MINI-REVIEW:
EXPERT OPINIONS
Adult Stem Cell Therapy in Perspective
Emerson C. Perin, MD, PhD; Yong-Jian Geng, MD, PhD; James T. Willerson, MD
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Brave New World
Therapeutic Use of Stem Cells
Ventricular remodeling and ultimately heart failure are the
inexorable consequences of substantial myocardial infarction.
In recent years, the understanding that regenerative processes
exist at the level of the myocardium has placed stem cell
research at center stage in cardiology. Through cellular
therapies, the concept of “growing” heart muscle and vascular
tissue and manipulating the myocardial cellular environment
has revolutionized the approach to treating heart disease.
Unfortunately, however, the vast field of possibilities opened
by stem cell therapy has frequently given rise to more
questions than answers. A few of these questions include:
Which patients with cardiovascular diseases should be considered for stem cell therapy? Which type of stem cell(s)
should be used? What quantity and concentration of cells
should be administered? By what mechanisms do stem cells
engraft, survive, and differentiate? Is the functional and
morphological cardiac improvement achieved actively (ie, by
increasing contractility) or passively (ie, by limiting infarct
expansion and remodeling)? What is the lifespan of transplanted stem cells in the heart? How safe is this therapy, and
is there potential tumorigenesis of stem cells? What might be
the potential benefits of cell transplantation in nonischemic
heart failure?
In this report, we wish to review available information
about cardiovascular stem cell therapy, share our early
experience in this new field, and speculate about future
directions. Although embryonic stem cells have been shown
to have greater potency for proliferation and differentiation
than adult stem cells, their lack of availability and ethical
issues hamper clinical applications. This report will, therefore, focus on the therapeutic applications of adult stem cells.
The diverse literature on stem cell research comprises the
work of basic and clinical scientists from many different
subspecialties. This may account for the heterogeneous mixture of models, methods, types, quantity, and nature of the
cells employed and the timing of experiments. Certain landmark findings and concepts should be highlighted, however,
as they have shaped our understanding of what may be
accomplished and what potential mechanisms may be explored to achieve clinically successful results in the future.
Paradigm Shift
The pivotal finding by Ashahara and colleagues1 that postnatal vasculogenesis exists (ie, that stem cells contribute
directly to the formation of new blood vessels in adults)
provided new insights into mechanisms of cardiac repair. In
the adult, neovascularization does not rely exclusively on
angiogenesis (sprouting from preexisting blood vessels).
Furthermore, endothelial progenitor cells (EPCs) that originate in the bone marrow play a role in vasculogenesis
(physiological and pathological) and circulate in adult peripheral blood.1 The intriguing observation in heart transplant
patients that putative stem cells and progenitor cells from a
recipient were present in the transplanted heart further supports the notion of ongoing regenerative and reparative
mechanisms mediated by circulating stem cells from the bone
marrow.2
Finding a Home
The microenvironment plays a fundamental role in the
transdifferentiation of stem cells. Human mesenchymal stem
cells (from adult bone marrow), when engrafted into murine
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
From the Department of Cardiology, Texas Heart Institute, and the University of Texas Health Science Center, Houston.
Correspondence to Emerson C. Perin, MD, 6624 Fannin, Suite 2220, Houston, TX 77030. E-mail [email protected]
(Circulation. 2003;107:935-938.)
© 2003 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/01.CIR.0000057526.10455.BD
935
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Circulation
February 25, 2003
hearts, seem to differentiate into cardiomyocytes that are
indistinguishable from the host’s cardiomyocytes.3
Although its mechanism is incompletely understood, the
“homing” of stem cells to the injured myocardium is essential, as it concentrates the implanted cells in an environment
favorable to their growth and function. Ischemia or hypoxia
may increase vascular permeability, enhance the release of
chemoattractive factors, and promote the expression of adhesion proteins, which may facilitate the homing process.
Putting Stem Cells to Work
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Because the normal reparative mechanisms seem to be
overwhelmed when clinically significant myocardial injury
occurs, a logical next step would be to artificially amplify one
part of this response by locally applying stem cells in the
setting of ischemia or infarction when a large amount of heart
muscle has been injured. Experimentally, circulating EPCs
have been shown to be mobilized endogenously in response
to tissue ischemia (or exogenously by cytokine therapy), after
which they augmented the neovascularization of ischemic
tissues.4 Implantation of bone marrow mononuclear cells into
ischemic myocardium in swine enhanced collateral perfusion
and regional myocardial function.5 This therapeutic angiogenesis may have been due to the natural ability of the bone
marrow cells to secrete potent angiogenic ligands and cytokines, as well as to be incorporated into foci of neovascularization.6 Other observations have shown that EPCs prevented
cardiomyocyte apoptosis, reducing remodeling and improving cardiac function in areas of neovascularized ischemic
myocardium in rats.7
Systemic and local growth factors almost certainly influence stem cells homing and biology. EPCs and their precursors are mobilized during an acute myocardial infarction.
