Cardiac cell therapy: Lessons from clinical trials
Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Department of Cardiovascular Surgery; Université Paris Descartes; INSERM U 633, Paris, France
a b s t r a c ta r t i c l e i n f o
Received 18 May 2010
Received in revised form 21 June 2010
Accepted 21 June 2010
Available online 30 June 2010
Cardiac cell therapy has now been in clinical use since 10 years. Both autologous skeletal myoblasts and bone
marrow-derived different cell subsets (mononuclear cells, hematopoietic progenitors, mesenchymal stem
cells) have been investigated in different settings (acute myocardial infarction, refractory angina and chronic
heart failure). Despite the huge variability in cell processing techniques, dosing, timing of delivery and route
for cell transfer, some lessons can yet be drawn, primarily from randomized controlled trials and
summarized as follows: Techniques used for cell preparation are reasonably well controlled although better
standardization and improvement in scale-up procedures remain necessary; cell therapy is overall safe, with
the caveat of ventricular arrhythmias which still require careful scrutinization; the cell type needs to be
tailored to the primary clinical indication, whereas the paracrine effects of bone marrow cells may be
therapeutically efficacious for limitation of remodelling or relief of angina, only cells endowed with a true
cardiomyogenic differentiation potential are likely to effect regeneration of chronic scars; autologous cells
are primarily limited by their variable and unpredictable functionality, thereby calling attention to banked,
consistent and readily available allogeneic cell products provided the immunological issues inherent in their
use can be satisfactorily addressed; regardless of the cell type, a meaningful and sustained therapeutic
benefit is unlikely to occur until cell transfer and survival techniques are improved to allow greater
engraftment rates; and trial end points probably need to be reassessed to focus on mechanistic issues or hard
end points depending on whether new or already extensively used cells are investigated. Hopefully, these
lessons may serve as a building block whose incorporation in the design of second-generation trials will help
making them more clinically successful. This article is part of a special issue entitled, "Cardiovascular Stem
© 2010 Elsevier Ltd. All rights reserved.
Updated results of cardiac cell therapy trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Major lessons drawn from early cardiac cell therapy trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.Procedural aspects need to be fine-tuned and better standardized . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.Cardiac cell therapy is overall safe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3. The cell type needs to be tailored to the primary clinical indication. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4.Autologous cell therapy products have serious limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.5. Regardless of the cell type, cell therapy will remain suboptimally efficacious until engraftment techniques are optimized . . . . . . .
2.6.Trial end points may need to be revisited . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Disclosures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Before trying to draw some lessons from the first wave of clinical
trials, it seems appropriate to provide a brief update of where we
currently stand, assuming that small-sized uncontrolled, unblinded
studies or anecdotal cases are meaningless, not to say misleading,
and that, consequently, only randomized controlled trials will be
1. Updated results of cardiac cell therapy trials
For sake of clarity, the main results will be stratified according to
the primary clinical indication.
Journal of Molecular and Cellular Cardiology 50 (2011) 258–265
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In patients with acute myocardial infarction, bone marrow-derived
mononuclear cells (MNC) infused through the recently reopened
infarct-related coronary artery have been the most widely investi-
gated. A recent meta-analysis  has compiled the data of 811
patients included in 13 randomized trials witha 3- to 6-monthfollow-
up duration. Overall, stem cell therapy was found to improve left
ventricular ejection fraction (LVEF) by 2.99% [95% confidence interval
(CI), 1.26–4.72%, p=0.0007], despite a considerable degree of
heterogeneity in LVEF comparisons, and to reduce LV end-systolic
volume by 4.74 mL (95% CI, −7.84 to −1.64 mL, p=0.003), and
myocardial lesion area by 3.51% (95% CI, −5.91 to −1.11%, p=0.004)
compared with controls. However, bone marrow cell therapy failed to
alter postinfarction remodelling which is a major predictor of late
adverse outcomes .
Indeed, these encouraging hints in favour of stem cell therapy early
after coronary artery angioplasty and stenting for acute infarction are
largely driven by the positive outcomes of the largest 204-patient trial
Remodelingin AcuteMyocardialInfarction (REPAIR-MI) trial, which
has even reported a reduction in the 2-year incidence of major adverse
cardiovascular events . It is fair to recognize that this enthusiasm
probably needs to be tempered in light of theresults of some additional
large trials which have been reported after publication of the meta-
analysis. The HEBE trial included 200 patients and failed to show an
improvement in LVEF, measured by cardiac magnetic resonance
imaging (MRI) at 4 months, between the three study groups (bone
marrow-derived cells, peripheral blood-derived cells and standard
therapy) although a post-hoc analysis demonstrated that in patients
with initially dilated ventricles, treatment prevented further remodel-
ling . The REGENT trial also enrolled 200 patients randomized to a
nuclear cells MNC or select CD34+CXCR4+cells; it equally failed to
document a difference in LVEF or volumes (measured by MRI) after
6 months between the three groups despite a trend in favour of cell
therapy in patients with most severely impaired LVEF and longer delay
between the symptoms and revascularization . In contrast, the
FINCEL trial  which randomized 80 patients to intracoronary
infusions of MNC or placebo reported a “positive” outcome based on
the finding that LVEF (measured by by left ventricular angiography and
2-D echocardiography) increased to a greater extent in the treated
group compared with controls but interpretation of these data needs to
becautious since a head-to-headcomparison of absolute LVEFvalues at
6 months shows similar values in the two groups. In the most recently
published SCAMI (Stem Cell therapy in patients with Acute Myocardial
Infarction) study which used serial MRI for assessing results in 42
patients, of whom 29 were allocated to the treated arm), there was no
either evidence for a positive effect of intracoronarily infused MNC
treatment versus placebo with regard to LVEF, volumes or infarct size
. In this study, the centrifugation technique used for collecting MNC
was similar to that used in the REPAIR-MI trial and a greater number of
cells (381×106versus 240×106in REPAIR-MI) was injected at was has
been identified as the optimal time point, i.e., at a median of 6.1 days
after infarction, a noticeable difference between these two conflicting
trials being the longer interval between symptom onset and revascu-
larizationintheSCAMIpatients(14.3 hoursversus4.5 hoursinREPAIR-
MI). However, a salient feature of the SCAMI protocol has been the
rigorousness of the blinding since the control preparation consisted of
autologous erythrocytes, which made the placebo syringes indistin-
strongly validates its conclusions. Although not yet published but
presented at the November 2008 American Heart Association Scientific
Sessions meeting, the French BONAMI trial was also reported to have
missed its primary end point.
