Stem cell transplantation for the treatment of myocardial infarction
Introduction
Coronary artery occlusion leads to ischemia and cell death in the heart [1]. Cardiomyocyte death results in scar formation and reduced contractility of the ventricle. Although the traditional concept that the adult cardiomyocyte is terminally differentiated has been challenged by evidence that some myocytes are mitotic in adult hearts [2], [3], [4], the ratio of myocytes undergoing proliferation is only 0.015–0.08% [3], [4]. The number of resident cardiac muscle stem cells within the heart is also too small to significantly repair the damage after myocardial infarction [5]. The irreversible loss of muscle after acute myocardial infarction followed by fibrosis of myocardial scar, infarct expansion, concentric hypertrophy, and left ventricular dilatation ultimately leads to progressive heart failure [6]. While the quality of life after acute myocardial infarction has been improved due to the enormous progress in the cardiovascular therapeutics [7], the root cause of heart failure, which is characterized by cardiomyocyte death and ventricular remodeling, remains a major contributor to cardiac morbidity and mortality.
Cellular cardiomyoplasty provides a potential approach to the treatment of heart failure after myocardial infarction. The basic concept of cellular cardiomyoplasty is to increase the number of functional cardiomyocytes by cell transplantation. Many types of cells, such as cardiomyocytes, skeletal myoblasts and stem cells, have been used in the attempt to regenerate myocardium and treatment of heart failure (for review, see Ref. [8]). In this review, we focus on the use of stem cell transplantation for cellular cardiomyoplasty.
Section snippets
Definition and sources of stem cells
Stem cells are a group of undifferentiated cells that have the capacity to self-renew, as well as the ability to generate differentiated cells. There are somatic stem cells and embryonic stem cells. Somatic stem cells are derived from adult somatic tissue, such as bone marrow, adipose tissue, peripheral blood, umbilical cord blood, and skeletal muscle. Embryonic stem cells are isolated from the embryo at the blastocyst stage and can form all fully differentiated cells of the body, including
Routes of stem cell delivery
Stem cells can be delivered to infarcted myocardium by injecting them directly into the cardiac muscle. Direct injection of stem cells into infarcted myocardium can be performed during open-heart surgery, by minimally invasive thoracoscopic procedures or percutaneously by injecting cells via a catheter. Catheter injection includes catheter-based needle injection from the left ventricular cavity and ultrasound-directed intramyocardial injection through the coronary sinus or the great cardiac
Tracking stem cells after transplantation
Many methods have been developed to track the destination of the injected stem cells to follow their engraftment and to determine their long-term fate after transplantation. In animal studies, green fluorescent protein [23], beta-galactosidase [24], 1,1′-dioctadecyl-3,3,3′3′-tetramethylindocarbocyanine perchlorate (DiI) [25], bromodeoxyuridine [26], PCR analysis of the male-specific Sry gene, and Y chromosome fluorescence in situ hybridization [27] have been used as cell labels to confirm the
Potential mechanism of stem cell therapy
The aim of stem cell transplantation for myocardial infarction is the regeneration of damaged myocardium. Numerous studies have been undertaken in animals and humans to analyze the safety and efficacy of this new approach. However, the results have been inconclusive, and the mechanism by which stem cells could improve cardiac function remains unclear. One possible mechanism is that transplanted stem cells improve cardiac function through myogenesis and angiogenesis. Orlic et al. [31] have
Debatable issues on the differentiation of stem cell
Contrary to the concept of myogenesis after stem cell transplantation in heart, several recent studies have suggested that transplanted stem cells fuse with the host cardiomyocytes to produce a hybrid cell that expresses both stem cell and differentiated cardiac cell markers. Alvarez-Dolado et al. [40] demonstrated that bone-marrow-derived cells fuse in vivo with cardiomyocytes. This fact raised the possibility that cell fusion may contribute to the transplanted stem cell's ability to adopt the
Methods to induce the differentiation of stem cells into myogenic cells in vitro
A high efficiency of cardiac myocyte differentiation from stem cells is a major requirement to regenerate damaged myocardium. Although the local microenvironment in the myocardium is considered to be an important factor for the differentiation of stem cells to cardiomyocyte-like cells [45], inducing differentiation of stem cells into myogenic cells before transplantation may increase the beneficial effects of stem cell therapy for cardiac regeneration. Tomita et al. [46] cultured bone marrow
Combination of stem cell and gene therapy
Recently, several studies have investigated the effects of genetically modified stem cells as a therapy for myocardial infarction. Studies have demonstrated that this combination of stem cell and gene therapy may be a useful approach. Genetic modification can increase the survival of transplanted stem cells in ischemic tissue. Mangi et al. [49] genetically engineered rat mesenchymal stem cells using an ex vivo retroviral transduction to overexpress the prosurvival gene Akt1 (encoding the Akt
Clinical trials
Currently, a variety of stem cells have been used in clinical studies, ranging from case reports to formal trials, to evaluate their beneficial effect and safety on the therapy of damaged myocardium (for review see Refs. [9], [54], [55]). Bone marrow-derived cells are the most frequent source used for clinical trials, because they are easy to obtain. For example, Stamm et al. [56] injected autologous AC133+ bone-marrow cells into the infarct border zone in six patients with myocardial
Potential problems of stem cell therapy
Besides raising intense ethical concerns in some [63], the use of human embryonic stem cell transplantation to repair damaged tissues has many other potential scientific problems. The first problem is the risk of teratoma formation. There is a possibility of spontaneous differentiation of stem cells into undesired lineages beside the cardiomyogenic differentiation after transplantation into myocardium [64].
