Adult Stem Cells for Myocardial Repair
Felipe Prósper, Ana Perez, Juana Merino(1), Gregorio Rábago(3), Juan Carlos
Chachques(2), Milagros Hernández, Joaquín Barba(3), Eduardo Alegria(3), Juan José
Gavira(3), Angel Panizo(4) and Jesús Herreros(3)
Hematology and Cell Therapy Area, (1) Service of Immunology, (2) Clínica Uni-
versitaria, Universidad de Navarra, Spain and Department of Cardiovascular Sur-
gery, Hospital Georges Pompidou, (3) Department of Cardiology and Cardiovas-
cular Surgery and (4) Department of Pathology
Cell transplantation for myocardial repair has emerged as a promising therapy for patients
with heart failure. Recent in vitro and in vivo animal studies have suggested the potential of
different cell types to differentiate into tissues required for cardiac repair namely endothe-
lial cells and cardiomyocytes. In this review, we will focus on the potential of adult stem
cells obtained from adult muscle and adult bone marrow to regenerate cardiac tissue. There
are a number of studies suggesting that autologous myoblast or satellite cells can contribute
in vivo to improve cardiac contractility. In fact, several clinical studies have been initiated
using autologous ex vivo expanded myoblast in patients with myocardial infarction. We
will review the rationale for this approach. Although attractive, the use of muscle derived
progenitors has been questioned as these cells may not have the potential to differentiate
into cardiac tissues. Besides, initial studies have been associated with a high incidence of
cardiac arrythmias. Bone marrow derived stem cells have also been explored in vitro and in
animal models in the context of cardiac repair. The potential of adult bone marrow derived
stem cells to differentiate into cardiomyocytes and endothelial cells will be summarized as
well as the initial results of clinical trials using autologous bone marrow cells.
Key words: stem cells, cardiomyopathy
Basic Appl Myol 13 (1): 15-22, 2003
Cardiovascular diseases are the leading cause of death [36, 37], endothelial progenitors , mesenchymal stem
in the developed countries. Loss and dysfunction of car- cells , fetal cardiomyocytes  or even induction of
diomyocytes are characteristic of heart diseases and lead undamaged cardiomyocytes to replicate . The goal of
to heart failure as a consequence of irreversible cell loss. each of this cell population is to generate cells that can
Unlike other tissues, the heart muscle has none or very perform cardiac work, respond appropriately to adjacent
small capacity of regeneration due to the lack of stem cardiomyocytes and non-myocyte cells and exhibit a fa-
cells in the heart and the inability of the damaged heart vorable response to physiological stimuli. Successful car-
cells to undergo repair or divide at least to a significant diac tissue engineering would provide a valuable alterna-
extent [2, 23]. The development of new techniques aim to tive therapy for end-stage heart failure.
repair the damaged heart with the introduction of stem In this article we will focus on the potential of adult
cells with myogenic potential or the induction of resident stem cells to differentiate into tissues amenable for car-
myocardial cells to proliferate have great potential for diac repair meaning not only cardiomyocytes but also
treating heart failure and cardiomyopathy. The ultimate other tissues that may contribute to improve cardiac
goal of cell therapy for cardiac diseases is to repair, re- function. In particular we will examine the current evi-
place or enhance the biological function of damaged cells dence that supports a role for muscle and bone marrow
in order to strengthen the heart muscle. derived adult stem cells in cardiac regeneration and will
Studies of cell therapy for cardiac diseases have been an also described where we are from a clinical standpoint.