Put together, these data clearly show that the potential benefit of
bone marrow-derived stem cell therapy shortly after acute myocar-
dial infarction still remains conflicting and the major lesson drawn
from this first wave of clinical studies is therefore that there is a real
need for a large, adequately powered trial incorporating some of the
key findings of the previous studies regarding cell preparation, dosing
and timing of delivery (see below) and focusing on clinically relevant
“hard” end points such as mortality, re-infarction and heart failure.
However, since it is difficult to claim intellectual property on
autologously derived MNC, there is little chance that industry may
be interested in getting involved and as such, public funding of such a
large, necessarily multicenter trial remains highly problematic.
This issue of intellectual property does not apply to mesenchymal
stem cells (MSC) which can be expanded according to proprietary
processes and have thus rapidly captured the attention of biotech
companies. Indeed, many of them are now claiming that they have
developed the “most effective” cell therapy product for “regenerative
medicine” but since thesciencebehindis often weak and because there
difficult to determine whether the different MSC subsets which have
undergone and still undergo clinical trials with the hope of rapid
marketing really reflect different cell fractions with distinct properties
or simply represent the same MSC population assessed at different
developmental stages and with the use of different surface markers. So
far, the major trial in this field has been the company-sponsored
randomized controlled double-blind dose-ranging trial (Provacel™
study) which has assessed the effects of injecting intravenously
allogeneic MSC in patients with acute myocardial infarction (34 and
19 patients in the treated and control groups, respectively). The major
finding of this study has been the documentation of the safety of the
procedure. Efficacy data are more questionable. After 6 months, the
in treated patients than in controls but these outcome measurements
did not differ significantly between the two groups . The major is
issue raised by the intravenous approach used in this study is the
expectedly low rate of cell homing due to trapping in the lungs and,
interestingly, a subsequent experimental study has shown that this
stem cell pulmonary sequestration was associated with the release of
to the alleged benefits of MSC . Whatsoever, the Provacel™ study is
use of readily available off-the-shelf MSC-based cell products which,
robust guarantees on batch consistency and functionality.
In the perspective of increasing myocardial homing of bone
marrow cells without relying on exogenous infusions, it has also
been proposed to use granulocyte colony-stimulating factor (G-CSF)
tostimulate bonemarrowcell mobilization.Despite someearly claims
of efficacy, the meta-analysis of randomized trials has failed to show
that this cytokine treatment provided a functional benefit, even
though subgroup analyses suggested some degree of improvement in
patients with the most pronounced LV dysfunctions and when
treatment was started early after the ischemic injury but with the
caveat that some of these “positive” studies apparently lacked a
blinded assessment . Overall, there is currently no evidence that
G-CSF provides any real additional benefit over best-of-care manage-
ment of patients with acute myocardial infarction.
The picture is different for patients with refractory angina who
have exhausted conventional revascularization therapies, most likely
because the restrictive objective is here to increase angiogenesis,
which can reasonably expected from the angiogenic growth factors
released by bone marrow cells and particularly by its CD34+fraction.
In this context, the most compelling evidence for the efficacy of cell
therapy has come from the randomized trial of catheter-based
endoventricular injections of CD34+progenitors sorted following G-
CSF-induced cell mobilization and apheresis, which has shown trends
in efficacy end points (angina frequency, nitroglycerine usage,
exercise time, Canadian Cardiovascular Society class) favouring
treatment versus placebo . A phase II b study is currently under
P. Menasche / Journal of Molecular and Cellular Cardiology 50 (2011) 258–265
way and will allow to determine whether these hints are confirmed or
not in a larger patient population. Another trial which has included a
similar group of patients with chronic ischemia refractory to medical
treatment and who were treated by endocardial injections of
unfractionated bone marrow-derived MNC has reached fairly similar
conclusions in that efficacy parameters improved to a consistently
greater extent in the treated arm than in the placebo cohort but
without significant differences between the two groups at the
different study points .
The third clinical scenario in which stem cell therapy has been
investigated is chronic heart failure. It should be recognized, from the
onset, that, again, the results have not matched the initial hopes. The
randomized, double-blind, placebo-controlled trial (MAGIC, an acro-
nym for Myoblast Autologous Grafting in Ischemic Cardiomyopathy)
included 97 patients with severe LV dysfunction who underwent
transepicardial injections of autologous skeletal myoblasts (at two
doses) or a placebo medium at the time of coronary artery bypass
grafting (CABG). At the 6-month study point, myoblast injections
failed to improve LV function beyond that seen in the placebo group,
even though the high dose group experienced a significant reduction
in LV volumes (which was a prespecified secondary end point) .
catheter have been more conflicting. Only Dib et al.  reported 1-
year improvements in quality of life and echocardiographically
measured LV dimensions but this series only included 12 treatment
subjects and 11 controls. In contrast, in the SEISMIC trial which has
included 14 patients with ischemic cardiomyopathy compared with
28 nonrandomized matched control patients, the 4-year results failed
so show a benefit of cell therapy on global and regional LV function
measured by contrast echocardiography and tissue Doppler imaging
(TDI) . Adjunct-to-coronary artery bypass grafting (CABG)
intramyocardial injections of bone marrow-derived MNC (reviewed
in ) havenotresulted in betteroutcomes,exceptfor twostudies in
which extremely high doses were used (see below). Despite some
enthusiastic claims, intracoronary delivery of MNC in patients with
ischemic  and nonischemic  cardiomyopathies still remains of
unproven efficacy and one can question the magnitude of transen-
dothelial trafficking and subsequent engraftment of intracoronarily
delivered cells at a time remote from the acute event, i.e., when
homing signals which may promote such trafficking have likely
subsided. Indeed, the most compelling evidence for a positive effect of
bone marrow-derived cellshas come from the studyof Stamm and co-
workers  in which epicardially injected CD133+cells during CABG
improved LV function and perfusion at 6 months postoperatively,
particularly in patients with the poorest preoperative LV function but
this effect is probably more related to the angiogenic potency of these
cells than to a de novo graft-derived myogenesis.
2. Major lessons drawn from early cardiac cell therapy trials
2.1. Procedural aspects need to be fine-tuned and better standardized
These aspects encompass the method of cell processing, dosing,
timing and route for cell delivery.
