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CONTROVERSIES IN
CARDIOVASCULAR MEDICINE
Is stem cell therapy ready for patients?
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
From the Department of Medicine, Division of Cardiology, Institute for Cell Engineering, and Specialized Center for Cell-Based Therapy, The Johns
Hopkins University School of Medicine, Baltimore, Md.
Correspondence to Joshua M. Hare, MD, Johns Hopkins Medical Institutions and Institute for Cell Engineering (ICE), Division of Cardiology, BRB
651, 733 N Broadway, Baltimore, MD 21205. E-mail [email protected]
(Circulation. 2006;114:339-352.)
2006 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/CIRCULATIONAHA.105.590653
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TABLE 1.
Study
Treated, n
Cell Type
Mode of Delivery
Randomized
10
BMMNCs
Intracoronary
Safety
NA
TOPCARE-AMI51,52
59
BMMNCs/CPCs
Intracoronary
NA
Stamm et al103,104
12
BMMNCs
NA
Tse et al105
BMMNCs
Endomyocardial
NA
Perin et al56
14
BMMNCs
Endomyocardial
Safety
NA
BOOST53
30
BMMNCs
Intracoronary
LVEF
0.0026
Fernandez-Aviles et al106
20
BMMNCs
Intracoronary
NA
NA
Strauer et al
Li et al
50
107
BMMNCs
IACT study108
18
BMMNCs
Intracoronary
Not stated
Janssens et al54
33
BMMNCs
Intracoronary
LVEF
0.36
Chen et al72
34
MSCs
Intracoronary
LVEF
0.01
Katritsis et al109
11
MSCsEPCs
Intracoronary
Scar size
0.02
Galinanes et al110
14
Bone marrow
Safety
NA
Fuchs et al111
10
Bone marrow
Endomyocardial
NA
MAGIC cell112
20
GCSF-mobilized PBMNCs
Intracoronary
NA
NA
GCSF-mobilized PBMNCs
13
GCSF-mobilized CPCs
Intracoronary
GCSF-mobilized CD34
Intracoronary
NA
GCSF-mobilized AC133
NA
Dib et al116
30
Skeletal myoblasts
NA
POZNAN117
10
Skeletal myoblasts
Transcoronary-venous
NA
Ince et al118
Skeletal myoblasts
Endomyocardial
NA
10
Skeletal myoblasts
NA
Ozbaran et al
113
Erb et al78
Boyle et al114
115
Pompilio et al
Siminiak et al45
Smits et al119
Menasche et al44
Pagani et al120
Herreros et al121
NA
0.05
Skeletal myoblasts
Endomyocardial
NA
10
Skeletal myoblasts
NA
Skeletal myoblasts
Histology
NA
12
Skeletal myoblasts
NA
CPC indicates circulating progenitor cell; GCSF, granulocyte colony stimulating factor; PBMNC, peripheral blood mononuclear cell; CFR, coronary
flow reserve; and LVEF, LV ejection fraction.
active myocardial regeneration resulting from transdifferentiation of the administered stem cells.4,1214 However, new
data have led to the recognition of alternative mechanisms of
action (Figure 1): Exogenous stem cells may also stimulate
proliferation of endogenous cardiac precursors or stem cells
through neovascularization6,15 or paracrine signaling actions.16 In fact, observations in preclinical and clinical scenarios that all of these events occur allow us to generate a new
concept that cellular therapy contributes to the restoration of
stem cell niches, facilitating the ability of the heart to heal
itself.17 Still other mechanisms are proposed: Exogenous stem
cells may lead to cardiac repair via fusion of donor cells with
host cardiomyocytes.18 Finally, other investigators suggest
that the effects of stem cells are mediated by altering
mechanical properties to strengthen the MI scar, thereby
preventing deterioration in cardiac function19 (see Figure 1).
This ongoing debate about mechanism fuels the case for
slowing the pace of clinical trials; ie, we should not pursue
work in patients until we thoroughly understand, with a high
degree of scientific precision, the outcome of cell therapy in
TABLE 2.
