Review
Cell Therapy for Heart Disease: Great Expectations, As Yet Unmet

https://doi.org/10.1016/j.hlc.2008.10.014Get rights and content

Regenerative medicine is often touted as an achievement of the new millennium, but many approaches to improve health by stimulating the organism's own capacity for healing have existed for a long time. Some components of today's regenerative medicine, however, are indeed fundamentally new developments, and one of those is the concept of increasing the number of contractile cells in the heart to cure heart failure, either by stimulating intrinsic regeneration processes or by transplanting exogenous cells. The aim of this paper is to review the current status of some key aspects of cell therapy and obstacles to clinical translation.

Section snippets

Transplanting Contractile Cells

The primary goal of cardiac cell therapy is to increase the number of contractile cells in the ventricular myocardium to improve systolic heart function. Additional possible actions of cell therapy in the heart include paracrine effects supporting angiogenesis, modulation of extracellular matrix components, supportive effects on cardiomyocytes suffering from ischaemic stress, and stimulating interactions with resident cardiac progenitor cells (Fig. 2). Originally, immortalised myocyte lines and

Clinical Cell Therapy

The spectrum of cell products for clinical cardiac cell therapy is currently limited to adult progenitor cells that are freshly isolated or undergo in vitro expansion with minimal manipulation of their biologic characteristics. Clinical stem cell products that require a more complex manufacturing process are under development, but have not yet been used in humans. Much of the clinical cell therapy data is being discussed with vehemence. Even though clinical cell therapy has been performed for

Clinical Translation Problems

Although the experimental basis of myocardial cell therapy is incomplete, numerous clinical applications have already been initiated. Attention mainly focuses on the cell product, but there are many other factors that need to be considered to maximise the likelihood of successful cell-based myocardial regeneration. The following sections will look at these factors.

Summary

While cardiac cell therapy has initially caused tremendous excitement, reluctance currently dominates. There have been – and will be more – substantial obstacles and setbacks along the road to success, but only about 15 years have so far been spent trying to develop therapies involving cell-based cardiac regeneration. The early clinical use of marrow-derived cells for heart disease has been much criticised, but it is understandable that physicians began by testing the clinical efficacy of bone

References (96)

  • D. Nurzynska et al.

    Shock waves activate in vitro cultured progenitors and precursors of cardiac cell lineages from the human heart

    Ultrasound Med Biol

    (2008)
  • T.E. Robey et al.

    Systems approaches to preventing transplanted cell death in cardiac repair

    J Mol Cell Cardiol

    (2008)
  • K.C. Wollert et al.

    Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the boost randomised controlled clinical trial

    Lancet

    (2004)
  • S. Janssens et al.

    Autologous bone marrow-derived stem-cell transfer in patients with st-segment elevation myocardial infarction: double-blind, randomised controlled trial

    Lancet

    (2006)
  • T.J. Povsic et al.

    Circulating progenitor cells can be reliably identified on the basis of aldehyde dehydrogenase activity

    J Am Coll Cardiol

    (2007)
  • C. Stamm et al.

    Autologous bone-marrow stem-cell transplantation for myocardial regeneration

    Lancet

    (2003)
  • K.H. Grinnemo et al.

    Xenoreactivity and engraftment of human mesenchymal stem cells transplanted into infarcted rat myocardium

    J Thorac Cardiovasc Surg

    (2004)
  • G. Pompilio et al.

    Autologous peripheral blood stem cell transplantation for myocardial regeneration: a novel strategy for cell collection and surgical injection

    Ann Thorac Surg

    (2004)
  • E. Messas et al.

    Autologous myoblast transplantation for chronic ischemic mitral regurgitation

    J Am Coll Cardiol

    (2006)
  • T.M. Yau et al.

    Increasing transplanted cell survival with cell-based angiogenic gene therapy

    Ann Thorac Surg

    (2005)
  • M. Zhang et al.

    Cardiomyocyte grafting for cardiac repair: graft cell death and anti-death strategies

    J Mol Cell Cardiol

    (2001)
  • C. Stamm et al.

