Elsevier

Transplant Immunology

Volume 15, Issue 2, December 2005, Pages 91-97
Transplant Immunology

Stem cell transplantation for the treatment of myocardial infarction

https://doi.org/10.1016/j.trim.2005.09.004Get rights and content

Abstract

Stem cell transplantation provides a potential regenerative therapy for the heart damaged by myocardial infarction. Numerous scientific studies have been undertaken in animals and humans to analyze the safety and efficacy of this new approach. However, at the present time, the results have been mixed and inconclusive, and the mechanism of stem cell transplantation therapy remains unclear. This review discusses the controversies and problems that need to be addressed in future investigations.

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)

  • V. Schachinger et al.

    Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction: final one-year results of the TOPCARE-AMI Trial

    J Am Coll Cardiol

    (2004)
  • H.J. Kang et al.

    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

    (2004 (Mar 6))
  • T. Siminiak et al.

    Autologous skeletal myoblast transplantation for the treatment of postinfarction myocardial injury: phase I clinical study with 12 months of follow-up

    Am Heart J

    (2004)
  • J. Suarez de Lezo et al.

    Effects of stem-cell mobilization with recombinant human granulocyte colony stimulating factor in patients with percutaneously revascularized acute anterior myocardial infarction

    Rev Esp Cardiol

    (2005)
  • C. Connelly et al.

    Movement of necrotic wavefront after coronary artery occlusion in rabbit

    Am J Physiol

    (1982)
  • J. Kajstura et al.

    Myocyte proliferation in end-stage cardiac failure in humans

    Proc Natl Acad Sci U S A

    (1998)
  • A.P. Beltrami et al.

    Evidence that human cardiac myocytes divide after myocardial infarction

    N Engl J Med

    (2001)
  • F. Quaini et al.

    Chimerism of the transplanted heart

    N Engl J Med

    (2002)
  • M.A. Pfeffer

    Left ventricular remodeling after acute myocardial infarction

    Annu Rev Med

    (1995)
  • P. Seth et al.

    Treatment of acute myocardial infarction: better, but still not good enough

    Arch Intern Med

    (2003)
  • T. Reffelmann et al.

    Cellular cardiomyoplasty-cardiomyocytes, skeletal myoblasts, or stem cells for regenerating myocardium and treatment of heart failure?

    Cardiovasc Res

    (2003)
  • L.E. Wold et al.

    Stem cell therapy for the heart

    Congest Heart Fail

    (2004)
  • S. Dimmeler et al.

    Unchain my heart: the scientific foundations of cardiac repair

    J Clin Invest

    (2005)
  • E.C. Perin et al.

    Adult stem cell therapy in perspective

    Circulation

    (2003)
  • A.M. Leone et al.

    Mobilization of bone marrow-derived stem cells after myocardial infarction and left ventricular function

    Eur Heart J

    (2005)
  • M. Valgimigli et al.

    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

    (2005)
  • U. Landmesser et al.

    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

    (2004)
  • M. Ohtsuka et al.

    Cytokine therapy prevents left ventricular remodeling and dysfunction after myocardial infarction through neovascularization

    FASEB J

    (2004)
  • Sesti Casilde, Hale Sharon L, Lutzko Carolyn, Kloner Robert A. Granulocyte colony-stimulating factor and stem cell...
  • B. Dawn et al.

    Cardiac stem cells delivered intravascularly traverse the vessel barrier, regenerate infarcted myocardium, and improve cardiac function

    Proc Natl Acad Sci U S A

    (2005)
  • A. Linke et al.

    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

    (2005)
  • J. Liu et al.

    Autologous stem cell transplantation for myocardial repair

    Am J Physiol Heart Circ Physiol

    (2004)
  • L.B. Balsam et al.

    Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium

    Nature

    (2004)
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