341
Clinical Trials of Stem Cell Therapy for Cardiac Repair Registered With ClinicalTrials.gov
Randomized
Total Patients
to Be
Enrolled, n
Primary
Outcome
Sponsor
Region
Myocardial ischemia
40
Perfusion
Rigshospitalet
Copenhagen, Denmark
Trial
Design,
Phase
Condition
Treated
I/II
Autologous BMMNCs
75
LV function
University of
Pittsburgh
Pittsburgh, Pa
Autologous BMMNCs
10
LV function
University of
Pittsburgh
Pittsburgh, Pa
Intramyocardial BMMNCs
Ischemic cardiomyopathy
30
Safety
Texas
Intracoronary BMMNCs
Acute MI
60
Safety
Minneapolis Heart
Institute Foundation
Minneapolis, Minn
Intravenous MSCs
Acute MI
48
Safety
Osiris Therapeutics
Autologous Intramyocardial
CD34
Chronic myocardial
ischemia
24
Not stated
St Elizabeths Medical
Center
Boston, Mass
I/II
Chronic myocardial
ischemia
10
Perfusion
Translational Research
Informatics Center,
Japan
Kobe, Japan
Intramyocardial autologous
BMMNCs
II
Ischemic cardiomyopathy
35
LV function
Odense University
Hospital
Odense, Denmark
Intracoronary autologous
BMMNCs
II
Acute MI
100
Myocardial viability
Nantes University
Hospital
Nantes, France
Intramyocardial autologous
skeletal myoblasts
Ischemic cardiomyopathy
15
Safety
Bioheart
Intramyocardial autologous
skeletal myoblasts
II
Ischemic cardiomyopathy
Not stated
LV function
Genzyme
Multicenter, Europe/United
Kingdom
Intramyocardial autologous
skeletal myoblasts
Ischemic cardiomyopathy
undergoing CABG
15
Safety
Bioheart
Autologous CD34
CABG indicates coronary artery bypass grafting; VAD, ventricular assist device.
blood vessels. Both murine and human ES cells spontaneously differentiate to form endothelial and smooth muscle
cells in vitro27 and in vivo.28,29 To date, no human clinical
studies have been initiated because of both the ethical issues
surrounding access to embryos and the possibility of teratoma
formation, suggested by a study injecting ES cells in skeletal
muscle.30
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Circulation
ity of clinical testing of this approach feasible. The Specialized Centers for Cell-Based Therapy initiative of the NHLBI
has funded clinical trials of cardiac stem cells that should
begin in the near future.
Skeletal Myoblasts
Autologous skeletal myoblasts are another potential source
for cardiac repair because of their biological properties and
lack of ethical and immunological problems. Skeletal myoblasts or satellite cells are the reservoir of regenerative cells
for skeletal muscle tissue; they have the ability for selfrenewal and differentiation if muscle injury occurs.39 They
have many desirable features as donor cells, including the
ability to be amplified in an undifferentiated state in vitro and
high resistance to tissue ischemia. They also have been shown
to continue proliferation in vivo to a certain extent, which
gives rise to a larger graft size.3 Satellite cells are committed
solely to the myogenic lineage. Therefore, regardless of
environmental influences, even if implanted into a scar made
up mainly of fibroblasts, myoblasts differentiate into functional muscle cells. A growing body of experimental data and
initial clinical studies has shown not only engraftment of
donor cells but also improvement in global cardiac pump
function.8,11,40 42 However, the exact mechanism by which
they improve LV function is still debated. There may be
beneficial effects of contracting noncardiac myocytes, some
paracrine actions and an effect on scar strengthening to
prevent LV dilatation and remodeling.43 The critical importance of progressing to clinical trials is underscored by the
early clinical experience with skeletal myoblasts. Myoblast
transfer in early studies44,45 was associated with sustained
ventricular tachycardia, a life-threatening arrhythmia. This
finding guided changes in future protocols involving skeletal
myoblasts, which now require prophylactic cardioverterdefibrillator implantation and/or amiodarone therapy to prevent ventricular tachycardia. This protocol change resulted in
less frequent clinically evident arrhythmias and is a powerful
demonstration of how clinical trials are integral in guiding
and refining the way in which stem cell therapy should be
administered in patients. Phase II studies of skeletal myoblast
therapy are presently underway.