Regarding cell processing, there are no real issues with skeletal
myoblasts because it is well established since the initial phase I trials
that the muscle biopsy can be cultured and scaled-up under good
manufacturing practice (GMP) conditions so as to yield several
hundred million cells in a 2- to 3-week period with a high degree of
viability and myogenic purity. Paradoxically, the case of bone
marrow-derived cells is still more controversial because even though
the extemporaneous centrifugation of the harvested bone marrow to
collect the mononuclear fraction is supposed to be a straightforward
procedure, differences in the centrifugation methods that have been
implemented (Ficoll and Lymproprep) may affect cell function to the
point that they have been linked to the divergent outcomes of clinical
trials . In addition, the degree of red blood cell  and platelet
 contamination of the MNC yield has also been identified as
additional factors influencing the final phenotype and functional
quality of the cell preparation. Put together, these findings call for the
development of robust, consistent and reproducible cell processing
protocols allowing both to optimize cell functionality and to reduce
variability among clinical trials. They also raise the question of the
appropriate controls and, at least in the setting of experimental
studies, it might be more accurate to use preparations of erythrocytes
(like in the previously mentioned SCAMI  trial) or platelet-derived
microparticles instead of the conventional saline to specifically assess
the effects of the unfractionated MNC fraction. In the more limited
number of studies which have entailed the use of select progenitors
(CD34+or CD133+), immunomagnetic sorting has proven to be
reliable, which is not unexpected in view of the long-standing
experience with these procedures in hematology. Finally, isolation
and expansion of bone marrow-derived mesenchymal stem cells
(MSC) are also relatively easy to accomplish with the caveat of a
potential risk of phenotypic changes and karyotypic abnormalities
that may develop with repeat passaging even though the significance
of these alterations and their potential impact on the final outcome
Despite the huge variability in cell doses that have been used
clinically, some findings emerge that point out to some dose–effect
relationship. Thus, in the MAGIC trial, only patients injected with 800
million skeletal myoblasts incurred significant reductions in LV
volumes compared with those of the low-dose (400 million) and
controlgroups.Inthemeta-analysis ofBMCin patientswithacute
myocardial infarction, statistically significant differences favouring
the treatment groups were only seen when the number of injected
cells exceeded 108. These findings are in line with the observation
that in surgical studies which have tested intramyocardial injections
of MNC in conjunction with CABG, positive outcomes were only seen
those in which the highest doses (6.59×108 and 1.29×109MNC
 were used whereas dosing ranged between 60 and 292 million in
the negative trials . In contrast, no dose–effect relationship could
be identified in the trials of CD34+ and MSC , but this
conclusion should be compounded by the fact that only a small
number of patients were included per dose group. Thus, the overall
message emerging from the bulk of reported data is that cell number
is likely oneof the factors associated with a successful outcome,which
calls attention to the importance of further improving cell scale-up
Like dosing, timing of bone marrow cell delivery in patients with
acute infarction has varied from a few hours to several days after
revascularization in the first generation of clinical trials. Using
radiolabeled progenitor cells, Schächinger et al.  have assessed
cell homing at different time points and showed a decay over time as
the average activity within the first 24 hours of cell infusion was
highest among patients with acute myocardial infarction of or less
than 14 days of age and declined thereafter, most likely because of the
reduced expression of chemoattractive cytokines. These data are on
line with the findings of the REPAIR-MI trial showing that the
beneficial effects of BMC on contractile function were limited to
patients who were given cells more than 4 days after the percutane-
ous intervention . Additional support for a relatively early
implementation of intracoronary BMC infusion is provided by the
meta-analysis of Martin-Rendon et al.  where subgroup analysis
revealed a significant difference in LVEF in favour of bone marrow
cell-treated groups when patients were treated within 7 days fol-
Finally, it is not unexpected that direct intramyocardial cell
injections allow a greater retention of the cells compared with
intracoronary or systemic approaches , which may account for the
factthatthis route is associated withsuperior functional improvements
. However, at the acute stage of infarction, only the intracoronary
P. Menasche / Journal of Molecular and Cellular Cardiology 50 (2011) 258–265
route seems reasonably feasible and efforts should thus be directed at
in patients withchronic disease amenable to elective procedures, direct
catheter-based or surgical epicardial injections should probably be
preferred. This issue will hopefully be clarified by the REGEN-IHD trial
which compares the transendocardial and intracoronary routes of cell
delivery in patients with chronic ischemic heart failure.
Thus, the major lessons drawn from early-phase trials regarding
procedural aspects are that high doses of cells generated by standard-
ized techniques should be delivered relatively early after infarct and
To put these lessons in perspective, it is also important to remind that
multiply tests designed to accurately qualify cell therapy products
which are not prepared on the point of care, particularly from the
standpoints of raw material characterization and traceability, maximal
avoidance of animal-derived products, potential viral contamination,
potency, purity and genetic stability. The implementation of validated
and quality-assured traceability processes during manufacturing and
shipment is now also required along with laboratory testing of the
compatibility of cells with the device used for their delivery. Put
together, these constraints end up to a stringent definition of the cell
of being approved for clinical use, a cell therapy program needs to be
realisticallyframed in such a waythat thefinal cell product will address
these multiple hurdles. Academic investigators have thus been
increasingly aware that an early dialogue with the regulatory admin-
istrators was mandatory to ensure that guidelines would be appropri-
trials is now that their design has progressively moved closer to that of
biologics and tissues cannot be assimilated to the more straightforward
receptor-ligand coupling which characterizes the traditional pharma-
2.2. Cardiac cell therapy is overall safe
In surgical studies where cells have been injected with hand-held
syringes directly in the myocardium, no bleeding complications have
been reported. Catheter-based endocardial injections have been
equally safe without an increased risk of in-stent restenosis. Likewise,
there has been no report of cell-derived tumor formation in the
myocardium or elsewhere. This is clinically relevant as the longest
follow-up periods now span almost 10 years.
