trials using BMMNCs in patients
with acute MI.
Trials with no sham bone marrow harvest or intracoronary
re-infusion in the control group
In the fi rst human trial, Strauer and colleagues  re-
infused intracoronary BMMNCs 7 days after myocardial
infarction (MI). Th e mean number of mononuclear cells
was 2.8 × 107. Th ere was a signifi cant improvement in
myocardial perfusion and a reduction in the infarct
region in the cell therapy group. Th e Transplantation of
Progenitor Cells and Regeneration Enhancement in
Acute Myocardial Infarction (TOPCARE-AMI) investi-
gators randomised patients into intracoronary infusion of
BMMNCs or ex vivo expanded circulating progenitor
cells 4 days after MI . Th ere was a signifi cant
improve ment in global and regional left ventricular (LV)
function in both groups and a benefi cial eff ect on the
post-infarction remodelling process manifest by a
profound improvement in wall motion abnormalities in
the infarct area and a signifi cant reduction in end-systolic
LV volume at 4 months post-MI. Th e LV ejection fraction
(LVEF) further improved at 12 months, resulting in a
total increase of 9.3% at 1 year . Of interest, there was
no diff erence between the two active treatment groups.
Th e mean number of infused cells was 245 × 106, which
contained haematopoietic progenitor, mesenchymal and
stromal cells. However, a major limitation of both of
these trials was the lack of a control group receiving sham
bone marrow harvest or intracoronary re-infusion.
Another trial in which there was no sham procedure is
the Autologous Stem-Cell Transplantation in Acute
Myocardial Infarction (ASTAMI) trial, which included
only patients with acute anterior MI. Th e intracoronary
re-infusion of BMMNCs 4 to 8 days after infarction did
not have a benefi cial eff ect on LVEF compared to percu-
taneous coronary intervention (PCI) alone at 6 months
. Th is lack of benefi cial eff ect may be explained by the
diff erent cell processing protocols used in this trial. Cell
processing protocols may have a signifi cant impact on
the functional capacity of bone marrow-derived stem
cells . Comparison of diff erent isolation protocols
revealed a vastly reduced recovery of mononuclear cells
and nullifi cation of the neovascularisation capacity when
the ASTAMI cell isolation and storage protocol was used
Th e Bone Marrow Transfer to Enhance ST-Elevation
Infarct Regeneration (BOOST) trial, a slightly larger trial,
included 60 patients that were randomised to receive
intra coronary BMMNCs or standard therapy 4.8 days
after successful PCI following AMI. Th ere was a signi-
fi cant improvement in global LVEF in the cell treatment
group at 6 months without an eff ect on LV remodelling
. However, this improvement was not maintained at
18 months. Th e mean number of bone marrow cells that
were infused contained 9.5 × 106 CD34+ and 3.6 × 106
haematopoietic colony-forming cells. Th e improvement
in LVEF did not correlate with the number of CD34+ cells
or haematopoietic colony forming cells. Again, a major
limitation of the BOOST trial is that the control group
did not undergo a sham bone marrow harvest or
Th e fi rst long-term study involving 62 patients who
underwent intracoronary BMMNC transplantation
7 days post-AMI not only resulted in an early signifi cant
improvement in ejection fraction (EF) and infarct size,
but there was also a signifi cant reduction in mortality
and improvement in exercise capacity compared to
controls at 5 years .
Randomised controlled trials
Th e Transcatheter Transplantation of Stem Cells for
Treat ment of Acute Myocardial Infarction (TCT-STAMI)
trial, which included a control group receiving a placebo
infusion, showed a signifi cant (approximately 5%) improve-
ment in LVEF of patients receiving intracoronary
BMMNCs at 6 months .
Intracoronary bone marrow derived progenitor cells
in acute infarction (REPAIR-AMI), a large random ized
double-blind controlled trial that included over 200
patients, showed an improvement in the primary
endpoint in the treatment group that was an absolute
change in global LVEF from baseline to 4 months, as
measured by quantitative left ventricular angiography
. Furthermore, the pre-specifi ed cumulative end-
point of death, MI, or revascularisation was signifi cantly
reduced, and this benefi t was maintained at one year
follow-up . Th e mean increase in LVEF in the
BMMNC group was 2.5% and there was an inverse
relationship between the baseline EF and the degree of
improvement. For example, patients with a baseline EF
below the median value (48.9%) had an absolute
increase in global EF that was three times higher than
that in the placebo group. In contrast, the improvement
in LVEF in patients with a baseline EF that was above
the median value was non-signifi cant (0.3%). Th e timing
of cell infusion post-PCI also had an eff ect on the
primary endpoint. Patients in whom the cells were
infused ≥5 days post-PCI were the only ones who
derived benefi t.
Arnous et al. Stem Cell Research & Therapy 2012, 3:2
Page 2 of 9
By contrast, the LEUVEN-AMI study by Janssens and
colleagues  showed that intracoronary re-infusion of
BMMNCs within 24 hours of reperfusion was asso-
ciated with a greater reduction in infarct size and
improved regional systolic function, but no overall
improve ment in global left ventricular function com-
pared to controls.
Trials that used two diff erent cell populations
More recently, the Myocardial Regeneration by Intra-
coronary Infusion of Selected Population of Stem Cells in
Acute Myocardial Infarction (REGENT) trial, which
included patients with anterior MI, uniquely compared
two cell types. Patients were random ized to receive
intracoronary infusion of unselected (n = 80) or selected
CD34+CXCR4+ (n = 80) BMMNCs, or to the control
group (n = 40) . Although patients in the treatment
group had a 3% improvement in LVEF, this did not reach
statistical signifi cance. However, the primary endpoint
analysis included <60% of the total population of patients,
which is likely to be responsible for the failure in the
improvement in LVEF to achieve statistical signifi cance.
Subgroup analysis showed that baseline EF below the
median value (37%) was an indepen dent predictor of
signifi cant (≥5%) increase in LVEF after treatment with
Table 1. Clinical trials using autologous bone marrow mononuclear cells in patients with acute myocardial infarction
method post-infarction procedure
Meluzin et al. 
Dose-dependent improvement of regional myocardial
function by PET
Fernandez-Aviles et al. 
13.5 ± 5.5 days
Decrease in end systolic volume, improvement in regional
and global function
Janssens et al. 
No eff ect on global LVEF, but may favourably aff ect infarct
Lunde et al.  (ASTAMI) RCT BMMNC IC 6 days PCI No eff ect on global LVEF
Schächinger et al. 