active field of research since the introduction of exoge-
nous cells in a dog heart was first reported . Subse- Stem cells
quent studies have used immortalized myogenic cells [12, Although not directly related to cardiac repair, but be-
26], embryonic stem cells , hematopoietic stem cells cause the recent amount of information published regard-
Adult stem cells for myocardial repair
ing potential of stem cells we believe a few words about muscle fibers but in response to injury, SC have the ca-
stem cells may help the reader to understand some of the pacity to undergo proliferation and terminal differentia-
concepts regarding stem cells and transdifferentiation. tion into new functional muscle [47, 48]. Although there
Stem cells have been defined as clonogenic cells that can is some evidence suggesting that under special condi-
undergo self-renewal as well as differentiation to commit- tions, SC may adapt a different fate that muscle , it is
ted progenitors and eventually to functional differentiated generally accepted that SC are predetermined to differen-
tissues. Stem cells can be subdivided according to their tiation into skeletal muscle fibers. The use of skeletal
potential in totipotent stem cells capable of giving rise to cells to repair cardiac defect is based on in vitro as well as
both embryonic and extra-embryonic tissues, pluripotent in vivo experiments. Unlike cardiac muscle, skeletal mus-
stem cells, that may differentiate into tissues derived from cle is characterized by fast-twitch fibers amenable of fa-
any of the three germ layers, or multipotent stem cells, tigue. However, it has been demonstrated that chronic
with a more limited differentiating capacity [1, 7, 65, 66]. electrical stimulation of skeletal muscle induces changes
It is generally accepted that ES cells are pluripotent. In such as expression of slow-twitch fibers and can trans-
contrast, it is generally accepted that adult stem cells are form skeletal muscle into indefatigable muscle more akin
multi- but not pluripotent. However, recent studies de- to cardiac muscle . The clinical experience with dy-
scribing adult stem cell plasticity have lead to intense dis- namic cardiomyoplasty has further demonstrated that
cussions whether some or all adult stem cells may have autologous grafts of skeletal muscle can be adapted to
the same pluripotent capacity as ES cells. Although there perform cardiac work and enhance cardiac function .
is yet no “official” definition of stem cell plasticity it Initial studies were performed with the goal of deter-
could be defined as the capacity of a given cell to acquire mining the fate of myogenic cells grafted into the hearts
morphological and functional characteristics of a tissue of animals and in general utilized myogenic cells lines as
different than the one from which the cell is originally they were homogenous populations of well characterized
derived [1, 41, 62]. True stem cell plasticity should in- cells . The use of autologous graft of primary SC was
clude the following criteria: a single tissue-specific adult facilitated by the development of culture protocols for the
stem cell, for instance a hematopoietic stem cell (HSC), isolation and ex vivo expansion of SC and skeletal
thought to be committed to a given cell lineage can under myoblast thus limiting the potential for tumor formation
certain microenvironmental conditions acquire the ability associated with cells lines . One of the limitations of
to differentiate to cells of a different tissue. The differen- culturing primary myoblast is the contamination with
tiated cell types should be functional in vitro and in vivo, other non-myogenic cells including fibroblast .
and engraftment robust and persistently in the presence Transplantation of autologous skeletal myoblast has been
(and absence) of tissue damage. successfully demonstrated in small (mice and rat) and
Adult stem cells have been found in most tissues in- large (sheep and dogs) animal models of myocardial in-
cluding hematopoietic , neural , epidermal , farction both by intramural implantation [5, 12, 17, 19,
gastrointestinal , skeletal muscle , cardiac mus- 34, 42, 54, 56] or by arterial delivery [53, 57]. Animal
cle , liver , pancreas  or lung tissue  (for studies have suggested that myoblast delivered intracoro-
review of organ specific stem cells see special issue nary are capable of transmigrate and integrate into the
from J Pathol 2002, volume 197). Until recently it was myocardial interstitium . After introduction into the
accepted that tissue specific cells could only differenti- heart either directly or intracoronary, myoblast terminally
ate into cells present in the tissue of origin. However, differentiate into skeletal muscle and by day 7 they loss
this concept has been challenged by recent studies sug- their proliferative capacity . Implanted myoblast may
gesting that cells originating from one germ layer (e.g. survive for prolonged periods of time [17, 46]. These
mesoderm) can generate tissues derived from a second findings suggest that the cardiac environment is permis-
germ layer (e.g. ectoderm or endoderm) [32, 41]. In ad- sive for myogenic differentiation. There is more contro-
dition, several recent studies have suggested that adult versy regarding the potential of myoblast to adapt charac-
pluripotent stem cells may be obtained from the BM teristics of cardiac muscle after implantation. Although
[20, 27] and from the brain [13, 21], capable of given some initial reports had suggested that after implantation,
rise to tissues derived from all three germ layers. How- myoblast may transdifferentiate into cardiac muscle or at
ever, this unexpected plasticity of adult stem cells has least acquire certain properties of cardiac muscle like ex-
been questioned by the observation of in vitro cell fu- pression of connexin 43, intercalated discs or slow-twitch
sion between BM or neural stem cells (NSC) and ES MHC [12, 14, 34, 56] more recent studies indicate that
cells [58, 67], and by the fact that some experiments myoblast do not transdifferentiate into cardiac muscle
have not been reproduced despite the intense efforts of . Differences between cell sources (neonatal or adult
different groups of investigators [6, 33]. myoblast), species or the use of more rigorous techniques
may explain some of these differences. In conclusion, the
Skeletal Myoblast for Cardiac Repair existing evidence does not support transdifferentiation of
Satellite cells (SC) or skeletal myoblast are precursor myoblast but only some conversion from fast to slow
cells of human skeletal cells. Under steady state condi- twitch phenotype. Another issue pertains to the capacity
tions, satellite cells lie below the basal membrane of
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Adult stem cells for myocardial repair
of myoblast for electromechanical coupling between im- patient with myocardial infarction successfully received
planted myoblast and cardiac cells. Although in vitro direct intramyocardial injection of autologous skeletal
studies have suggested that electromechanical coupling myoblast simultaneously with coronary bypass surgery.