Indeed, the major safety associated with cardiac cell therapy has
been the occurrence of sustained ventricular arrhythmias in some of
the patients injected with skeletal myoblasts . The prevailing
hypothesis is that failure of differentiated myotubes to express gap
junction proteins resulted in electrically insulated cell clusters which
could slow the conduction velocity of electrical impulses and
consequently predispose to reentry circuits . Support for this
hypothesis has come from co-culture experimental data showing that
myoblast transfection with connexin 43 actually decreased arrhyth-
mogenicity . However in the randomized controlled trial of
myoblast transplantation where all patients were instrumented with
an internal cardioverter-defibrillator (ICD), the proportion of those
experiencing ventricular arrhythmias at the 6-month follow-up study
point did not differ significantly between the control and treated
groupseven thoughthelatter tendedto havemore clusteredevents in
the early postoperative period. It is therefore likely that aside
from the cell type, other factors contribute to cell-associated
ventricular arrhythmias, which include needle-induced disruption of
myocardial tissue and the associated inflammatory damage , graft
size , the location of cell injections (myoblasts injected in the core
of the scar seem less arrhythmogenic than those lining the border
zone), graft–host mismatches in cell size, shape and alignment,
possible cell-induced sympathetic hyperinnervation and the intrinsi-
cally arrhythmogenic nature of the underlying heart failure .
Thus, with regard to safety, an important lesson drawn from the
early wave of clinical trials is that the risk of ventricular arrhythmias
must not be underscored, and this might become even more relevant
if, in the future, cardiac-committed progenitor cells are to be used
because their relative immaturity may increase the risk of action
potential mismatch with the adult host cardiomyocytes and that of
persistent automaticity. It appears thus that usual methods for
tracking arrhythmic events like EKGs or 24-Holter monitoring may
not be reliable enough and that future clinical protocols should
incorporate more sensitive techniques such as implantable event
recorders or ICDs with appropriate arrhythmia detection settings .
This is particularly important if one keeps in mind that the good safety
record of cardiac cell therapy may be currently biased by the absence
of sustained engraftmentof the transplanted cells. Should we succeed,
in the future, to enhance cell survival over time, the safety issues,
including the risk of arrhythmias, will need to be reassessed to ensure
that the engrafted cells do not cause delayed adverse effects.
Finally, lessons pertaining to safety cannot ignore the report of a
multifocal brain tumor in a child with ataxia telangiectasia who had
been treated 4 years earlier with intracerebellar and intrathecal
injection of poorly characterized human fetal neural stem cells .
Two apparently opposite lessons can be drawn from this complica-
tion: the first is that it is critical to have an accurate characterization of
the cell therapy product; the second is that, paradoxically, the
regulatory constraints should not be pushed too far because the risk
is then that desperate patients look for stem cell therapies in poorly
regulated foreign countries where inappropriate treatments may
result is severe adverse events which could set the complete field
back. The optimal trade-off still needs to be found.
2.3. The cell type needs to be tailored to the primary clinical indication
What is clearly apparent from the initial bulk of clinical studies is
that the popular “one size fits all” cannot be applied to cell therapy.
In patients with acute myocardial infarction, two major practical
constraints (an almost immediate availability of the cell product and a
cell size compatible with a safe intracoronary infusion) have largely
dictated the choice of bone marrow-derived cells. The major objective
assigned to the cells in this setting is to prevent late remodelling
which has long been identified as a predictor of a poor outcome. It is
sound to hypothesize that the growth factors and cytokines released
by bone marrow-derived cells may boost endogenous reparative
pathways, limit apoptosis of jeopardized cardiomyocytes or favour-
ably change the elastic properties of the scar in such a way that the
ultimate result may be a reduction in ventricular dilation [34–36].
However,weare still waiting unequivocal evidencethatthiscan occur
in humans and this end point should probably be central to the next
generation of clinical trials. Having admitted that bone marrow-
derived cells will likely not transdifferentiate into cardiomyocytes but
may still may exert paracrine beneficial effects , it remains to
determine which population should be preferentially used and, in a
probably longer term perspective, whether secretome analyses of
these populations will allow identification of key soluble factors that
could be used therapeutically by their own [38,39]. Some will argue
that it makes sense to draw maximal benefits from subsets of cells
endowed with a high secretory profile (CD34+, CD133+, endothelial
progenitors, MSC) but others will consider that our ignorance about
the “best” fraction makes legitimate to use a mixed population to take
advantage of the expected cross-talks between different cell types.
Head-to-head comparisons such as that of the TAC-HFT trial (which
comparestransendocardially delivered “bonemarrowcells”andMSC)
should help clarifying this issue. Aside from bone marrow cells,
adipose cells are also currently considered with the similar premise
that they should release a blend of trophic factors . The industry-
P. Menasche / Journal of Molecular and Cellular Cardiology 50 (2011) 258–265
sponsored APOLLO trial has recently investigated these cells,
harvested by liposuction, processed at the point of care by a dedicated
presented orally at a recent stem cell meeting have documented that
this approach was both feasible and safe. Efficacy now needs to be
more convincingly demonstrated.
Indeed, data from early trials have yielded three important
lessons: (1) the greatest benefits of stem cell therapy seem to occur
in patients who present with the greatest infarct-induced myocardial
damage identified by severely decreased post-revascularization LVEF
(even though the cutoff point remains uncertain, the median value
ranging from 37% to 62% in the studies) or a high degree of infarct
transmurality [20,41,42]. This has major implications for the design of
future studies which will likely maximize their chances of success by
restricting inclusions to this patient cohort, knowing, however, that
the current management of myocardial infarction in developed
countries has drastically reduced the number of these patients; (2)
dose and timing of injection matter, as previously discussed above,
and (3) the great variability in the functionality of bone marrow cells
retrieved from patients with risk factors of atherosclerosis needs to be
fixed to allow delivery of a consistent, controlled and reproducible
product, which may give advantage to allogeneic cells (also discussed
in one of the following sections).
This paracrine line of reasoning can be similarly applied to patients
with refractory angina in whom the primary target is to increase
angiogenesis, an objective which can theoretically be met by the
multiple angiogenic mediators released by bone marrow cells .
from acute events, offers more flexibility about the cell type (for
and the route of delivery since the possibility of endocardial injections
The issue of heart failure is different since theparadigm, here, is that
cells are used in a replacement setting to replenish myocardial tissue
lost after infarction as their paracrine effects are likely not sufficient to
induce a true “regeneration” of the scar. This probably accounts for the
endowed with a cardiomyogenic differentiation potential which will
a coordinated fashion, as these are the prerequisites for transplanted
cells to meaningfully improve heart function. Despite the interest they
currently generate, MSC derived from bone marrow or fat tissue are
these cells are unable to convert into structurally and functionally
integrated new cardiomyocytes , with the possible exception of
those currently investigated in a trial where they are pre-treated by
growth factors intended to reproduce key steps of the natural
cardiopoiesis . Actually, this category of cardiac-specified cells
includes cardiac stem cells , which despite the uncertainty still
surrounding their persistence in adult diseased human hearts  are
yet the subject of two ongoing phase I clinical trials, and cardiac
progenitors committed from pluripotent cells derived from embryonic
cell types raises specific ethical, procurement, processing and safety
issues the discussion of which is beyond the scope of this review.