RCT BMMNC IC 3-7 days PCI Improvement in global LVEF
Ge et al.  RCT BMMNC IC Immediately PCI Improvement in LVEF
De Lezo et al. 
IV Improvement in LVEF
Zhan-quan et al.  NRC PBSC IC 6 days PCI Improvement in LVEF
Wollert et al.  (BOOST) RCT BMMNC IC 4.8 days PCI Improvement in LV systolic function
Lipiec et al. 
Improvement in myocardial perfusion with no eff ect on
Huikuri et al. 
IV Improvement in global LVEF
Kang et al. 
Improvement in myocardial perfusion and systolic
Assmus et al. 
IC 3-7 days PCI Improvement in LVEF
Schächinger et al. 
IC 3-7 days PCI Improvement in EF
Strauer et al.  NRC BMMNC IC 5-9 days PCI Reduction in infarct region
Bartunek et al.  NRC BMMNC (CD133) IC 11.6 days PCI Improvement in LVEF
Hirsch et al.  RCT BMMNC IC 3-8 days PCI No eff ect on global or regional LV function
Tendera et al.  RCT BMMNC IC 3-12 days PCI No signifi cant improvement in LVEF
Chen et al.  RCT BMMNC IC 18 days PCI Improvement in LVEF
Yousef et al.  (BALANCE) NRC BMMNC IC 7 days PCI Improvement in LVEF, exercise capacity and mortality
Time from myocardial infarction to transplantation and outcomes measured are listed. ASTAMI, Autologous Stem-Cell Transplantation in Acute Myocardial Infarction;
BMMNC, bone marrow-derived mononuclear cell; BOOST, Bone Marrow Transfer to Enhance ST-Elevation Infarct Regeneration; CPC, circulating progenitor cell; EF,
ejection fraction; GCSF, granulocyte-colony stimulating factor; IC, intracoronary; IM, intramyocardial; LVEF, left ventricular ejection fraction; NR, non-randomised; NRC,
non-randomised with control group; PBSC, peripheral blood stem cell; PCI, percutaneous coronary intervention; PET, positron emission tomography; RCT, randomised
controlled trial; REPAIR-AMI, Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction; TOPCARE-AMI, Transplantation of
Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction.
Arnous et al. Stem Cell Research & Therapy 2012, 3:2
Page 3 of 9
Th e HEBE trial compared the intracoronary infusion of
BMMNCs or mononuclear peripheral blood cells to
standard therapy alone following an AMI . Th e intra-
coronary BMMNCs were delivered between 3 to 8 days
after AMI. Th ey showed no eff ect of either treatment on
regional or global left ventricular function.
Benefi ts beyond ejection fraction
A recent comprehensive systematic review that included
13 trials with a total of 811 patients showed an
improvement in LVEF by 2.99% in the BMMNC group
compared to standard reperfusion therapy .
A previous meta-analysis by Lipinski and colleagues
 that included 10 trials with AMI showed that intra-
coronary stem cell therapy (within the fi rst 14 days after
infarction) was associated with a small but signifi cant
(3.0%) improvement in LV systolic function compared
to standard medical therapy. It was also associated with
a non-signifi cant reduction in death and re-
hospitalisation from heart failure. Although they found
no signifi cant association between the benefi ts of
intracoronary cell injection and the number of injected
cells, there was a trend toward a statistically signifi cant
association with the injected volume, suggesting the
possible presence of a dose-response relationship. Th e
improvement in LVEF was observed in both bone
marrow and peripheral mononuclear cells. Similar
conclusions were reached in the meta-analysis by
Abdel-Latif and colleagues , which included 18
studies and showed that stem cell therapy signifi cantly
increased LVEF by 3.66%.
In contrast to animal models, the improvement in LV
function in most clinical trials is at best modest.
However, it should be noted that several of our
established therapies that have an impact on prognosis
in patients with MI and a reduced LV function, such as
angiotensin-converting enzyme inhibitors, β-blockers
, thrombolytic therapy and percutaneous coronary
intervention [26,27], are associated with similar
improve ments in LVEF. It is likely that adult stem cells
exert their benefi t on cardiac remodelling through an
‘indirect’ para crine eff ect, and that the small functional
benefi t seen with this therapy may translate into signifi -
cant long-term improvement in exercise tolerance and
Th e main surrogate markers used as an end-point have
been EF and perfusion defects, which correlate poorly
with prognosis and quality of life [28,29]. Th erefore, in
the future, the validation of progenitor cell therapy for
clinical use may depend on the demonstration of a
benefi t with regard to clinical outcomes such as improve-
ment in prognosis, quality of life , New York Heart
Association functional classifi cation and exercise
The debated hypothesis
Th e divergent fi ndings from current trials may be due to
several factors. Th ere appears to be an inverse relation-
ship between the benefi t seen with stem/progenitor cell
therapy and the baseline LV function, with cell therapy
being most eff ective in patients with a lower LVEF
[17,20]. Furthermore, patients with longer ischaemic
time (>5 hours) may be more likely to have signifi cant
improve ment of LVEF following the BMMNC infusion
Th e timing of cell infusion may also play a role on the
derived benefi t. Although the REPAIR-AMI trial suggests
that the enhanced improvement of the LVEF was con-
fi ned to patients who were treated ≥5 days after primary
PCI, the investigators of the HEBE and REGENT trials
showed no interaction between the timing of cell infusion
and derived benefi t. Th e meta-analysis by Martin-
Rendon and colleagues , however, showed that the
benefi t of stem cell therapy was even greater when the
BMMNCs were infused >7 days after MI. Th e eff ect of
timing on the benefi cial eff ects of BMMNC adminis tra-
tion is further supported by the study by Lai and
colleagues  that showed that intracoronary BMMNC
administration provided cardio-protection in a fashion
similar to ishaemic preconditioning. Th is benefi t was
only seen when the myocardium had not been pre-
conditioned by other means. An ongoing study at our
centre, the REGENERATE-AMI
NCT00765453), is designed to study the delivery of
BMMNCs at very early time points (within 6 hours of
PCI). Th e purpose of this design is to replicate the animal
models where very early interventions lead to a signifi -
cant (40%) improvement in cardiac function .