The potential for accelerated atherogenesis or enhanced restenosis induced by stem cell
Conclusion
Although some of the current scientific data support the concept that the stem cells can be used for the myocardial regeneration, there are still many hurdles to be cleared before this promising approach can be performed effectively, safely and routinely in human subjects. Questions such as how to induce the transplanted stem cells to differentiate only into cardiomyocytes, and not other cells or teratomas; which type of stem cell and which model of delivery are the most efficacious; whether
References (66)
- et al.
Myocyte growth and cardiac repair
J Mol Cell Cardiol
(2002) - et al.
Increased circulating hematopoietic and endothelial progenitor cells in the early phase of acute myocardial infarction
Blood
(2005) - et al.
Nonhematopoietic mesenchymal stem cells can be mobilized and differentiate into cardiomyocytes after myocardial infarction
Blood
(2004) - et al.
Injectable fibrin scaffold improves cell transplant survival, reduces infarct expansion, and induces neovasculature formation in ischemic myocardium
J Am Coll Cardiol
(2004) - et al.
Skeletal muscle stem cells do not transdifferentiate into cardiomyocytes after cardiac grafting
J Mol Cell Cardiol
(2002) - et al.
Comparison of human skeletal myoblasts and bone marrow-derived CD133+ progenitors for the repair of infarcted myocardium
J Am Coll Cardiol
(2004) - et al.
Adult-derived stem cells from the liver become myocytes in the heart in vivo
Am J Pathol
(2001) - et al.
Mobilizing of haematopoietic stem cells to ischemic myocardium by plasmid mediated stromal-cell-derived factor-1alpha (SDF-1alpha) treatment
Regul Pept
(2005) - et al.
Bone marrow cell transplantation in clinical perspective
J Mol Cell Cardiol
(2005) - et al.
Autologous bone-marrow stem-cell transplantation for myocardial regeneration
Lancet
(2003)
Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction: final one-year results of the TOPCARE-AMI Trial
J Am Coll Cardiol
Effects of intracoronary infusion of peripheral blood stem-cells mobilised with granulocyte-colony stimulating factor on left ventricular systolic function and restenosis after coronary stenting in myocardial infarction: the MAGIC cell randomised clinical trial
Lancet
Autologous skeletal myoblast transplantation for the treatment of postinfarction myocardial injury: phase I clinical study with 12 months of follow-up
Am Heart J
Effects of stem-cell mobilization with recombinant human granulocyte colony stimulating factor in patients with percutaneously revascularized acute anterior myocardial infarction
Rev Esp Cardiol
Movement of necrotic wavefront after coronary artery occlusion in rabbit
Am J Physiol
Myocyte proliferation in end-stage cardiac failure in humans
Proc Natl Acad Sci U S A
Evidence that human cardiac myocytes divide after myocardial infarction
N Engl J Med
Chimerism of the transplanted heart
N Engl J Med
Left ventricular remodeling after acute myocardial infarction
Annu Rev Med
Treatment of acute myocardial infarction: better, but still not good enough
Arch Intern Med
Cellular cardiomyoplasty-cardiomyocytes, skeletal myoblasts, or stem cells for regenerating myocardium and treatment of heart failure?