Tackling these various problems is undoubtedly a tough task but will
likely determine directly whether the myth of cardiac regeneration can
be translated into a clinical reality.
2.4. Autologous cell therapy products have serious limitations
Most of the clinical experience accumulated so far has dealt with
autologous cells. While the advantages of this tissue source related to
availability and immune tolerance are well known, an important lesson
drawn from this first decade of clinical cell therapy has also been to
increasingly recognize the drawbacks associated with patient-specific
the treatment relies on a core manufacturing facility and cost of
customized quality controls, the greatest limitation is the wide inter-
patient variability in cell functionality. This issue is particularly relevant
to the use of bone marrow cells the function of which is affected by
advanced age  and the risk factors of atherosclerosis [51,52], which
the treatment outcome  and the divergent results of several clinical
trials likely reflect the fact that the seemingly similar phenotype of
infused cells actually encompassed varying degrees of functionality.
These findings have progressively led to consider that allogeneic
tissue sources would likely be required to upgrade cells to the level of a
“product”. Not unexpectedly, a banking model whereby allogeneic cells
large number of patients has progressively been identified as a more
attractive business model which has rapidly captured the interest of
biotech companies (a recent marker report indicated that among cell
therapy products currently undergoing clinical trials for various
diseases, not restrictedtothe heart, already 37% were of nonautologous
origin). Clearly, the main advantage of this approach is that the
functional variability of autologous cells is alleviated by preparing a
master bank of validated fully tested clinical-grade cells from which a
working bank is established and then allows a well-qualified off-the-
shelf product to be readily available. The obvious disadvantage is the
this hurdle, MSC have gained an increased interest because of a
purported immune privilege attributed to their lack of major histocom-
patibility complex (MHC) class II and co-stimulatory molecules, the
suppressive phenotype and indirectly by interfering with dendritic cell
maturation) and the secretion of soluble mediators which induce a
allogeneic banked MSC in patients with acute myocardial infarction 
and other industry-sponsored studies are under way in patients with
It is fair however to acknowledge that the immune privilege of MSC is
cells to become cardiomyocytes structurally integrated into the
myocardium, their rejection may not be an issue if it is delayed enough
Another issue related to MSC is the optimal route of their delivery. We
have previously mentioned that homing of intravenously infused cells
of the spleen and lung filters. Direct endoventricular injections allow
early higher engraftment rates but are primarily suitable for patients
in whom the intracoronary route is the only available, MSC have raise
safety concerns related to their size although this problem seems to be
addressed by an appropriate cell dosing and a bracketing of the
procedure by a robust anti-thrombotic therapy .
Thus, an important lesson is the potential benefit of allogeneic cell
products which emphasizes the need for bringing into the field
immunologists whose expertise is eagerly awaited for help control-
ling the potential allorejection inherent in their use.
2.5. Regardless of the cell type, cell therapy will remain suboptimally
efficacious until engraftment techniques are optimized
It is now widely documented that engraftment of delivered cells is
poor. This low rate of sustained cell retention is the result of two
P. Menasche / Journal of Molecular and Cellular Cardiology 50 (2011) 258–265
temporally distinct events. First, the initial transfer of cells is in-
efficient in that the actual number of cells delivered to the myo-
cardium relative to that present in the syringe is distressingly low
because of the magnitude of cell losses which occur through multiple
mechanisms (leakage through transepicardial puncture holes, wash-
out through the venous system, squeezing of cells by the heartbeats).
Subsequently, a huge number of the cells that have been initially
retained die, also because of multiple causes (ischemia inherent in the
poor vascularization of the target areas, apoptosis subsequent to the
loss of cell anchorage to their matrix, immune destruction of cells of
allogeneic origin). Even though one admits that cells will predomi-
nantly act through paracrine mechanisms and do not necessarily need
to be permanently present as if they were to structurally integrate
within the recipient myocardium, at least a minimal graft size is
initially required for providing some therapeutic benefits. This is well
demonstrated by the relationship between the engraftment rate and
the improvement in LV function . The human imaging studies
showing that only 2–5% of unselected MNC infused into the coronary
arteries are retained in the myocardium after a few hours  clearly
emphasize the clinical relevance of the problem, even though, as
previously mentioned,the timedependency of homingmay resultin a
greater retention of cells if they are delivered shortly after the acute
ischemic event .
A detailed discussion of the strategies that can be implemented to
address the issues of cell transfer and survival is beyond the scope of
this paper. The general guideline is that these strategies should be as
simple, safe and user-friendly as possible to be realistically approvable
by the regulatory agencies and widely implemented by clinicians. In
brief, if cells are to be injected directly into the coronary arteries,
catheters allowing a perivascular delivery of cells may afford a greater
initial intramyocardial retention . If an intravenous approach is
planned, driving cells towards the site of injury might be safer and
easier to accomplish by physical methods like low-energy shock wave
(currently tested clinically in the CELLWAVE trial), focused ultra-
sound-mediated destruction of microbubbles  or magnetic
targeting  than by genetic engineering targeted at increasing the
expression of homing signals (SDF-1/CXCR4) in the injected cells or
the target tissue [61,62]. Enhancement of subsequent survival should
be optimized in parallel. Although pretreatment of cells to increase
their resistance by heat shock  or pharmacologic preconditioning
 could be realistically implemented in practice, co-transplantation
of cells featuring an angiogenic potential  and incorporation of
cells in three-dimensional scaffolds [66,67] are particularly appealing
for counteracting ischemia and apoptosis, respectively. This scaffold-
based approach might find elective applications in cardiac surgery
which offers the possibility of a fast and atraumatic epicardial
coverage with a cellularized bioresorbable patch [68–70]. Thus, an
important lesson is that like the previously mentioned immunolo-
gists, bioengineers and experts in biomaterials should now be fully
integrated into the groups working on cell therapy.