Th e dose of infused BMMNCs has varied between
diff erent trials with variable results. Th ere appears to be a
dose-dependent improvement in EF, with the benefi t of
BMMNCs only seen when doses higher than 108 are
Direct (transdiff erentiation) and indirect (paracrine
and angiogenesis) eff ects of stem cells
To date, there is no direct clinical evidence that cellular
cardiomyogenesis in fact occurs in the human heart after
transplantation of progenitor cells, and over the past few
years, various experiments using diff erent types of stem
cells have shown that <2% of the transplanted cells trans-
diff erentiate into cardiomyocytes . Th erefore, the
number of cardiac cells produced by cardiac re genera tion
alone is unlikely to explain the eff ects seen. In experi ments
using a mouse model of MI, bone marrow-derived cells
were shown to undergo a very low level of trans-
diff erentiation into cardiomyocytes and most of these cells
continued to diff erentiate along the haematopoietic lineage
[33,34]. However, engraftment of these haemato poietic
Arnous et al. Stem Cell Research & Therapy 2012, 3:2
Page 4 of 9
cells at the infarct site led to an improvement in
myocardial function that is likely attributed to vasculo-
genesis, angiogenesis and a paracrine eff ect. Adult stem
cells secrete a variety of cytokines, chemokines, and
growth factors that are involved in cardiac repair  and
the production of these factors is increased in response
to the hypoxic stress associated with AMI . Takahashi
and colleagues  showed that BMMNCs in rats pro-
duce and release various cytoprotective factors, including
vascular endothelial growth factor, platelet-derived
growth factor, interleukin-1β, and insulin-like growth
factor-1, some of which are signifi cantly up-regulated by
hypoxia. Th ese paracrine factors may infl uence adjacent
cells and exert their actions via several mechanisms,
including myocardial protection and neovascularisation.
Furthermore, in humans, direct injection of BMMNCs
during acute ischaemia results in a direct cardioprotective
eff ect, by abolishing the process of apoptosis and necrosis
, which in part explains the clinical benefi t seen in
clinical trials. Th is cardioprotective mechanism appears
to be dose related with the benefi t only seen with injected
doses that are ≥5 × 106.
Neo-angiogenesis in the peri-infarct zone is an integral
part of the cardiac remodelling process . Under
normal circumstances, however, this is seldom suffi cient
to meet the demands of the hypertrophied myocardium,
and the compensatory tissue growth required for myo-
cardial contractility. One of the therapeutic advantages of
bone marrow-derived cells is to induce therapeutic
angiogenesis in ischaemic tissues, which in turn would
augment oxygen supply [40-43], and help rescue cells
from critical ischaemia . Dowell and colleagues 
have shown with histological examination at 2 weeks post-
infarction that injection of CD34+ cells was accompanied
by a signifi cant increase in infarct zone microvascularity,
cellularity and fi brosis in comparison to controls. Th ey
also showed that neoangiogenesis was increased within
both the infarct zone and the peri-infarct rim in rats
receiving CD34+ cells compared with saline controls .
Paracrine factors released by transplanted stem cells
may alter the extracellular matrix, resulting in more
favourable post-infarction remodelling and strengthening
of the infarct scar. In animal models of MI, the injection
of endothelial progenitor cells or bone marrow-derived
stem cells signifi cantly improved blood fl ow and cardiac
function and reduced left ventricular scarring [46,47].
After an ischaemic event, the effi ciency of engrafment
diff ers between diff erent progenitor subpopulations
[48,49]. Th e formation of new blood vessels occurs as a
result of the interaction of diff erent types of stem cells
with cardiomyocytes [46,50-53]. Neovascularisation is
mediated by the physical integration of progenitor cells
into new capillaries [48,54], or through a paracrine eff ect
by releasing growth factors that promote angiogenesis
, depending on the cell type and the circumstances of
the cardiac injury.
Route of cell administration
Th e three routes of stem cell delivery that have been used
so far in clinical trials are through intracoronary or
intramyocardial injection or peripherally through the
systemic circulation. It is not yet possible on the basis of
existing clinical studies to assert a ‘best’ mode of delivery.
However, it is likely that patients’ individual pathobiology
as well as the aetiology of their cardiac dysfunction will
ultimately dictate the route chosen among potential
progenitor cell therapies. Th e advantage of intracoronary
delivery is that cells are directly injected into areas of
good blood supply rich in nutrients and oxygen, which is
essential for cell survival. Myocardial ischemia is a major
stimulus for incorporation of circulating progenitor cells,
and potently up-regulates the chemo-attractants for
neoangiogenesis. Even after infarction, however, the
absolute number of progenitor cells detected in the heart
is very low [40,41,56,57], but intracoronary infusion of
progenitor cells may enhance local accumulation and
homing compared to intravenous injection.
By contrast, the benefi t of direct intramyocardial cell
delivery into hibernating myocardium is that it negates
the need for the uptake of progenitor cells from the
circulation. Electromechanical (NOGA) mapping is
essential to ensure that the cells are injected in areas of
hibernating myocardium , as necrotic areas of
myocardium and scar tissue lack the necessary cues for
cells to engraft and diff erentiate, and cells injected in
these areas die immediately .
While homing of haematopoietic progenitor cells to bone
marrow has been widely studied , the mechanisms of
homing of progenitor cells to areas of tissue injury remain
poorly understood. Homing is a complex process involving
integrins and chemokine receptors, which is greatly
enhanced after myocardial ischaemia and hypoxia. It
includes adhesion to and transmigration through the
endothelium followed by migration and invasion of the
target tissue. Homing of cells is dependent on migration out
of the vessel into the surrounding myocardium; therefore,
underperfused regions of the myocardium are targeted in a
less effi cient manner . Th e two key factors that play an
important role in homing after a MI are the release of
stromal-cell-derived factor (SDF)-1 and a chromatin
binding protein (HMGB1). SDF-1 regulates homing of stem
cells to ischaemic tissue through integrin-dependent
adhesion [62-64], and local delivery of SDF-1 can enhance
progenitor cell recruitment and neovasculari sation [65,66].
Th e release of HMGB1 may act as a danger signal and
stimulate the homing of stem cells to ischaemic tissue .
Arnous et al. Stem Cell Research & Therapy 2012, 3:2
Page 5 of 9
Furthermore, endothelial progenitor cells express a
number of chemokine receptors, such as CXCR2, CXCR4
and CXCL12. Th ese chemokines play an important role
in the homing and mobilisation of endothelial progenitor
cells and their recruitment to the site of ischaemic injury
for endothelial recovery [68-71].