Cardiovasc Res
Stem cell therapy for the heart
Congest Heart Fail
Unchain my heart: the scientific foundations of cardiac repair
J Clin Invest
Adult stem cell therapy in perspective
Circulation
Mobilization of bone marrow-derived stem cells after myocardial infarction and left ventricular function
Eur Heart J
Use of granulocyte-colony stimulating factor during acute myocardial infarction to enhance bone marrow stem cell mobilization in humans: clinical and angiographic safety profile
Eur Heart J
Statin-induced improvement of endothelial progenitor cell mobilization, myocardial neovascularization, left ventricular function, and survival after experimental myocardial infarction requires endothelial nitric oxide synthase
Circulation
Cytokine therapy prevents left ventricular remodeling and dysfunction after myocardial infarction through neovascularization
FASEB J
Cardiac stem cells delivered intravascularly traverse the vessel barrier, regenerate infarcted myocardium, and improve cardiac function
Proc Natl Acad Sci U S A
Stem cells in the dog heart are self-renewing, clonogenic, and multipotent and regenerate infarcted myocardium, improving cardiac function
Proc Natl Acad Sci U S A
Autologous stem cell transplantation for myocardial repair
Am J Physiol Heart Circ Physiol
Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium
Nature
Cited by (26)
Cardiac stem cell transplantation with 2,3,5,4′-tetrahydroxystilbehe-2-O-β-D-glucoside improves cardiac function in rat myocardial infarction model
2016, Life SciencesCitation Excerpt :With the inadequacy of existing treatments and the shortage of organs for heart transplantation, stem cell therapy has generated a great deal of interest as a potential treatment. Various cell types have been used as sources for cell transplantation therapy in experimental and clinical studies of myocardial infarction therapeutics [4–6]. These have included embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), bone marrow–derived stem cells (BMSCs), mesenchymal stem cells (MSCs), and cardiac stem cells (CSCs) [7], the latter representing a research hotspot in recent years [8].
Transplantation of Bone Marrow-Derived Stem Cells Improves Myocardial Diastolic Function: Strain Rate Imaging in a Model of Hibernating Myocardium
2009, Journal of the American Society of EchocardiographyCitation Excerpt :In contrast to stem cell–treated animals, echocardiographic determinants of increased LV filling pressure increased significantly in the control group, indicating global cardiac remodeling after myocardial infarction. Regional as well as global cardioprotective effects play a role regarding the regenerative power of stem cells.30,31 Berry et al1 reported a softening effect of the scar tissue after MSC injection by increasing cellularity, leading to a more compliant scar and less global cardiac remodeling.
Intramyocardial Transplantation of Bone Marrow-Derived Stem Cells: Ultrasonic Strain Rate Imaging in a Model of Hibernating Myocardium
2008, Journal of Cardiac FailureCitation Excerpt :In addition, protective effects by recruitment of endogenous cardiac progenitors and enhancement of native cardiomyocyte survival and function and promotion of revascularization were previously discussed.2 Several studies have shown that paracrine factors induce neovascularization in a chronic ischemia model.2,16,25–31 In our study, cardioprotective effects of stem cells were associated with angiogenesis and the assessment of immature arterial vessels.
Survival and maturation of human embryonic stem cell-derived cardiomyocytes in rat hearts
2007, Journal of Molecular and Cellular CardiologyCitation Excerpt :In addition, the time needed to process and expand autologous myoblast cultures would make it difficult to deliver them in a timely fashion following myocardial infarction. Although other adult stem cells (as for example, bone marrow-derived stem cells and mesenchymal stem cells) retain the advantage of being autologous in source, their ability to undergo “transdifferentiation” to bona fide cardiomyocytes remains controversial [2]. In recent early phase clinical trials with bone marrow cells, results were quite mixed and although small but significant effects were detected in some studies, the reasons for the functional impact on the heart remain unclear [26] and may be related to a paracrine effect rather than true replacement of muscle [27–29].
Myocardial regeneration, tissue engineering and therapy
2007, Artificial Cells, Cell Engineering and TherapyMyocardial regeneration by human amniotic fluid stem cells: Challenges to be overcome
2007, Journal of Molecular and Cellular Cardiology