2.6. Trial end points may need to be revisited
So far, EF has usually been the gold standard for assessing
outcomes in the first generation of clinical trials, regardless of the
method on which its calculation was based (echocardiography,
angiography, radionuclide imaging or magnetic resonance imaging
which is likely the most reliable but may not be always possible
because of a previously implanted ICD). There is mounting evidence
thatchangesin EF may notbe themost suitedcriteria for assessingthe
effectsof cell therapy.Indeed,basedonthe accumulated experience,it
should be possible to consider, in the future, two distinct categories of
trials. In those exploring a new cell type in a limited number of
patients, measurements in regional geometryand function with state-
of-the-art imaging modalities may be more useful than global assess-
ments for establishing the proof of concept and providing mechanistic
cues. Conversely, forthosecellswhich,like thoseofbonemarrow,
have already been extensively investigated, well-powered random-
ized double-blind outcome trials focusing on hard clinically mean-
ingful end points (primarily death and rehospitalisation for heart
failure) assessed by external core committees seem to be justified if
one wants to really determine the place, if any, of cell transplantation
in the routine treatment of cardiac diseases. One of the issues, though,
is that funding of such large studies is very difficult if cells are
autologous because the lack of intellectual property is likely to
prevent an involvement of private companies.
To close, it is worth reminding that injury models used in rodents
cannot faithfully mimic the complex physiopathology of human
diseases, a first reason being that they feature such a thin fibrous wall
that any cell type can elicit beneficial effects simply by increasing the
chamber wall mass and subsequently improving function by
decreasing wall stress. Moving to large animal models before
extrapolating data collected in rats and mice to humans is therefore
mandatory even though the discrepancy between the often positive
results yielded by sheep or pig experiments and the marginal or
transient effects of cell therapy seen in patients indicates that even
these models are not fully predictive of clinical success. This is
certainly the last, but not the least, lesson drawn from this first decade
of cell therapy trials. It calls for humility,implementation of a constant
bench-to-bedside roundtrip and commitment to consider that cells,
regardless of what they are, are unlikely to be therapeutically
successful if the strategy does not integrate them within their
necessary vascular and matrix support. Hopefully, some of these
lessons may serve as a building block whose incorporation in the
design of second-generation trials will help making them more
No conflict of interest to disclose.
 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;29:1807–18.
 Udelson JE,Konstam MA.Relation between left ventricular remodeling and clinical
outcomes in heart failure patients with left ventricular systolic dysfunction. J Card
 Schächinger V, Erbs S, Elsässer A, Haberbosch W, Hambrecht R, Hölschermann H,
et al. Intracoronary bone marrow-derived progenitor cells in acute myocardial
infarction. N Engl J Med 2006;355:1210–21.
 Assmus B, Rolf A, Erbs S, Elsässer A, Haberbosch W, Hambrecht R, et al. REPAIR-
AMI Investigators. Clinical outcome 2 years after intracoronary administration of
bone marrow-derived progenitor cells in acute myocardial infarction. Circ Heart
 van der Laan A, Hirsch A, Nijveldt R, van der Vleuten PA, van der Giessen WJ,
Doevendans PA, et al. Bone marrow cell therapy after acute myocardial infarction:
the HEBE trial in perspective, first results. Neth Heart J 2008;16:436–9.
 Tendera M, Wojakowski W, Ruzyłło W, Chojnowska L, Kepka C, Tracz W, et al.
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 2009;30:1313–21.
 Huikuri HV, Kervinen K, Niemelä M, Ylitalo K, Säily M, Koistinen P, et al. Effects of
intracoronary injection of mononuclear bone marrow cells on left ventricular
function, arrhythmia risk profile, and restenosis after thrombolytic therapy of
acute myocardial infarction. Eur Heart J 2008;29:2723–32.
 Wöhrle J, Merkle N, Mailänder V, Nusser T, Schauwecker P, von Scheidt F, et al.
Results of intracoronary stem cell therapy after acute myocardial infarction. Am J
double-blind, placebo-controlled, dose-escalation study of intravenous adult human
mesenchymal stem cells (prochymal) after acute myocardial infarction. J Am Coll
 Lee RH, Pulin AA, Seo MJ, Kota DJ, Ylostalo J, Larson BL, et al. Intravenous hMSCs
improve myocardial infarction in mice because cells embolized in lung are
activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell 2009;5:
P. Menasche / Journal of Molecular and Cellular Cardiology 50 (2011) 258–265
 Abdel-Latif A, Bolli R, Zuba-Surma EK, Tleyjeh IM, Hornung CA, Dawn B.
Granulocyte colony-stimulating factor therapy for cardiac repair after acute
myocardial infarction: a systematic review and meta-analysis of randomized
controlled trials. Am Heart J 2008;156:216–26.
 Losordo DW, Schatz RA, White CJ, Udelson JE, Veereshwarayya V, Durgin M, et al.
Intramyocardial transplantation of autologous CD34+ stem cells for intractable
 van Ramshorst J, Bax, Jeroen J, Dibbets-Schneider P, Roes SD, Stokkel MP, et al.
Intramyocardial bone marrow cell injection for chronic myocardial ischemia: a
randomized controlled trial. JAMA 2009;301:1997–2004.
 Menasché Ph, Alfieri O, Janssens S, McKenna W, Reichenspurner H, Trinquart L,
et al. The Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC)
Trial. First randomized placebo-controlled study of myoblast transplantation.
 Dib N, Dinsmore J, Lababidi Z, White B, Moravec S, Campbell A. One-year follow-
up of feasibility and safety of the first U.S., randomized, controlled study using 3-
dimensional guided catheter-based delivery of autologous skeletal myoblasts
for ischemic cardiomyopathy (CAuSMIC study). JACC Cardiovasc Interv 2009;2:
 Veltman CE, Soliman OI, Geleijnse ML, Vletter WB, Smits PC, ten Cate FJ, et al. Four-
year follow-up of treatment with intramyocardial skeletal myoblasts injection in
patients with ischaemic cardiomyopathy. Eur Heart J 2008;29:1386–96.
 Menasche P. Cell-based therapy for heart disease: a clinically oriented perspective.
Mol Ther 2009;17:758–66.
 Strauer BE, Brehm M, Zeus T, Bartsch T, Schannwell C, Antke C, et al. Regeneration
of human infarcted heart muscle by intracoronary autologous bone marrow cell
transplantation in chronic coronary artery disease: the IACT Study. J Am Coll
 Fischer-Rasokat U, Assmus B, Seeger FH, Honold J, Leistner D, Fichtlscherer S, et al. A
pilot trial to assess potential effects of slective intra-coronary bone marrow-derived
progenitor cell infusion in patients with nonischemic dilated cardiomyopathy: final
1-year results of the TOPCARE-DCM trial. Circ Heart Fail 2009;2:417–23.