343
most widely studied cell-based therapy for human applications (Table 1). Several studies using autologous bone marrow warrant special mention. The initial studies used intracoronary delivery of BMMNCs in the post-MI setting
because animal studies demonstrate that tissue damage in MI
resulted in bone marrow stem cell homing to the infarcted
myocardium.6 In the first published human trial, Strauer et
al50 aspirated BMMNCs and reinfused them into the infarctrelated artery 7 days after MI in 10 patients and had a control
group comprising 10 patients who refused the treatment. This
method resulted in significantly improved myocardial perfusion and wall motion indexes. The Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI) investigators 51,52
randomized 59 patients after acute MI to receive intracoronary infusion of BMMNCs or ex vivo expanded circulating
progenitor cells. They delivered the cells into the infarctrelated artery 4 days after MI and showed improvement in LV
ejection fraction from 51% to 58% (P0.001), as well as
significantly enhanced myocardial viability and regional wall
motion in the infarct area. Interestingly, they were unable to
show a difference between the 2 active cell treatment groups.
In the BOne marrOw transfer to enhance ST-elevation infarct
regeneration (BOOST) trial, Wollert and coworkers53 randomized 60 patients after successful percutaneous coronary
intervention for acute MI to receive either intracoronary
BMMNCs or standard therapy. They demonstrated an improvement in LV ejection fraction of 6.7% in the treatment
group and 0.7% in the control group at 6 months (P0.0026).
Taken together, these studies with control groups suggest that
BMMNCs are safe and may improve cardiac function by a
substantial and clinically meaningful degree following MI.
However, more recently, Janssens and colleagues presented
their findings that intracoronary transfer of BMMNCs failed
to achieve their primary end point, improvement in global LV
function.54 They demonstrated a significant reduction in scar
size and an improvement in regional function, but there was
no improvement in LV ejection fraction (P0.36). Their
patient population differed from the BOOST trial in that they
were reperfused earlier and may therefore have gained only a
small benefit from cell therapy because they derived maximal
benefit from earlier reperfusion. In the 18-month follow-up to
the BOOST study, the improvement in LV ejection fraction in
the cell therapy group was sustained.55 However, the control
group also had improved by this time, and the difference
between the 2 groups was no longer significantly different.
This catch-up phenomenon in the control group suggests that,
rather than the effect of cell therapy being transient, cell
therapy may in fact accelerate the postinfarction LV functional recovery that is achievable with standard medical
therapy.
In contrast to the acute MI setting, patients with chronic
ischemic cardiomyopathy are unlikely to release signals from
damaged myocardium to induce stem cell homing. Therefore,
an alternative approach to intracoronary infusion of cells in
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Circulation
TABLE 3.
Study
Autologous/
Allogeneic
Indication
Randomized
34
Autologous
MI
Bang et al122
Autologous
Stroke
Garcia-Olmo et al123
Autologous
Horwitz et al124
Allogeneic
Osteogenesis
imperfecta
LeBlanc et al125
Allogeneic
GVHD
72
Chen et al
345
346
Circulation
Balance of Risk
The risk of exposing patients to possible adverse outcomes
of a new treatment must be weighed against the risk of
depriving all patients of a new and possibly effective
treatment to alleviate suffering or to prolong life. There is
now sufficient preclinical and clinical data to warrant
larger randomized controlled trials evaluating stem cell
therapy. The argument that these trials should be delayed
until mechanisms are further understood will unnecessarily
deprive large numbers of patients of therapeutic approaches that may improve their clinical outcome. Only
clinical trials can lead to optimization of stem cell therapy
with recognition of the best type of cell and the best
delivery method for our patients.
Another compelling argument for initiating clinical
research is that the results of these investigations often
provide pivotal insights that allow a new field to advance.
Several examples in cardiovascular medicine illustrate this
concept. ACE inhibitors89 and 3-hydroxy-3-methylglutaryl
coenzyme A reductase inhibitors (statins),90 widely used
drugs with solid mechanistic underpinning supporting their
use, were both appreciated after entry into clinical practice
to have pharmacological effects that extended beyond their
initially intended design. The additional mechanistic effects were suggested by results obtained in clinical trails,
demonstrating the important synergy between in vitro/
animal studies and clinical trials conducted in parallel in
guiding clinical therapies.