Where is research in this area heading in the next
Th e need for new therapies to treat patients with AMI
has led to a swift transition from bench to bedside and a
number of clinical trials showing promising potential for
stem cell therapy in heart disease. Th e ultimate aim of
this research is to develop a technique that grows new
functioning heart muscle. However, many obstacles still
lie ahead. One of the many remaining unanswered
questions is which type of stem/progenitor cell is the best
candidate for cardiac regeneration. Th e bone marrow is
an attractive source because it is easily accessible and
contains a number of stem cells, including haemato-
poietic and mesenchymal cells. It is likely, however, that
bone marrow cells in humans work through an indirect
paracrine mechanism. Th e safety and feasibility of bone
marrow cells in AMI have been well established in
clinical trials. Th is, therefore, supports the need for
robust evidence from large double-blind randomised
controlled trials to assess their eff ect on clinical end-
points such as mortality and symptoms.
Th e European Society of Cardiology established a task
force to investigate the role of stem cells in cardiac repair
and published its consensus in a 2006 report . Th e
future focus in stem cell therapy should be to provide a
better understanding of the mechanism of functional
improvements observed and the development of safe and
eff ective cell tracking modalities. Th ese areas of research
would aid the identifi cation of the best cell candidate for
therapeutic use as well as better understanding of myo-
cardial homing and cell survival post-transplantation. It
is important to note, however, that the clinical experience
has provided a lot of valuable information regarding the
approaches to cell therapy in humans, which will of
course provide a platform for future trials in this fi eld.
One of the challenges in the future is improving the
durability and survival of stem cells in the adverse
environ ment they are engrafted into. One of the proper-
ties of stem cells is stress resistance , although several
studies have shown that most stem cells die within a few
weeks of delivery into the myocardium [34,74-76]. Th is is
probably due to the lack of nutrients and oxygen within
the ischaemic environment. Furthermore, heart failure
, atherosclerosis [78,79] and advanced age [80,81]
correlate inversely with the number and function of
circulating endothelial progenitor cells. Allogenic cells
from young and healthy donors may represent a good
solution, but cell rejection requiring immunosuppressive
therapies would pose a new problem. Th ere is some evi-
dence that statins improve the survival of the circulating
endothelial progenitor cells [82,83]. Furthermore, higher
doses of statin therapy are associated with a greater
increase in circulating CD34+ and CXCR4+ from the bone
marrow, resulting in an increase in coronary fl ow reserve
at 8 months . Future trials are on the horizon assess-
ing the role of statin therapy on enhancing the number of
endothelial cells in patients with coronary artery disease
(Clinicaltrials.gov CT01096875). Endothelial progenitor
cells are a subset of haematopoietic cells that have an
important role to play in ischaemia by promoting angio-
genesis, preventing cardiomyocyte apoptosis and reduc-
ing adverse remodelling. It may be that future potential
remedies, such as statins, that enhance the function of
endothelial progenitor cells may play an important role in
improving stem cell survival and function. One of the
ways of improving cell survival may be achieved by using
viral vectors encoding multiple cytoprotective genes that
act on diff erent cell death and apoptotic pathways, or by
preconditioning the stem cells with cytokines that result
in improved cell engraftment.
Another important issue is the timing of cell adminis-
tration post-MI. Although animal studies have supported
early administration of stem cells post-infarction, in
humans the benefi ts of this therapy were greater when
administered >4 days after reperfusion (based on avail able
evidence). Furthermore, given the seemingly small
improvements that these trials have shown, the cost-
eff ective ness of cell therapy will also need to be addressed.
Two ongoing randomised controlled trials (TIME and
late TIME studies) may help us understand whether the
timing of cell administration plays an important role. Th e
TIME study (Clinicaltrials.gov NCT00684021) is a trial
designed to assess the eff ect of timing (3 versus 7 days) of
BMMNC administration versus placebo in patients with
acute MI. Th e LATE TIME study (Clinicaltrials.gov
NCT00684060) will assess the eff ect of BMMNC adminis-
tra tion 2 to 3 weeks after a MI.
Animal and human studies have clearly shown that stem
cell engraftment into the myocardium is associated with
improvement in cardiac function; however, the quest for
the optimal population of cells remains a challenge
[85,86]. Embryonic stem cells are able to transform into
cardiomyocytes and can replicate indefi nitely, although
ethical issues - their potential to form teratomas and the
need for immunosuppressive therapy - have hindered
their use in clinical trials. Furthermore, one of the major
limitations of adult stem cells, including skeletal
myoblasts and bone marrow-derived stem cells, is their
limited ability to cross their lineage boundaries.
Arnous et al. Stem Cell Research & Therapy 2012, 3:2
Page 6 of 9
Fat tissue-derived multipotent stem cells , multi-
potential cells from bone marrow or skeletal muscle
[88,89], somatic stem cells from placental cord blood ,
and cardiac-resident progenitor cells [32,91] all show
promising pre-clinical and some clinical applications.
Ultimately, cells that more closely resemble embryonic
stem cells in their regenerative potential without the
ethical issues provide an important future direction. A
cell type that comes close, and is on the horizon of being
tested for potential clinical application, is the inducible
pluripotent stem cell (iPSC). iPSCs can be generated
from adult human somatic cells by retroviral transduction
, have similar diff erentiation potential and may
provide an alternative to pluripotent embryonic stem
The future of bone marrow stem cells
For the time being, it is important to establish whether
the simple unfractionated bone marrow cell approach
has clinical benefi t, given the large number of studies that
have been performed using this cell type without provid-
ing a clear answer. Meta-analysis suggests a positive
eff ect on surrogate cardiac end-points in studies using
BMMNCs to treat AMI. Th ere is now a need to perform
a large scale clinical trial using clinical hard end-points
such as mortality to establish whether the positive eff ects
seen on surrogate end-points can indeed translate to
meaningful clinical benefi ts.
AMI, acute myocardial infarction; ASTAMI, Autologous Stem-Cell
Transplantation in Acute Myocardial Infarction; BMMNC, bone marrow-
derived mononuclear cell; BOOST, Bone Marrow Transfer to Enhance ST-
Elevation Infarct Regeneration; EF, ejection fraction; LV, left ventricular; LVEF,
left ventricular ejection fraction; MI, myocardial infarction; PCI, percutaneous
coronary intervention; REPAIR-AMI, Intracoronary bone marrow derived
progenitor cells in acute infarction; SDF, stromal-cell-derived factor.