This mobilization may be due to the increased levels of
vascular endothelial growth factor (VEGF) associated with
acute myocardial infarctions,8 as VEGF has been shown to
augment the mobilization of EPCs from bone marrow.9
Increased levels of transcriptional activators for VEGF have
been found in response to early ischemia and infarction.10
A Call to Arms
There is intense, ongoing investigation into the identification
of the ideal cell for use in therapeutic applications. On the
basis of experimental evidence, several types of stem cells
might be administered for therapeutic angiogenesis. These
include filtered bone marrow cells, mononuclear bone marrow cells, or even a subfraction of bone marrow stem cells,
including endothelial precursor cells, as well as stromal or
mesenchymal cells and hemopoietic stem cells. Selection of a
specific cell type may require highly sophisticated facilities
and technology. A sufficient quantity of cells may be obtained from direct bone marrow aspiration (as with mononuclear bone marrow cells), but expansion of a selected cell will
likely necessitate cell culture. Cells may also be obtained
from peripheral blood after cytokine or growth factor stimulation. Skeletal myoblasts are easily harvested from a small
sample of skeletal muscle, which is subsequently processed,
and further expansion of myoblasts is achieved through
culture.11 Stem cells may also be harvested and cultured from
other autologous sources such as adipose tissue. Umbilical
cord blood harboring a large number of autologous embryonic stem cells may be saved for future use.
Fresh administration of cells after brief manipulation (for a
matter of hours) offers a simpler approach than culturing
cells, which involves more extensive manipulation (for 2
weeks) and a greater concern about infection.
Administration of Stem Cells
General Considerations
Although the ideal route for administering stems cells has still
yet to be determined, it may be important to take certain
factors into consideration. The strength of homing signals
may vary in different clinical scenarios. In more acutely
ischemic scenarios, the stem cells may be administered either
peripherally or locally through the circulatory system. When
the homing signals may be less intense, as may be the case for
chronic ischemia or nonischemic cardiomyopathies, injection
of the cells directly into the cardiac muscle may produce a
more favorable outcome. Certain stem cells, such as skeletal
myoblasts, are best administered by means of direct tissue
injection because of the potential for embolization when large
numbers of these cells are administered.
Surgical Intramyocardial Injection
Although the most invasive approach, this method is suited to
patients who already have a surgical procedure scheduled.
The injection process is simple and can be performed under
direct visualization, allowing evaluation by direct inspection
of the potential target zones. Not all areas, however, can be
readily accessed with this approach.
Transendocardial Injection
This method primarily involves the NOGA system (Cordis),
for which previous experimental5 and clinical12 experience is
available. An injection catheter incorporates the mapping
capabilities of the system. This provides a means by which
tissues with different degrees of viability13 and ischemia can
be mapped in detail, allowing therapy to be precisely targeted
(eg, at the border zone of an infarct). NOGA application in
humans has a long learning curve but has been used very
safely in our experience.
Ultimately, noninvasive imaging, possibly with MRI,
echocardiography, or computed tomography, needs to developed for the purpose of monitoring stem cell concentrations
in cardiac and vascular tissue and their contributions to tissue
function and angiogenesis.
Intracoronary/Transvascular Injections
Performed successfully in a clinical trial,14 intracoronary
injection is especially well suited for the delivery of cells to
a specific coronary territory. It is less complex than transen-
Perin et al
Adult Stem Cell Therapy in Perspective
937
Left, Electromechanical linear local shortening map in the postero-lateral view
from a stem cell injection procedure. The
red color represents extremely low contractility throughout the entire left ventricle (severe cardiomyopathy). The black
dots are stem cell injection sites. Right,
Similar map obtained at 4-month followup, showing dramatic improvement in
contractility (purple, blue, and green
areas) at the site of prior cell injection.