Another important example of how mechanistic, novel,
pathophysiological, and therapeutic insights can progress
in parallel during clinical development is percutaneous
transluminal coronary angioplasty (PTCA). In 1977, pioneer Andreas Gruntzig published results obtained in 8
dogs, then progressed to human postmortem experiments91
and next to human clinical trials, publishing his first series
of 5 patients only 1 year later.92 The first study of 50
patients followed in 1979.93 This translational research
program introduced PTCA as a new clinical treatmen, but
was not free of serious complications. Soon the problem of
restenosis, the Achilles heel of PTCA, was appreciated,
347
prompting substantial new basic research and the development of the coronary artery stent, which reduced but did
not eliminate the incidence of restenosis. As is now well
known, drug-coated stents that nearly eliminate restensosis
have been developed.94 Before the publication of this
seminal article, safety and feasibility data had been published on 100 patients,9597 substantially less than the
number who have been enrolled in preliminary stem cell
trials. This stepwise progression to clinical trials was
appropriate and timely, with patients receiving the benefits
of the proven therapies, while clinical trial results guided
further basic and preclinical research to eventually refine
and improve these clinical therapies. We anticipate a
similar iterative pathway for the development of stem cell
therapy (see Figure 2).
Importantly, clinical trials do not always produce positive outcomes, yet unexpectedly negative results are often
pivotal to the understanding of disease pathophysiology.
For example, in the Cardiac Arrhythmia Suppression Trial
(CAST), administration of antiarrhythmic drugs for
asymptomatic nonsustained ventricular tachycardia after
MI resulted in an excess of deaths in the treatment arms.98
No animal study had suggested that this would happen. In
fact, further laboratory investigations and animal studies
would have pursued a wrong path and would have wasted
valuable resources. Although the outcome was unfortunate
and unexpected, a properly designed prospective clinical
trial discovered this deadly complication of antiarrhythmic
therapy and changed future therapeutic approaches. The
appropriate progression into prospective, randomized, controlled clinical trials will prevent exposing more patients to
potentially dangerous therapies in uncontrolled trials or in
the proliferation of delivering the therapy out of the
clinical trial context.99 Additionally, the transition from
348
Circulation
Conclusions
Although at this time no data support either cell-based or
specific stem cell therapies as standard clinical practice for
cardiac applications, there is a wealth of preclinical and early
clinical data showing safety, feasibility, and early efficacy of
adult cell-based therapy. Adult stem cell therapies should
therefore proceed into randomized, placebo-controlled,
double-blind clinical trials. The ongoing rigorously designed
trials will contribute greatly to this emerging and exciting
new therapeutic approach for diseases of the cardiovascular
system.
Funding
This work was supported by The Johns Hopkins Specialized Center
for Cell-Based Therapy (U54 HL081028), The Johns Hopkins
University School of Medicine Institute for Cell Engineering (ICE),
Disclosures
Dr Hare received a research grant from Osiris Therapeutics. The
other authors report no conflicts.
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Orlic D, Kajstura J, Chimenti S, Limana F, Jakoniuk I, Quaini F,
Nadal-Ginard B, Bodine DM, Leri A, Anversa P. Mobilized bone
marrow cells repair the infarcted heart, improving function and survival.
Proc Natl Acad Sci U S A. 2001;98:10344 10349.
Murry CE, Soonpaa MH, Reinecke H, Nakajima H, Nakajima HO,
Rubart M, Pasumarthi KBS, Ismail Virag J, Bartelmez SH, Poppa V,
Bradford G, Dowell JD, Williams DA, Field LJ. Haematopoietic stem
cells do not transdifferentiate into cardiac myocytes in myocardial
infarcts. Nature. 2004;428:664 668.
Balsam LB, Wagers AJ, Christensen JL, Kofidis T, Weissman IL,
Robbins RC. Haematopoietic stem cells adopt mature haematopoietic
fates in ischaemic myocardium. Nature. 2004;428:668 673.
Strauer BE, Brehm M, Zeus T, Kostering M, Hernandez A, Sorg RV,
Kogler G, Wernet P. Repair of infarcted myocardium by autologous
intracoronary mononuclear bone marrow cell transplantation in humans.
Circulation. 2002;106:19131918.
Assmus B, Schachinger V, Teupe C, Britten M, Lehmann R, Dobert N,
Grunwald F, Aicher A, Urbich C, Martin H, Hoelzer D, Dimmeler S,
Zeiher A. Transplantation of Progenitor Cells and Regeneration
Enhancement in Acute Myocardial Infarction (TOPCARE-AMI). Circulation. 2002;106:3009 3017.