 Stamm C, Kleine HD, Choi YH, Dunkelmann S, Lauffs JA, Lorenzen B, et al.
Intramyocardial delivery of CD133+ bone marrow cells and coronary artery
bypass grafting for chronic ischemic heart disease: safety and efficacy studies. J
Thorac Cardiovasc Surg 2007;133:717–25.
 Seeger FH, Tonn T, Krzossok N, Zeiher AM, Dimmeler S. Cell isolation procedures
matter: a comparison of different isolation protocols of bone marrow mononu-
clear cells used for cell therapy in patients with acute myocardial infarction. Eur
Heart J 2007;28:766–72.
 Assmus B, Tonn T, Seeger FH, Yoon CH, Leistner D, Klotsche J, et al. Red blood cell
contamination of the final cell product impairs the efficacy of autologous bone
marrow mononuclear cell therapy. J Am Coll Cardiol 2010;55:1385–94.
 Prokopi M, Pula G, Mayr U, Devue C, Gallagher J, Xiao Q, et al. Proteomic analysis
reveals presence of platelet microparticles in endothelial progenitor cell cultures.
 Zhao Q, Sun Y, Xia L, Chen A, Wang Z. Randomized study of mononuclear bone
marrow cell transplantation in patients with coronary surgery. Ann Thorac Surg
 Akar AR, Durdu S, Arat M, Kilickap M, Kucuk NO, Arslan O, et al. Five-year follow-
up after transepicardial implantation of autologous bone marrow mononuclear
cells to ungraftable coronary territories for patients with ischaemic cardiomyop-
athy. Eur J Cardiothorac Surg 2009;36:633–43.
 Schächinger V,Aicher A, Döbert N, Röver R, Diener J, Fichtlscherer S, et al. Pilot trial
on determinants of progenitor cell recruitment to the infarcted human
myocardium. Circulation 2008;118:1425–32.
 Freyman T, Polin G, Osman H, Crary J, Lu M, Cheng L, et al. A quantitative,
randomized study evaluating three methods of mesenchymal stem cell delivery
following myocardial infarction. Eur Heart J 2006;27:1114–22.
 Brunskill SJ, Hyde CJ, Doree CJ, Watt SM, Martin-Rendon E. Route of delivery and
baseline left ventricular ejection fraction, key factors of bone-marrow-derived cell
therapy for ischaemic heart disease. Eur J Heart Fail 2009;11:887–96.
 Abraham MR, Henrikson CA, Tung L, Chang MG, Aon M, Xue T, et al.
Antiarrhythmic engineering of skeletal myoblasts for cardiac transplantation.
Circ Res 2005;97:159–67.
 Fukushima S, Varela-Carver A, Coppen SR, Yamahara K, Felkin LE, Lee J, et al. Direct
intramyocardial but not intracoronary injection of bone marrow cells induces
ventricular arrhythmias in a rat chronic ischemic heart failure model. Circulation
 Soliman AM, Krucoff MW, Crater S, Morimoto Y, Taylor DA. Cell location may be a
primary determinant of safety after myoblast transplantation into the infarcted
heart. J Am Coll Cardiol 2004;43:15A [abstract].
 Chen HS, Kim C, Mercola M. Electrophysiological challenges of cell-based
myocardial repair. Circulation 2009;120:2496–508.
 Amariglio N, Hirshberg A,Scheithauer BW, Cohen Y, Loewenthal R, Trakhtenbrot L,
et al. Donor-derived brain tumor following neural stem cell transplantation in an
ataxia telangiectasia patient. PLoS Med 2009;6:e1000029.
 Uemura R, Xu M, Ahmad N, Ashraf M. Bone marrow stem cells prevent left
ventricular remodeling of ischemic heart through paracrine signaling. Circ Res
 Dai Y, Ashraf M, Zuo S, Uemura R, Dai YS, Wang Y, et al. Mobilized bone marrow
progenitor cells serve as donors of cytoprotective genes for cardiac repair. J Mol
Cell Cardiol 2008;44:607–17.
 Kinnaird T, Stabile E, Burnett MS, Lee CW, Barr S, Fuchs S, et al. 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;94:678–85.
 Cho HJ, Lee N, Lee JY, Choi YJ, Ii M, Wecker A, et al. Role of host tissues for sustained
humoral effects after endothelial progenitor cell transplantation into the ischemic
heart. J Exp Med 2007;204:3257–69.
of myocardial infarct size by human mesenchymal stem cell conditioned medium.
Stem Cell Res 2007;1:129–37.
 Lai RC, Arslan F, Lee MM, Sze NS, Choo A, Chen TS, et al. Exosome secreted by
MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res 2010;4:
 Rehman J, Traktuev D, Li J, Merfeld-Clauss S, Temm-Grove CJ, Bovenkerk JE, et al.
Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells.
 Miettinen JA, Ylitalo K, Hedberg P, Jokelainen J, Kervinen K, Niemelä M, et al.
Determinants of functional recovery after myocardial infarction of patients
treated with bone marrow-derived stem cells after thrombolytic therapy. Heart
 Schaefer A, Zwadlo C, Fuchs M, Meyer GP, Lippolt P, Wollert KC, et al. Long-term
effects of intracoronary bone marrow cell transfer on diastolic function in patients
after acute myocardial infarction: 5-year results from the randomized-controlled
BOOST trial–an echocardiographic study. Eur J Echocardiogr 2010;11:165–71.
 Valina C, Pinkernell K, Song YH, Bai X, Sadat S, Campeau RJ, et al. Intracoronary
administration of autologous adipose tissue-derived stem cells improves left
ventricular function, perfusion, and remodelling after acute myocardial infarction.
Eur Heart J 2007;28:2667–77.
 Caplan AI, Dennis JE. Mesenchymal stem cells as trophic mediators. J Cell Biochem
 Bartunek J, Croissant JD, Wijns W, Gofflot S, de Lavareille A, Vanderheyden M, et al.
Pretreatment of adult bone marrow mesenchymal stem cells with cardiomyo-
genic growth factors and repair of the chronically infarcted myocardium. Am J
Physiol Heart Circ Physiol 2007;292:H1095–104.
 Bearzi C, Rota M, Hosoda T, Tillmanns J, Nascimbene A, De Angelis A, et al. Human
cardiac stem cells. Proc Natl Acad Sci USA 2007;104:14068–73.
 Pouly J, Bruneval P, Mandet C, Proksch S, Peyrard S, Amrein C, et al. Cardiac stem
cells in the real world. J Thorac Cardiovasc Surg 2008;135:673–8.