The authors have no relevant affi liations or fi nancial involvement with any
organisation or entity with a fi nancial interest in or fi nancial confl ict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties. No writing
assistance was utilized in the production of this manuscript.
This work forms part of the research themes contributing to the translational
research portfolio of Barts and the London Cardiovascular Biomedical
Research Unit, which is supported and funded by the National Institute of
1Department of Cardiology, London Chest Hospital, Bonner Road, London
E2 9JX, UK. 2Department of Cardiology, London Chest Hospital, Queen Mary
University of London, Barts and the London NHS Trust, Bonner Road, London
E2 9JX, UK.
Published: 17 January 2012
1. Pfeff er M, John J, McMurray M, Velazquez E, Rouleau J: Valsartan, captopril,
or both in myocardial infarction complicated by heart failure, left
ventricular dysfunction, or both. N Eng J Med 2003, 349:1893-1906.
Braunwald E: Cardiovascular medicine at the turn of the millennium:
triumphs, concerns, and opportunities. N Eng J Med 1997, 337:1360-1369.
Mathur A, Martin JF: Stem cells and repair of the heart. Lancet 2004,
Yeh TH, Zhang S, Wu H: Transdiff erentiation of human peripheral blood
CD34+ enriched cell population into cardiomyocytes, endothelial cell and
smooth muscle cells in vivo. Circulation 2003, 108:2070-2073.
Badorff C: Transdiff erentiation of blood-derived human adult endothelial
progenitor cells into functionally active cardiomyocytes. Circulation 2003,
Kawada H, Fujita J, Kinjo K: Non-haematopoietic mesenchymal stem cells
can be mobilized and diff erentiate into cardiomyocytes after myocardial
infarction. Blood 2004, 104:3581-3587.
Orlic D: Mobilized bone marrow cells repair the infarcted heart, improving
function and survival. Proc Natl Acad Sci U S A 2001, 98:10344-10349.
Orlic D, Kajstrua J, Chimenti S: Bone marrow cells regenerate infracted
myocardium. Nature 2001, 410:701-705.
Strauer B, Brehm M, Zeus T: Repair of infracted myocardium by autologous
intracoronary mononuclear bone marrow cell transplantation in humans.
Circulation 2002, 106:1913-1918.
10. Assmus B, Schächinger V, Teupe C: Transplantation of progenitor cells and
regeneration enhancement in acute myocardial infarction
(TOPCARE-AMI). Circulation 2002, 106:3009-3017.
11. Schächinger V, Assmus B, Britten M: Transplantation of progenitor cells and
regeneration enhancement in acute myocardial infarction: Final one year
results of the TOPCARE-AMI trial. J Am College Cardiol 2004, 44:1690-1699.
12. Lunde K, Solheim S, Aakhus S, Arnesen H, Abdelnoor M, Egeland T, Endresen
K, Ilebekk A, Mangschau A, Fjeld JG, Smith HJ, Taraldsrud E, Grøgaard HK,
Bjørnerheim R, Brekke M, Müller C, Hopp E, Ragnarsson A, Brinchmann JE,
Forfang K: Intracoronary injection of mononuclear bone marrow cells in
acute myocardial infarction. N Eng J Med 2006, 355:1199-1209.
13. Seeger FH, Tonn T, Krzossok N, Zeiher AM, Dimmeler S: Cell isolation
procedures matter: a comparison of diff erent isolation protocols of bone
marrow mononuclear cells used for cell therapy in patients with acute
myocardial infarction. Eur Heart J 2007, 28:766-772.
14. Wollert K, Meyer G, Joachim L: Intracoronary autologous bone-marrow cell
transfer after myocardial infarction: the BOOST randomised controlled
clinical trial. Lancet 2004, 364:141-148.
15. Yousef M, Schannwell CM, Kostering M, Zeus T, Brehm M, Strauer BE: The
BALANCE Study: clinical benefi t and long-term outcome after
intracoronary autologous bone marrow cell transplantation in patients
with acute myocardial infarction. J Am Coll Cardiol 2009, 53:2262-2269.
16. Ge J, Qian J: Effi cacy of emergent transcatheter transplantation of stem
cells for treatment of acute myocardial infarction (TCT-STAMI). Heart 2006,
17. Schächinger V, Erbs S, Elsässer A: REPAIR-AMI investigators. Intracoronary
bone marrow derived progenitor cells in acute infarction. N Eng J Med
18. Schächinger V, Erbs S, Elsässer A, Haberbosch W, Hambrecht R, Hölschermann
H, Yu J, Corti R, Mathey DG, Hamm CW, Süselbeck T, Werner N, Haase J,
Neuzner J, Germing A, Mark B, Assmus B, Tonn T, Dimmeler S, Zeiher AM;
REPAIR-AMI Investigators: Improved clinical outcome after intracoronary
administration of bone-marrow-derived progenitor cells in acute
myocardial infarction: fi nal 1-year results of the REPAIR-AMI trial. Eur Heart
J 2006, 27:2775-2783.
19. Janssens S, Dubois C, Bogaert J: Autologous bone marrow derived stem cell
transfer in patients with ST-segment elevation myocardial infarction:
double blind randomised controlled trial. Lancet 2006, 367:113-121.
20. Tendera M, Wojakowski W, Ruzyłło W, Chojnowska L, Kepka C, Tracz W,
Musiałek P, Piwowarska W, Nessler J, Buszman P, Grajek S, Breborowicz P, Majka
M, Ratajczak MZ; REGENT Investigators: Intracoronary infusion of bone
marrow-derived selected CD34+CXCR4+ cells and non-selected
mononuclear cells in patients with acute STEMI and reduced left
ventricular ejection fraction: results of randomized, multicentre
Myocardial Regeneration by Intracoronary Infusion of Selected Population
of Stem Cells in Acute Myocardial Infarction (REGENT) Trial. Eur Heart J
21. Hirsch A, Nijveldt R, van der Vleuten PA, Tijssen JG, van der Giessen WJ, Tio RA,
Waltenberger J, ten Berg JM, Doevendans PA, Aengevaeren WR, Zwaginga JJ,
Biemond BJ, van Rossum AC, Piek JJ, Zijlstra F; HEBE Investigators:
Arnous et al. Stem Cell Research & Therapy 2012, 3:2
Page 7 of 9
Intracoronary infusion of mononuclear cells from bone marrow or
peripheral blood compared with standard therapy in patients after acute
myocardial infarction treated by primary percutaneous coronary
intervention: results of the randomized controlled HEBE trial. Eur Heart J
22. Martin-Rendon E, Brunskill SJ, Hyde CJ, Stanworth SJ, Mathur A, Watt SM:
Autologous bone marrow stem cells to treat acute myocardial infarction:
a systematic review. Eur Heart J 2008, 29:1807-1818.