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docardial delivery, and because of the segmental nature of
coronary artery disease, may prove very practical. Retention
of cells in the target area remains a central issue that suggests
that this technique will be particularly suited for treating
relatively intense ischemia. The quantity of cells and time of
infusion should be carefully considered to avoid coronary
flow impairment and myocardial cell necrosis. This technique
may not be suitable for certain types of larger stem cells, such
as skeletal myoblasts, which may be prone to embolization.
In addition, both the coronary sinus and the great cardiac
vein provide low pressure venous– conduit access to the
interior and anterolateral left ventricular myocardium by
which ultrasound-directed (Transvascular Inc) intramyocardial injections of stem cells may be performed.
Intravenous Injections
This is the simplest method of cell administration, but a
greater degree of dependence on homing of the stem cells is
required in order for them to reach the myocardium. Intravenously injected cells may become trapped in other organs (eg,
liver, spleen, lung, etc) so that only a small portion enters the
coronary circulation and migrates into ischemic myocardium.
Homing signals are also present at other sites in the body,
particularly in lymphoid tissues. Dosing will likely play an
important role in the viability of this method.
Initial Experience in Humans
The currently available knowledge and the scope of the
clinical problem are compelling and have prompted the
initiation of clinical trials. They are currently being performed as single-center studies using mononuclear bone
marrow cells or skeletal myoblasts. Safety and feasibility
have initially been favorable in trials utilizing human adult
bone marrow stem cells, but unresolved issues remain regarding the initial arrhythmogenic potential of myoblasts.16
In the published reports of human stem cell trials thus far,14
the use of mononuclear bone marrow cells, delivered via the
intracoronary route in patients with previous myocardial
infarcts but a preserved ventricular ejection fraction, was
shown to improve function and perfusion in a small number
of patients at 3- and 4-month follow-up.
Several other groups, including our own (in collaboration
with Procardiaco Hospital in Rio de Janeiro, Brazil) are
actively pursuing clinical studies. We have delivered mononuclear bone marrow cells using electromechanical mapping
in patients with end-stage heart failure. Viable/ischemic
zones were targeted for delivery. According to our as yet
unpublished data, these patients have shown symptomatic
improvement associated with increased contractility (Figure)
and perfusion at 4- and 6-month follow-up examinations.
How Much Is Enough?
Future Perspectives
An important issue concerning the therapeutic use of stem
cells is the quantity of cells necessary to achieve an optimal
effect. In current human studies of autologous mononuclear
bone marrow cells, empirical doses of 10 to 40 ⫻ 106 are
being used with encouraging results. However, further studies
are needed to explore the efficacy of different doses. Recently, in a study designed to treat peripheral vascular disease
with autologous bone marrow, much larger doses were
administered to the gastrocnemius muscle (2.7 ⫻ 109 cells),
with minimal inflammation and positive results.15
When the primary focus is not on angiogenesis, but rather
on transplantation of contractile muscular tissue,11 a much
higher quantity of cells may be needed to obtain a clinical
effect.
Combining stem cell therapy with other treatments may
increase therapeutic options in the future. Gene therapy has
shown encouraging results in promoting angiogenesis, but the
safety of gene delivery by means of viral vectors has become
of increasing public concern. Stem cells may serve as new
vehicles for carrying genes into tissues. For instance, through
genetically manipulated stem cells, a VEGF gene that is
critical for angiogenesis can be transferred into stem cells
that, in turn, may have a more potent action than VEGFnegative cells. Treatment achieved with adenoviral vectoraided delivery of genes encoding VEGF has shown positive
results in a hind-limb experimental ischemia model.17
Combined pharmacological, surgical, and interventional
treatments with stem cell therapy (eg, injection of stem cells
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Circulation
February 25, 2003
during placement of a ventricular assist device) may also
provide added benefit, but it is too early to speculate further.
The Fountain of Youth
Recently, a study suggested that cellular restoration of the
platelet-derived growth factor pathway by young bone
marrow-derived EPCs could reverse the aging-associated
decline in cardiac angiogenic activity in mice.18 The very
notion that within each one of us lies a treasure-trove of
renewable life that can be directed toward healing and
revitalizing cardiac function should be reason enough to
propel us on a journey to answer the myriad questions
involved in understanding the application of stem cells and
their associated therapies. As the song suggests, “the future’s
so bright, [we’ve] gotta wear shades”!19
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From Timbuk 3. Universal City, Calif: MCA Records; 1986.
Adult Stem Cell Therapy in Perspective
Emerson C. Perin, Yong-Jian Geng and James T. Willerson
Circulation. 2003;107:935-938
doi: 10.1161/01.CIR.0000057526.10455.BD
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
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