 Blin G, Nury D, Stefanovic S, Neri T, Guillevic O, Brinon B, et al. A purified
population of multipotent cardiovascular progenitors derived from primate
pluripotent stem cells engrafts in postmyocardial infarcted nonhuman primates.
J Clin Invest 2010;120:1125–39.
 Nelson TJ, Martinez-Fernandez A, Yamada S, Perez-Terzic C, Ikeda Y, Terzic A.
Repair of acute myocardial infarction with induced pluripotent stem cells Induced
by human stemness factors. Circulation 2009;120:408–16.
 Li TS, Kubo M, Ueda K, Murakami M, Mikamo A, Hamano K. Impaired angiogeneic
potency of bone marrow cells from patients with advanced age, anemia and renal
failure. J Thorac Cardiovasc Surg 2010;139:459–65.
 Kissel CK, Lehmann R, Assmus B, Aicher A, Honold J, Fischer-Rasokat U, et al.
Selective functional exhaustion of hematopoietic progenitor cells in the bone
marrow of patients with postinfarction heart failure. J Am Coll Cardiol 2007;49:
 Sorrentino SA, Bahlmann FH, Besler C, Muller M, Schulz S, Kirchhoff N, et al.
Oxidant stress impairs in vivo reendothelialization capacity of endothelial
progenitor cells from patients with type 2 diabetes mellitus: Restoration by the
peroxisome proliferator-activated receptor-gamma agonist rosiglitazone. Circu-
 Assmus B, Fischer-Rasokat U, Honold J, Seeger FH, Fichtlscherer S, Tonn T, et al.
TOPCARE-CHD Registry. Transcoronary transplantation of functionally competent
BMCs is associated with a decrease in natriuretic peptide serum levels and
improved survival of patients with chronic postinfarction heart failure: Results of
the TOPCARE-CHD Registry. Circ Res 2007;100:1234–41.
 Ryan JM, Barry FP, Murphy JM, Mahon BP. Mesenchymal stem cells avoid
allogeneic rejection. J Inflamm (Lond) 2005;2:8.
 Uccelli A, Pistoia V, Moretta L. Mesenchymal stem cells: a new strategy for
immunosuppression? Trends Immunol 2007;28:219–26.
 Poncelet AJ, Vercruysse J, Saliez A, Gianello P. Although pig allogeneic
mesenchymal stem cells are not immunogenic in vitro, intracardiac injection
elicits an immune response in vivo. Transplantation 2007;83:783–90.
 Cheng K, Li TS, Malliaras K, Davis D, Zhang Y, Marbán E. Magnetic targeting
enhances engraftment and functional benefit of iron-labeled cardiosphere-
derived cells in myocardial infarction. Circ Res 2010 April8. Electronic Publication.
 Hofmann M, Wollert KC, Meyer GP, Menke A, Arseniev L, Hertenstein B, et al.
Monitoring of bone marrow cell homing into the infarcted human myocardium.
 Wang X, Jameel MN, Li Q, Mansoor A, Qiang X, Swingen C, et al. Stem cells for
myocardial repair with use of a transarterial catheter. Circulation 2009;120(11
 Ghanem A, Steingen C, Brenig F, Funcke F, Bai ZY, Hall C, et al. Focused ultrasound-
induced stimulation of microbubbles augments site-targeted engraftment of mesen-
chymal stem cells after acute myocardial infarction. J Mol Cell Cardiol 2009;47:411–8.
 Cheng Z, Ou L, Zhou X, Li F, Jia X, Zhang Y, et al. Targeted migration of
mesenchymal stem cells modified with CXCR4 gene to infarcted myocardium
improves cardiac performance. Mol Ther 2008;16:571–9.
 Elmadbouh I, Haider HKh, Jiang S, Idris NM, Lu G, Ashraf M. Ex vivo delivered
stromal cell-derived factor-1alpha promotes stem cell homing and induces
angiomyogenesis in the infarcted myocardium. J Mol Cell Cardiol 2007;42:
P. Menasche / Journal of Molecular and Cellular Cardiology 50 (2011) 258–265
 Zhang M, Methot D, Poppa V, Fujio Y, Walsh K, Murry CE. Cardiomyocyte grafting
for cardiac repair: graft cell death and anti-death strategies. J Mol Cell Cardiol
 Niagara MI, Haider HKh, Jiang S, Ashraf M. Pharmacologically preconditioned
skeletal myoblasts are resistant to oxidative stress and promote angiomyogenesis
via release of paracrine factors in the infarcted heart. Circ Res 2007;100:545–55.
 Winter EM, van Oorschot AAM, Hogers B, van der Graaf LM, Doevendans PA,
Poelmann RE, et al. A new direction for cardiac regeneration: application of
synergistically acting epicardium-derived cells and cardiomyocyte progenitor
cells. Circ Heart Fail 2009;2:643–53.
 Zhang G, Hu Q, Braunlin EA, Suggs LJ, Zhang J. Enhancing efficacy of stem cell
 Padin-Iruegas ME, Misao Y, Davis ME, Segers VF, Esposito G, Tokunou T, et al.
Cardiac progenitor cells and biotinylated insulin-like growth factor-1 nanofibers
improve endogenous and exogenous myocardial regeneration after infarction.
 Zimmermann WH, Melnychenko I, Wasmeier G, Didié M, Naito H, Nixdorff U, et al.
Engineered heart tissue grafts improve systolic and diastolic function in infarcted
rat hearts. Nat Med 2006;12:452–8.
 Hamdi H, Furuta A, Bellamy V, Bel A, Puymirat E, Peyrard S, et al. Cell delivery:
intramyocardial injections or epicardial deposition? A head-to-head comparison.
Ann Thorac Surg 2009;87:1196–203.
 Stevens KR, Kreutziger KL, Dupras SK, Korte FS, Regnier M, Muskheli V, et al.
Physiological function and transplantation of scaffold-free and vascularized
human cardiac muscle tissue. Proc Natl Acad Sci USA 2009;106:16568–73.
 Herbots L, D'hooge J, Eroglu E, Thijs D, Ganame J, Claus P, et al. Improved regional
function after autologous bone marrow-derived stem cell transfer in patients with
acute myocardial infarction: a randomized, double-blind strain rate imaging
study. Eur Heart J 2009;30:662–70.
P. Menasche / Journal of Molecular and Cellular Cardiology 50 (2011) 258–265