Schachinger V, Assmus B, Britten MB, Honold J, Lehmann R, Teupe C,
Abolmaali ND, Vogl TJ, Hofmann W-K, Martin H. Transplantation of
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350
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113.
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351
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Response to Boyle et al
Peter Oettgen, MD
Boyle et al raise several important points about the current status of stem cell therapy for cardiac repair and nicely review
the results of multiple clinical trials to date. The vast majority of these trials were conducted using small numbers of patients
with mixed results. Larger, recently completed, prospective, randomized, clinical trials have had similarly mixed results.
Significant gaps remain with respect to our understanding of which stem cells may ultimately be the most therapeutically
useful to promote cardiac tissue regeneration and how best to deliver the stem cells. Because the vast majority of stem cells
do not remain within the heart, even after local injection, it is critical that better ways be developed to promote retention
of the delivered cells within the heart and to be able to track and monitor the stem cells that do not remain within the heart
after delivery. Other safety concerns include the progression of vascular disease and the development of arrhythmias. Do
the results of the completed studies warrant initiation of larger additional clinical trials? The financial resources available
for conducting stem cell research are limited. Large clinical trials, in particular, are costly. Although a significant unmet
clinical need remains in patients with cardiovascular disease, we must carefully weigh how much of these resources should
be devoted to additional basic research in stem cell biology and studies aimed at optimizing their therapeutic potential in
animal models of cardiovascular disease versus conducting additional large clinical trials.
CONTROVERSIES IN
CARDIOVASCULAR MEDICINE
ES Cells
ES cells are derived from the inner mass of developing embryos
during the blastocyst stage. Characteristic features of ES cells
include their proliferative and self-renewing properties and their
ability to differentiate into a wide variety of cell types, including
cardiac myocytes.3 The major concerns with their use in human
trials include the formation of teratomas when ES cells are
injected into immunocompromised animals. This is particularly
important because the ES cells currently available for use in
humans would be of allogeneic origin and therefore would
require immunosuppression. As nuclear transfer techniques improve, they will provide a way of generating an unlimited supply
of histocompatible ES cells using the nuclei of cells obtained
directly from the recipient patients with heart disease.4
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
From the Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, Mass.
Correspondence to Peter Oettgen, MD, Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, MA 02115. E-mail
[email protected]
(Circulation. 2006;114:353-358.)
2006 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/CIRCULATIONAHA.106.639385
353
Downloaded from http://circ.ahajournals.org/
by guest on April 30, 2014
354
Circulation
Transvascular Route
A transvascular approach is particularly well suited to treat
patients with acutely infarcted and reperfused myocardium.
Stem cells can be infused directly into the coronary arteries
and have a greater likelihood of remaining in the injured
myocardium as a result of the activation of adhesion molecules and chemokines.10 The advantage of an intracoronary
infusion is that the cells can be directed to a particular
territory. An alternative approach is to inject stem cells
intravenously.11 In the setting of myocardial infarction, circulating stem cells have been shown to home to sites of
injury, but the number of cells that home to the heart in this
way is significantly less than by local injection.