23. Lipinski JM, Giuseppe GL, Zoccai B, Abbate A, Khianey R: Impact of
intracoronary cell therapy on left ventricular function in the setting of
acute myocardial infarction. J Am College Cardiol 2007, 50:1761-1767.
24. Abdel-Latif A, Bolli R, Tleyjeh IM, Montori VM, Perin EC, Hornung CA, Zuba-
Surma EK, Al-Mallah M, Dawn B: Adult bone marrow-derived cells for
cardiac repair: a systematic review and meta-analysis. Arch Intern Med 2007,
25. Reff elmann T, Konemann S, Kloner RA: Promise of blood- and bone marrow-
derived stem cell transplantation for functional cardiac repair: putting it in
perspective with existing therapy. J Am Coll Cardiol 2009, 53:305-308.
26. Stone GW, Grines CL, Cox DA, Garcia E, Tcheng JE, Griffi n JJ, Guagliumi G,
Stuckey T, Turco M, Carroll JD, Rutherford BD, Lansky AJ; Controlled
Abciximab and Device Investigation to Lower Late Angioplasty
Complications (CADILLAC) Investigators: Comparison of angioplasty with
stenting, with or without abciximab, in acute myocardial infarction. N Engl
J Med 2002, 346:957-966.
27. Montalescot G, Barragan P, Wittenberg O, Ecollan P, Elhadad S, Villain P,
Boulenc JM, Morice MC, Maillard L, Pansiéri M, Choussat R, Pinton P; ADMIRAL
Investigators. Abciximab before Direct Angioplasty and Stenting in
Myocardial Infarction Regarding Acute and Long-Term Follow-up: Platelet
glycoprotein IIb/IIIa inhibition with coronary stenting for acute myocardial
infarction. N Engl J Med 2001, 344:1895-1903.
28. Curtis JP, Sokol SI, Wang Y, Rathore SS, Ko DT, Jadbabaie F, Portnay EL,
Marshalko SJ, Radford MJ, Krumholz HM: The association of left ventricular
ejection fraction, mortality, and cause of death in stable outpatients with
heart failure. J Am Coll Cardiol 2003, 42:736-742.
29. Tribouilloy C, Rusinaru D, Mahjoub H, Soulière V, Lévy F, Peltier M, Slama M,
Massy Z: Prognosis of heart failure with preserved ejection fraction:
a 5 year prospective population-based study. Eur Heart J 2008, 29:339-347.
30. Sharif F, Bartunek J, Vanderheyden M: Adult stem cells in the treatment of
acute myocardial infarction. Catheter Cardiovasc Interv 2011, 77:72-83.
31. Lai VK, Ang KL, Rathbone W, Harvey NJ, Galinanes M: Randomized controlled
trial on the cardioprotective eff ect of bone marrow cells in patients
undergoing coronary bypass graft surgery. Eur Heart J 2009, 30:2354-2359.
32. Oh H: Cardiac progenitor cells from adult myocardium: homing,
diff erentiation, and fusion after infarction. Proc Natl Acad Sci U S A 2003,
33. Murry C, Soonpaa M, Reinecke H: Haematopoietic stem cells do not
transdiff erentiate into cardiac myocytes in myocardial infarcts. Nature
34. Balsam L, Wagers A, Christensen J: Haematopoietic stem cells adopt mature
haematopoietic fates in ischaemic myocardium. Nature 2004, 428:668-673.
35. Caplan AI, Dennis JE: Mesenchymal stem cells as trophic mediators. J Cell
Biochem 2006, 98:1076-1084.
36. Kinnaird T, Stabile E, Burnett MS, Lee CW, Barr S, Fuchs S, Epstein SE: Marrow-
derived stromal cells express genes encoding a broad spectrum of
arteriogenic cytokines and promote in vitro and in vivo arteriogenesis
through paracrine mechanisms. Circ Res 2004, 94:678-685.
37. Takahashi M, Li TS, Suzuki R, Kobayashi T, Ito H, Ikeda Y, Matsuzaki M, Hamano
K: Cytokines produced by bone marrow cells can contribute to functional
improvement of the infarcted heart by protecting cardiomyocytes from
ischemic injury. Am J Physiol Heart Circ Physiol 2006, 291:H886-H893.
38. Kubal C, Sheth K, Nadal-Ginard B, Galinanes M: Bone marrow cells have a
potent anti-ischemic eff ect against myocardial cell death in humans.
J Thorac Cardiovasc Surg 2006, 132:1112-1118.
39. Nelissen-Vrancken H, Debets J, Snoeckx L, Daemen M, Smits J: Time-related
normalization of maximal coronary fl ow in isolated perfused hearts of rats
with myocardial infarction. Circulation 1996, 93:349-355.
40. Takahashi T, Kalka C, Masuda H: Ischemia- and cytokine-induced
mobilization of bone marrow-derived endothelial progenitor cells for
neovascularization. Nat Med 1999, 5:434-438.
41. Kalka C, Masuda H, Takahashi T: Transplantation of ex vivo expanded
endothelial progenitor cells for therapeutic neovascularization. Proc Natl
Acad Sci U S A 2000, 97:3422-3427.
42. Folkman J: Therapeutic angiogenesis in ischemic limbs. Circulation 1998,
43. Asahara T: Isolation of putative progenitor cells for endothelial
angiogenesis. Science 1997, 275:964-967.
44. Isner J, Asahara T: Angiogenesis and vasculogenesis as therapeutic
strategies for postnatal neovascularization. J Clin Invest 1999,
45. Dowell JD, Rubart M, Pasumarthi KBS, Soonpaa MH, Field LJ: Myocyte and
myogenic stem cell transplantation in the heart. Cardiovasc Res 2003,
46. Kocher A: Neovascularization of ischemic myocardium by human bone-
marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces
remodeling and improves cardiac function. Nat Med 2001, 7:430-436.