    Cardiac cell therapy: a realistic concept for elderly patients?

    Exp Gerontol

    (2008)
  • E. Messina et al.

    Isolation and expansion of adult cardiac stem cells from human and murine heart

    Circ Res

    (2004)
  • M. Rota et al.

    The young mouse heart is composed of myocytes heterogeneous in age and function

    Circ Res

    (2007)
  • I. Bittmann et al.

    Endothelial cells but not epithelial cells or cardiomyocytes are partially replaced by donor cells after allogeneic bone marrow and stem cell transplantation

    J Hematother Stem Cell Res

    (2003)
  • A. Deb et al.

    Bone marrow-derived cardiomyocytes are present in adult human heart: a study of gender-mismatched bone marrow transplantation patients

    Circulation

    (2003)
  • S. Jiang et al.

    Transplanted human bone marrow contributes to vascular endothelium

    Proc Natl Acad Sci U S A

    (2004)
  • E. Minami et al.

    Extracardiac progenitor cells repopulate most major cell types in the transplanted human heart

    Circulation

    (2005)
  • M.A. Laflamme et al.

    Evidence for cardiomyocyte repopulation by extracardiac progenitors in transplanted human hearts

    Circ Res

    (2002)
  • D. Torella et al.

    Resident cardiac stem cells

    Cell Mol Life Sci

    (2007)
  • H. Oh et al.

    Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction

    Proc Natl Acad Sci U S A

    (2003)
  • C. Bearzi et al.

    Human cardiac stem cells

    Proc Natl Acad Sci U S A

    (2007)
  • R.R. Smith et al.

    Regenerative potential of cardiosphere-derived cells expanded from percutaneous endomyocardial biopsy specimens

    Circulation

    (2007)
  • K.L. Laugwitz et al.

    Postnatal isl1+ cardioblasts enter fully differentiated cardiomyocyte lineages

    Nature

    (2005)
  • D. Marelli et al.

    Cell transplantation for myocardial repair: an experimental approach

    Cell Transplant

    (1992)
  • J. Leor et al.

    Transplantation of fetal myocardial tissue into the infarcted myocardium of rat. A potential method for repair of infarcted myocardium?

    Circulation

    (1996)
  • D.A. Taylor et al.

    Regenerating functional myocardium: Improved performance after skeletal myoblast transplantation

    Nat Med

    (1998)
  • M. Rubart et al.

    Spontaneous and evoked intracellular calcium transients in donor-derived myocytes following intracardiac myoblast transplantation

    J Clin Invest

    (2004)
  • N. Dib et al.

    Safety and feasibility of autologous myoblast transplantation in patients with ischemic cardiomyopathy: four-year follow-up

    Circulation

    (2005)
  • F. Limana et al.

    Identification of myocardial and vascular precursor cells in human and mouse epicardium

    Circ Res

    (2007)
  • A. Behfar et al.

    Stem cell differentiation requires a paracrine pathway in the heart

    FASEB J

    (2002)
  • A. Behfar et al.

    Cardiopoietic programming of embryonic stem cells for tumor-free heart repair

    J Exp Med

    (2007)
  • J.A. Byrne et al.

    Producing primate embryonic stem cells by somatic cell nuclear transfer

    Nature

    (2007)
  • K. Guan et al.

    Generation of functional cardiomyocytes from adult mouse spermatogonial stem cells

    Circ Res

    (2007)
  • J.B. Kim et al.

    Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors

    Nature

    (2008)
  • G. Narazaki et al.

    Directed and systematic differentiation of cardiovascular cells from mouse induced pluripotent stem cells

    Circulation

    (2008)
  • K.B. Pasumarthi et al.

    Cardiomyocyte cell cycle regulation

    Circ Res

    (2002)
  • M.H. Soonpaa et al.

    Assessment of cardiomyocyte DNA synthesis in normal and injured adult mouse hearts

    Am J Physiol

    (1997)
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