Safety Concerns
Arrhythmias
Over the past few years, some of the early-phase clinical
studies have suggested the possibility of a proarrhythmic
effect associated with stem cell transplantation. In 1 study,
skeletal myoblasts were injected transepicardially at the time
of coronary artery bypass surgery. Four patients had documented ventricular tachycardia at 11, 12, 13, and 22 days
after stem cell implantation.14 Interestingly, these events
occurred early and were not observed in treated patients later
after several months of follow-up. A similar proarrhythmic
effect was observed when autologous skeletal myoblasts were
delivered via a transvascular route.15 Other studies have
similarly reported an increased frequency of nonsustained
ventricular tachycardia in patients treated with skeletal myoblasts, peaking 11 to 30 days after stem cell transplantation.16,17 A proposed mechanism for the increased incidence
of arrhythmias is that the injected stem cells do not communicate electrically with neighboring cardiac myocytes and/or
result in slowed conduction, thereby promoting reentrant
arrhythmias. It has recently been suggested that skeletal
myoblasts that have been genetically engineered to express
gap junction protein connexin 43 exhibited decreased arrhythmogenicity.18 Although proarrhythmic effects have been
observed predominantly in patients receiving skeletal myoblast transplantation, they also have been observed recently in
2 patients shortly after transplantation of CD133 cells.19,20
355
356
Circulation
Treated, n
Cell Type/Treatment
Mode of Delivery
End Point
Janssens et al37
67
BMMNCs
Intracoronary
LV ejection fraction
0.36
BOOST35
60
BMMNCs
Intracoronary
LV ejection fraction
0.0026
ASTAMI
100
BMMNCs
Intracoronary
LV ejection fraction
0.05*
REPAIR-AMI36
204
BMMNCs
Intracoronary
LV ejection fraction
0.021
Zohlnhoefer et al35
114
G-CSF
Subcutaneous
Infarct size
0.79
62
G-CSF
Subcutaneous
1.00
36,38
STEMMI42
BMMNCs indicates bone marrow mononuclear cells; G-CSF, granulocyte colony-stimulating factor; and STEMMI, Stem Cells in
Myocardial Infarction.
*LV ejection fraction was higher in the control group.
Conclusions
Stem cells remain a highly promising therapeutic modality
that could address the large, unmet clinical need of treating
patients throughout the world with significant cardiac dysfunction that cannot be adequately treated with conventional
therapeutic approaches or cardiac transplantation because of
the limited availability of this resource. On the basis of the
mixed results of more recent larger clinical trials, we should
err on the side of caution before committing precious resources to conduct additional large clinical trials. Several
questions need to be addressed. First, have we identified
which stem cell type to use? Second, have we determined the
mechanisms by which stem cells promote myocardial function or repair? At present, there is limited evidence to support
that stem cells used thus far in patients promote significant
cardiac tissue regeneration. Third, can the stem cell be
retained efficiently within the heart? Finally, can clinical
trials be done in such a way that important safety issues will
be adequately addressed? What methods will be used to
monitor the development of life-threatening arrhythmias and
to track injected stem cells throughout the body? Because the
financial resources available for clinical and basic stem cell
research are not unlimited and because of the high cost
associated with conducting larger clinical trials, it is particularly important that we address the aforementioned questions
before proceeding with larger clinical trials. It is clear that
additional basic research is needed to optimize ways to
promote cardiac tissue regeneration, to improve methods by
which delivered stem cells will remain in the heart, and to
optimize the way in which stem cells are tracked after
delivery.
Funding
This work was supported by National Institutes of Health grant
PO1-HL-76540.
Disclosures
Dr Oettgen has received a received a research grant from the NIH.
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Response to Oettgen
Andrew J. Boyle, MBBS, PhD; Steven P. Schulman, MD; Joshua M. Hare, MD
We agree with Dr Oettgen on many issues surrounding cell therapy. Preclinical studies demonstrate considerable promise for
many cell types to effect cardiac repair, yet the initial promise from small animal work is far more difficult to demonstrate in
humans. Moreover, early clinical trials of skeletal myoblasts and granulocyte colony-stimulating factor have discovered
unexpected side effects not apparent in animal models. These rigorously designed early clinical studies and their unanticipated
findings have now guided not only the design of next phase of clinical studies but also the future of basic and animal studies.
Most importantly, we agree that understanding the mechanistic underpinnings of cell-based therapy is essential. Our area of
fundamental disagreement relates to the role of the clinical trial in advancing the burgeoning field of cell-based therapy. We
believe that these trials must proceed but must be conducted by responsible investigators concerned with patient safety and
committed to incorporating mechanistic studies into the trials. Clinical development of any new therapy begins with a phase I
study aimed at proving safety, and major trials contain independent Data Safety and Monitoring boards. Every detail regarding
the mechanism of action of these cells cannot be appropriately determined in animal models because, by definition, that which
happens in controlled animal experiments may not translate into humans, who are much more heterogeneous and have many
comorbidities that affect responsiveness to novel therapies. There exists, by necessity, a synergy between basic science and
clinical research. An incomplete understanding of molecular/cellular mechanisms should not halt the progression of clinical trials;
quite the opposite is the case. The success or failure of clinical trials guides future basic science research, which, in turn, informs
future clinical trials to achieve improvements in health outcomes for patients.