47. Kawamoto A, Gwon HC, Iwaguro H, Yamaguchi JI, Uchida S, Masuda H, Silver
M, Ma H, Kearney M, Isner JM, Asahara T: Therapeutic potential of ex vivo
expanded endothelial progenitor cells for myocardial ischemia. Circulation
48. Urbich C, Heeschen C, Aicher A, Dembach E, Zeiher AM, Dimmeler S:
Relevance of monocytic features for neovascularization capacity of
circulating endothelial progenitor cells. Circulation 2003, 108:2511-2516.
49. Aicher A, Heeschen C, Mildner-Rihm C, Urbich C, Ihling C, Technau-Ihling K,
Zeiher AM, Dimmeler S: Essential role of endothelial nitric oxide synthase
for mobilization of stem and progenitor cells. Nat Med 2003, 9:1370-1376.
50. Fuchs S, Baff our R, Zhou Y: Transendocardial delivery of autologous bone
marrow enhances collateral perfusion and regional function in pigs with
chronic experimental myocardial ischaemia. J Am College Cardiol 2001,
51. Hamano K, Li T, Kobayashi T: Therapeutic angiogenesis induced by local
autologous bone marrow cell implantation. Ann Thoracic Surg 2002,
52. Kamihata H, Matsubara H, Nishiue T: Improvement of collateral perfusion
and regional function by implantation of peripheral blood mononuclear
cells into ischemic hibernating myocardium. Arterioscler Thromb Vasc Biol
53. Kamihata H, Matsubara H, Nishiue T: Implantation of bone marrow
mononuclear cells into ischemic myocardium enhances collateral
perfusion and regional function via side supply of angioblasts, angiogenic
ligands, and cytokines. Circulation 2001, 104:1046-1052.
54. Jackson K: Regeneration of ischemic cardiac muscle and vascular
endothelium by adult stem cells. J Clin Invest 2001, 107:1395-1402.
55. Rehman J, Li J, Orschell CM, March KL: Peripheral blood “endothelial
progenitor cells” are derived from monocyte/macrophages and secrete
angiogenic growth factors. Circulation 2003, 107:1164-1169.
56. Shintani S, Murohara T, Ikeda H: Mobilization of endothelial progenitor cells
in patients with acute myocardial infarction. Circulation 2001,
57. Iwaguro H, Yamaguchi J, Kalka C: Endothelial progenitor cell vascular
endothelial growth factor gene transfer for vascular regeneration.
Circulation 2002, 105:732-738.
58. Perin E: Transendocardial, autologous bone marrow cell transplantation
for severe, chronic ischemic heart failure. Circulation 2003, 107:2294-2302.
59. Beauchamp J, Morgan J, Pagel C, Partridge T: Dynamics of myoblast
transplantation reveal a discrete minority of precursors with stem cell-like
properties as the myogenic source. J Cell Biol 1999, 144:1113-1122.
60. Papayannopoulou T: Bone marrow homing: the players, the playfi eld, and
their evolving roles. Curr Opin Hematol 2003, 10:214-219.
61. Aicher A: Assessment of the tissue distribution of transplanted human
endothelial progenitor cells by radioactive labeling. Circulation 2003,
62. De Falco E: Sdf-1 involvement in endothelial phenotype and ischemia-
induced recruitment of bone marrow progenitor cells. Blood 2004,
63. Chavakis E: Role of b2-integrins for homing and neovascularization
capacity of endothelial progenitor cells. J Exp Med 2005, 201:63-72.
64. Vajkoczy P: Multistep nature of microvascular recruitment of ex vivo-
expanded embryonic endothelial progenitor cells during tumor
angiogenesis. J Exp Med 2003, 197:1755-1765.
65. Askari A: Eff ect of stromal-cell-derived factor 1 on stem-cell homing and
tissue regeneration in ischaemic cardiomyopathy. Lancet 2003,
Arnous et al. Stem Cell Research & Therapy 2012, 3:2
Page 8 of 9
66. Yamaguchi J: Stromal cell-derived factor-1 eff ects on ex vivo expanded
endothelial progenitor cell recruitment for ischemic neovascularization.
Circulation 2003, 107:1322-1328.
67. Scaffi di P, Misteli T, Bianchi M: Release of chromatin protein hmgb1 by
necrotic cells triggers infl ammation. Nature 2002, 418:191-195.
68. Hristov M, Zernecke A, Bidzhekov K, Liehn EA, Shagdarsuren E, Ludwig A,
Weber C: Importance of CXC chemokine receptor 2 in the homing of
human peripheral blood endothelial progenitor cells to sites of arterial
injury. Circ Res 2007, 100:590-597.
69. Levesque JP, Hendy J, Takamatsu Y, Simmons PJ, Bendall LJ: Disruption of the
CXCR4/CXCL12 chemotactic interaction during hematopoietic stem cell
mobilization induced by GCSF or cyclophosphamide. J Clin Invest 2003,
70. Petit I, Szyper-Kravitz M, Nagler A, Lahav M, Peled A, Habler L, Ponomaryov T,
Taichman RS, Arenzana-Seisdedos F, Fujii N, Sandbank J, Zipori D, Lapidot T:
G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1
and up-regulating CXCR4. Nat Immunol 2002, 3:687-694.
71. Yamaguchi J, Kusano KF, Masuo O, Kawamoto A, Silver M, Murasawa S, Bosch-
Marce M, Masuda H, Losordo DW, Isner JM, Asahara T: Stromal cell-derived
factor-1 eff ects on ex vivo expanded endothelial progenitor cell
recruitment for ischemic neovascularization. Circulation 2003,
72. Bartunek J, Dimmeler S, Drexler H, Fernández-Avilés F, Galinanes M, Janssens
S, Martin J, Mathur A, Menasche P, Priori S, Strauer B, Tendera M, Wijns W,
Zeiher A; task force of the European Society of Cardiology: The consensus of
the task force of the European Society of Cardiology concerning the
clinical investigation of the use of autologous adult stem cells for repair of
the heart. Eur Heart J 2006, 27:1338-1340.
73. Ramalho-Santos M, Yoon S, Matsuzaki Y, Mulligan R, Melton D: “Stemness”:
transcriptional profi ling of embryonic and adult stem cells. Science 2002,
74. Jiang S, Haider HK, Idris NM, Salim A, Ashraf M: Supportive interaction
between cell survival signaling and angiocompetent factors enhances
donor cell survival and promotes angiomyogenesis for cardiac repair. Circ
Res 2006, 99:776-784.