can be established between cardiac and skeletal muscle Currently, more than 30 patients throughout the world,
 there is only minor in vivo evidence that this may be enrolled in different clinical trials have been treated with
the case [34, 45, 46, 59]. Despite all these issues, the autologous myoblast administered intra-myocardium or
more relevant question resides on whether myoblast im- percutaneously. No results have been reported so far ex-
plantation improves cardiac function in damaged heart. cept in abstract form. From some of these preliminary
Primary myoblast have been grafted into the injured reports the mayor adverse event has been the incidence
myocardium of rats, rabbits, dogs, or sheeps [5, 14, 17, of cardiac arrythmias. It is difficult at this time to make
34, 42, 43, 54, 56, 57]. Collectively, these studies clearly an assessment of the real incidence and potential
show long-term survival and differentiation of cells and mechanism of this adverse event as results have not
importantly, functional improvement in left ventricular been yet reported fully.
function after myocardial infarction. Our group has transplanted so far 10 patients with
Despite a number of open questions, the use of skeletal autologous myoblast by direct myocardium injection as
myoblast for cardiac repair has moved to clinical trials adjunct to coronary bypass surgery. Although the follow
throughout the world. The use of SC for cardiac repair in up of our patients is very limited and the study has not
patients with myocardial infarction has several advan- been completed the procedure has been well tolerated
tages over other sources of stem cells. SC proliferation with no adverse events including cardiac arrythmias not
capacity is limited thus the potential of SC to undergo having been detected post surgery. Unlike other studies,
uncontrolled proliferation and tumor formation is mini- culture of autologous myoblast has been performed
mal. Another advantage is that being autologous cells, it without the use of growth factor supplements or fetal
can overcome the shortage of organ donor as well as the bovine serum. From experiments performed in animal
requirement of immune-suppression after transplantation models, we have some preliminary evidence that culture
of allogeneic tissues. Myoblast are relatively resistant to of myoblast with xenogeneic serum may result in a se-
ischemia so they may provide a more resistant tissue that vere inflammatory reaction within the heart (Rabago
cardiomyocytes. All these factors along with the fact that personal communication and unpublished observations).
there is no ethical controversy regarding their use have How many cells do we need to inject?, what is the pre-
prompted several groups to initiate clinical trials with ferred way for injection?, are these cells capable of sur-
autologous myoblast for cardiac repair (Table 1). The viving long-term and if so, do they acquire characteris-
first case of a patient treated with autologous myoblast tics of cardiac muscle?, can myoblast contribute to im-
was reported by the group of Philippe Menasche . A proved long-term cardiac function in patients with myo-
Table 1: Clinical trials of cellular cardiomyoplasty with myoblast
Country Sponsor Hospitals Approach Year1 N2
U.S.A Diacrin Temple Univ. Surgery 2.000
U.S.A Diacrin Cleveland Clinic; UCLA; Surgery 2.001
Arizona Heart Inst.