75. Norol F, Bonnet N, Peinnequin A, Chretien F, Legrand R, Isnard R, Herodin F,
Baillou C, Delache B, Negre D, Klatzmann D, Vernant JP, Lemoine FM:
GFP-transduced CD34+ and Lin- CD34- hematopoietic stem cells did not
adopt a cardiac phenotype in a nonhuman primate model of myocardial
infarct. Exp Hematol 2007, 35:653-661.
76. Nakamura Y, Wang X, Xu C, Asakura A, Yoshiyama M, From AH, Zhang J:
Xenotransplantation of long-term-cultured swine bone marrow-derived
mesenchymal stem cells. Stem Cells 2007, 25:612-620.
77. Heeschen C: Profoundly reduced neovascularization capacity of bone
marrow mononuclear cells derived from patients with chronic ischemic
heart disease. Circulation 2004, 109:1615-1622.
78. Vasa M: Number and migratory activity of circulating endothelial
progenitor cells inversely correlate with risk factors for coronary artery
disease. Circ Res 2001, 89:E1-E7.
79. Hill J: Circulating endothelial progenitor cells, vascular function, and
cardiovascular risk. N Eng J Med 2003, 348:593-600.
80. Edelberg J, Tang L, Hattori K, Lyden D, Rafi i S: Young adult bone marrow-
derived endothelial precursor cells restore aging-impaired cardiac
angiogenic function. Circ Res 2002, 90:E89-E93.
81. Torella D: Cardiac stem cell and myocyte aging, heart failure, and insulin-
like growth factor-1 overexpression. Circ Res 2004, 94:514-524.
82. Assmus B: Hmg-coa reductase inhibitors reduce senescence and increase
proliferation of endothelial progenitor cells via regulation of cell cycle
regulatory genes. Circ Res 2003, 92:1049-1055.
83. Spyridopoulos I: Statins enhance migratory capacity by upregulation of
the telomere repeat-binding factor trf2 in endothelial progenitor cells.
Circulation 2004, 110:3136-3142.
84. Hong SJ, Choi SC, Kim JS, Shim WJ, Park SM, Ahn CM, Park JH, Kim YH, Lim DS:
Low-dose versus moderate-dose atorvastatin after acute myocardial
infarction: 8-month eff ects on coronary fl ow reserve and angiogenic cell
mobilisation. Heart 2010, 96:756-764.
85. Smits AM, van VP, Hassink RJ, Goumans MJ, Doevendans PA: The role of stem
cells in cardiac regeneration. J Cell Mol Med 2005, 9:25-36.
86. Davani S, Deschaseaux F, Chalmers D, Tiberghien P, Kantelip JP: Can stem
cells mend a broken heart? Cardiovasc Res 2005, 65:305-316.
87. Planat-Benard V: Spontaneous cardiomyocyte diff erentiation from adipose
tissue stroma cells. Circ Res 2004, 94:223-229.
88. Jiang Y: Multipotent progenitor cells can be isolated from postnatal
murine bone marrow, muscle, and brain. Exp Hematol 2002, 30:896-904.
89. Jiang Y: Pluripotency of mesenchymal stem cells derived from adult
marrow. Nature 2002, 418:41-49.
90. Kogler G: A new human somatic stem cell from placental cord blood with
intrinsic pluripotent diff erentiation potential. J Exp Med 2004, 200:123-135.
91. Beltrami A: Adult cardiac stem cells are multipotent and support
myocardial regeneration. Cell 2003, 114:763-776.
92. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S:
Induction of pluripotent stem cells from adult human fi broblasts by
defi ned factors. Cell 2007, 131:861-872.
93. Meluzin J, Mayer J, Groch L: Autologous transplantation of mononuclear
bone marrow cells in patients with acute myocardial infarction: The eff ect
of the dose of transplanted cells on myocardial function. Am Heart J 2006,
94. Fernández-Avilés F, San Román JA, García-Frade J, Fernández ME, Peñarrubia
MJ, de la Fuente L, Gómez-Bueno M, Cantalapiedra A, Fernández J, Gutierrez
O, Sánchez PL, Hernández C, Sanz R, García-Sancho J, Sánchez A:
Experimental and clinical regenerative capability of human bone marrow
cells after myocardial infarction. Circ Res 2004, 95:742-748.
95. De Lezo J, Herrera C, Pan M: Regenerative therapy in patients with a
revascularized acute anterior myocardial infarction and depressed
ventricular function. Rev Esp Cardiol 2007, 60:357-365.
96. Zhan-quan L, Ming Z: The clinical study of autologous peripheral blood
stem cell transplantation by intracoronary infusion in patients with acute
myocardial infarction. Int J Cardiol 2007, 115:52-56.
97. Lipiec P, Pakula M, Plewka M: Impact of intracoronary injection of
mononuclear bone marrow cells in acute myocardial infarction on left
ventricular perfusion and function: a 6-month follow-up gated mTc-MIBI
single-photon emission computed tomography study. Eur J Nuclear Mol
Imaging 2009, 36:587-593.
98. Huikuri H, Kervinen K, Niemelä M: Eff ects of intracoronary injection of
mononuclear bone marrow cells on left ventricular function, arrhythmia
risk profi le, and restonosis after thrombolytic therapy of acute myocardial
infarction. Eur Heart J 2008, 29:2723-2732.
99. Kang H, Kim H, Zhang S, Park K, Cho H, Koo B: Eff ects of intracoronary
infusion of peripheral blood stem-cells mobilised with granulocyte-
colony stimulating factor on left ventricular systolic function and
restenosis after coronary stenting in myocardial infarction: the MAGIC cell
randomised clinical trial. Lancet 2004, 363:751-756.
100. Bartunek J, Vanderheyden M, Vandekerckhove B: Intracoronary injection of
CD133 positive enriched bone marrow progenitor cells promotes cardiac
recovery after recent myocardial infarction: feasibility and safety.
Circulation 2005, 112:I-178-I-183.
101. Chen SL, Fang WW, Ye F, Liu YH, Qian J, Shan SJ, Zhang JJ, Chunhua RZ, Liao
LM, Lin S, Sun JP: Eff ect on left ventricular function of intracoronary
transplantation of autologous bone marrow mesenchymal stem cell in
patients with acute myocardial infarction. Am J Cardiol 2004, 94:92-95.
Cite this article as: Arnous S, et al.: Bone marrow mononuclear cells and
acute myocardial infarction. Stem Cell Research & Therapy 2012, 3:2.
Arnous et al. Stem Cell Research & Therapy 2012, 3:2
Page 9 of 9