U.S.A Bioheart Mount Sinai; DuKe Univ. Surgery-Percut 2.003
Argentina Hosp. Avellaneda Hosp. Avellaneda Surgery 2.001 1
China Nanjing Univ. Nanjing Univ. Surgery 2.002 3
China Singapore Univ. Singapore Univ. Hosp. Surgery 2.002 1
Francia Assistance Publique Hôpital Bichat Surgery 2.000 11
Holanda –Italia Bioheart INC. Thorax Center; Milano Percutaneous 2.001 13
Polonia Poznan Univ. Poznan Univ. Hosp. Surgery 2.002 10
España Univ. Navarra Universitaria Navarra; Clínico Surgery 2.002 10
Salamanca; Juan Canalejo; Gregorio
1Year initiated, 2Number of patients included as of September 2002
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Adult stem cells for myocardial repair
cardial infarction or other cardiomyopathy?, what ad- pression of surface antigens such as AC133 and VEGFR-
verse effects can we expect from this therapy?, are some 2 also found on HSC [3, 25, 39, 50]. In mouse models of
of the questions that need to be answer before this limb ischemia, endothelial progenitors are mobilized
treatment can be translated into clinical practice. from the BM and contribute to neo-angiogenesis in the
ischemic limb [3, 4, 55]. Likewise, in a rat model of car-
Bone marrow derived stem cells for cardiac repair diac ischemia, mobilized CD34+ CD117bright AC133+
The bone marrow contains several populations of VEGFR2+ cells contribute to repair of the rat heart after
stem cells. In addition to blood- forming cells (hema- myocardial infarction by the remarkable capacity to gen-
topoietic stem cells), mesenchymal stem cells or stro- erate new capillaries within the infarct zone . Al-
mal stem cells and endothelial progenitor cells can be though neo-angiogenesis by mobilized PB stem cells
isolated from the bone marrow. All these types of stem could be demonstrated, no generation of new cardiac
cells have been utilized in animal models for cardiac muscle cells (myocytes) was observed in this study.
repair with different success. Very limited clinical ex- In contrast to hematopoietic and endothelial cells, mes-
perience has been reported with bone marrow mono- enchymal stem cells (MSCs) are derived from somatic
nuclear cell which includes different types of stem mesoderm. MSCs have demonstrated their potential to
cells as well as a large proportion of terminally differ- differentiate into functional mesodermal derived tissues.
entiated and committed progenitors, mesenchymal MSCs differentiate into osteoblasts, chondrocytes, adipo-
stem cells and hematopoietic cells . cytes, and skeletal myoblasts [28, 40]. Recent studies also
The potential of BM or PB cells to differentiate into suggested that MSCs differentiate into cardiac myoblasts
cardiac muscle has been suggested by several studies. in vitro as well as in vivo [28, 60, 61]. MSCs culture in
Some investigators have used BM mononuclear cells ei- the presence of 5-azacytidine acquire phenotypic charac-
ther directly implanted into the heart or by percutaneous teristics of cardiomyocytes including electro-
infusion  and even a small number of patients with physiological activity and spontaneous beating in culture
myocardial infarction treated with coronary angioplasty . Injection of human MSC into an infarct mouse heart
have received autologous BM into their coronary arteries resulted in differentiation to cells staining positive for
with some functional benefit . Because there is no certain cardiac muscle markers after 1 week . Using a
information regarding the nature of the cells that may swine model of myocardial infarction, 2 different groups
contribute to cardiac muscle regeneration, the relevance have demonstrated that injection of MSCs resulted not
of these studies is at best very limited. More compelling only in engraftment of cells that acquire characteristic of
evidence for the capacity of BM cells to regenerate car- cardiomyocytes but more importantly contribute to im-
diac muscle stems from the group of Orlic and Anversa provement of cardiac function [49, 61]. Although most
. These authors demonstrated in a mouse model of animal studies have employed direct intramyocardial in-
myocardial infarction that direct injection into the heart of jection, the intracoronary approach is undoubtedly attrac-
Lin- kit+ BM cells results in more than half the infarct tive from a clinical point of view. Patients not subsidiary
area being colonized by donor cells within 9 days. Donor of bypass surgery or patients with acute myocardial in-
cells acquired phenotypic characteristics of cardiomyo- farction could benefit from this approach without the risk
cytes and contributed to improved cardiac function and of surgery. Intracoronary injection may posse other limi-
improved survival of the animals. In a subsequent study tations for this type of treatment: cells may be trapped in
this same group of investigators demonstrated that car- small capillaries without reaching the myocardium, or
diac infarct size was significantly reduced and cardiac may distribute and be lost in the systemic circulation. All
function significantly improved in animals in which SCF this issues need to be addressed in animal models.
and G-CSF was used to mobilize HSC and progenitors Several clinical trials have also been initiated using
from the BM. This was associated with increased prolif- marrow stromal cells or MSCs for cardiac repair (Table
eration of cardiac myoblasts, smooth muscle cells and 2). However, the results of these studies are still awaited
endothelial cells in the infarct tissue, leading the authors and only some preliminary presentations have been done.
to conclude that progenitor cells for these three tissues The only clinical study of cardiac repair using bone mar-
were mobilized from the BM. Although these studies row derived cells published so far involves the use of BM
suggest that cardiac defects due to ischemia may improve mononuclear unselected cells directly administered intra-
by local infusion of or mobilization of progenitors from coronary . Ten patients were treated with intracoro-
the BM, the etiology of the cell(s) responsible for this ef- nary transplantation of autologous, mononuclear bone
fect is not clear. Despite the fact that these cells can be marrow cells in addition to standard therapy of MI that
found in the HSC-rich Lin-kit+ fraction of BM, proof included re-canalization of the infarct-related artery by
that HSC trans-differentiate into myoblasts is still lack- percutaneous transluminal coronary angioplasty (PTCA)
ing and in fact very recent reports have seriously ques- and subsequent stent implantation. Although the study
tioned the potential of hematopoietic stem cells to trans- was not randomized, the investigators compared 10 pa-
differentiate . tients treated with the PTCA standard procedure with an-
Angioblasts or endothelial progenitor cells can also be other 10 patients that were treated also with intracoronary
found both in the PB and BM and identified based on ex-
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Adult stem cells for myocardial repair
Table 2: Clinical Trials of Cellular Cardiomyoplasty with bone marrow cells
Country Sponsor Hospitals Approach Year Nº
Brasil Incor, Sao Paulo Incor, Sao Paulo Surgery - HSC 2.002 1
Japón Yamaguchi Univ. Yamaguchi Univ. Ube Surgery-MSC 2.001 10
Alemania Dusseldorf Clinic Heinrich Univ. Dusseldorf ACTP-IC-HSC 2.001 10
Alemania Rostock Univ. Rostock Univ. Surgery – MSC 2.001 3
Italia Padova-Milano Univ. Padova-Milano Univ. Surgery 2001
España Univ. Valladolid Universitario Valladolid PTCA-IC-HSC 2.002 3
España-Francia Univ.Navarra-Miltenyi Universitaria Navarra Surgery-AC133 2.003
Georges Pompidou. Paris
HSC: hematopoietic stem cells; EPC:endothelial progenitor cells; MSC:mesenchymal stem cells;
PTCA:percutaneous transluminal coronary angioplasty; IC: Intracoronary
infusion of 5-20 x 106 MNC from BM at a median of 7
days after acute myocardial infarction. The functional re- Acknowledgements
sults after 3 month follow-up suggested that cell therapy Supported in part by grants from the Ministerio de
was associated with a reduction in the infarct region, in- Ciencia y Tecnología (SAF 2002-04574-C02) to FP,
creased infarction wall movement, improvement in stroke Sociedad Española de Cardiología to GR and funds
volume index, left ventricular end-systolic volume, con- from FEDER (INTERREG IIIA).
tractility and myocardial perfusion of the infarct region.
Address correspondence to:
Although promising, these results are certainly question-
able as most of the effects observed could be due to the Felipe Prósper, Hematology and Cell Therapy Area,
standard treatment of the MI. Besides, the use of unse- Clínica Universitaria, Universidad de Navarra, Av Pio
lected cells prevents any conclusion regarding the poten- XII 36, Pamplona 31009, Spain, tel. +34 948 255400,
tial effect of the cells. fax +34 948 296500, Email: firstname.lastname@example.org.
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Adult stem cells for myocardial repair
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