Elsevier

The Lancet

Volume 379, Issue 9819, 10–16 March 2012, Pages 933-942
The Lancet

Series
Towards regenerative therapy for cardiac disease

https://doi.org/10.1016/S0140-6736(12)60075-0Get rights and content

Summary

Development of regenerative therapeutic strategies to reverse the progression of advanced heart failure is one of the most urgent clinical needs of this century. Insights gained from clinical trials of adult stem cells, together with fundamental scientific advances in cardiac stem cell and regenerative biology, are beginning to yield potential new targets and strategies for regenerative therapies. Of particular importance are new scientific discoveries related to intrinsic cardiac regeneration, renewal factors that can trigger regeneration, and tissue-engineering technology, which are beginning to change the way investigators view the scientific and clinical position of cardiovascular regenerative therapy.

Introduction

Heart failure is one of the key causes of morbidity and mortality worldwide.1 The effects of heart failure are growing very rapidly, especially in developing countries.2 Available medical and device-based therapies can ameliorate the effects of heart failure, but cannot reverse the loss of functional myocardium, which is the underlying cause of the problem.3 The only available cure for advanced heart failure is orthotopic heart transplantation, which is not a viable strategy in the general population because of a relative absence of donor hearts.4 Heart failure is thus evolving into a global epidemic for which medicine does not have an available solution. Design of an efficacious regenerative therapeutic strategy has therefore become a holy grail of modern cardiovascular science. Recent breakthroughs in stem cell biology provide large strides toward this goal. This report discusses key opportunities and challenges in movement from academic stem cell biology towards the development of cardiovascular regenerative therapy.

Section snippets

Attempted cardiac regeneration with non-cardiac progenitor cells

The severity of heart failure and the inability of available treatments to abrogate its effects have spurred intense interest in cardiac regeneration. Several organs, notably the liver, have clinically relevant regeneration after injury.5 Although cardiac regeneration is reported in lower vertebrates such as amphibians and zebrafish, equivalent regenerative capacity is not possessed by adult mammals.6, 7 Cardiomyocyte proliferation is present in neonatal mice, but diminishes rapidly after birth,

Endogenous cardiac progenitor cells

Augmentation of endogenous regenerative activity is a compelling strategy for cardiac repair. In theory, such amplification can be achieved with two distinct approaches. One approach would be to stimulate expansion of cardiomyocytes or putative cardiac progenitor cells with a drug or paracrine factor, in the same way that erythropoietin is given to stimulate bone marrow progenitor cells to produce erythrocytes. The second approach involves propagation of cardiac cells with regenerative

Genetic fate mapping and endogenous cardiac progenitor cells

The search for cardiac cells and paracrine factors that are capable of triggering cardiac repair has been challenging. Further progress will need more precise definitions of the phenotypes and biological roles of relevant cell populations. Use of genetic fate mapping to study embryonic cardiogenesis has eased the definition of progenitor populations and helped establish their roles in forming of discrete cardiac structures.

The heart contains a complex array of structures, including muscle,

The promise of induced pluripotent stem cells

Even if the phenotypes of cardiac cells with regenerative potential can be better defined, their rarity might make it difficult to generate enough cells to produce a clinically meaningful effect. Embryonic stem cells are an attractive source of starting material for cell-based therapies, mainly because they are self-renewing pluripotent cells that can be differentiated into tissues from all three germ layers.57 Cardiomyocytes produced from mouse embryonic stem cells in vitro are closer to the

Paracrine factors in cardiac regeneration

Paracrine factors, notably those in the renin–angiotensin system, have key roles in cardiac pathophysiological mechanisms.70 The benefit associated with bone marrow cell therapy might be attributable to paracrine factors, but neither the identity nor the actions of these putative factors are known. Several possible activities have been proposed, including activation of putative endogenous cardiac progenitor cells, direct stimulation of cardiomyocyte division, and modification of the tissue

Delivery of regenerative therapy

A safe, effective, and practical delivery system is crucial to the success of cardiac regenerative therapy. Such a platform would have to ensure reliable delivery of a sufficient amount of the therapeutics to trigger regeneration, have good visualisation of the target area, and provide specific delivery to the target area with minimal off-target delivery and little or no risk of haematogenous dissemination.72 Several delivery techniques have been reported, ranging from direct intramyocardial

Cardiac tissue engineering

Successful reconstitution of damaged cardiac tissue cannot rely solely on regeneration of cardiomyocytes because the architecture of myocardium is complex. Cardiomyocytes in the adult heart are oriented end-to-end in fibres, which are woven into anisotropically oriented sheets whose organisation forms the basis for chamber contraction. Among these sheets are complex webs of fibroblasts, blood vessels, and conduction-system tissue. Spatial organisation of these cells during embryogenesis is

Perspectives

The heart is made up of a complex mosaic of distinct anatomical elements that are substantially disrupted in cardiac injury. Because of this complexity, restoration of cardiac function would need recreation of the native architecture of the heart, not just regeneration of one cell type. An ideal cardiac regenerative therapy would possess a key cell and paracrine factor combination, a cardiac tissue niche optimised to enhance cell engraftment and differentiation, and a safe, minimally invasive

Search strategy and selection criteria

We searched PubMed for published articles with the terms “cardiovascular disease”, “heart failure”, “cardiac regeneration”, “cardiac progenitor”, “stem cell”, and “stem cell therapy”. Most selected publications were published in the past 5 years. Older publications were included if they were well regarded or widely referenced. We also included references listed in articles identified in the initial searches, and reports from governmental organisations. The date of the last search was Nov 30,

References (82)

  • JZ Stoller et al.

    Cardiac neural crest

    Semin Cell Dev Biol

    (2005)
  • A Moretti et al.

    Multipotent embryonic isl1+ progenitor cells lead to cardiac, smooth muscle, and endothelial cell diversification

    Cell

    (2006)
  • Y Qyang et al.

    The renewal and differentiation of Isl1+ cardiovascular progenitors are controlled by a Wnt/beta-catenin pathway

    Cell Stem Cell

    (2007)
  • LW van Laake et al.

    Human embryonic stem cell-derived cardiomyocytes survive and mature in the mouse heart and transiently improve function after myocardial infarction

    Stem Cell Res (Amst)

    (2007)
  • K Takahashi et al.

    Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors

    Cell

    (2006)
  • K Takahashi et al.

    Induction of pluripotent stem cells from adult human fibroblasts by defined factors

    Cell

    (2007)
  • L Warren et al.

    Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA

    Cell Stem Cell

    (2010)
  • M Ieda et al.

    Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors

    Cell

    (2010)
  • Y Sun

    Intracardiac renin-angiotensin system and myocardial repair/remodeling following infarction

    J Mol Cell Cardiol

    (2010)
  • BJ Gersh et al.

    Cardiac cell repair therapy: a clinical perspective

    Mayo Clin Proc

    (2009)
  • P Raake et al.

    Myocardial gene transfer by selective pressure-regulated retroinfusion of coronary veins: comparison with surgical and percutaneous intramyocardial gene delivery

    J Am Coll Cardiol

    (2004)
  • T Kimura et al.

    Safety and efficacy of pericardial endoscopy by percutaneous subxyphoid approach in swine heart in vivo

    J Thorac Cardiovasc Surg

    (2011)
  • J Leor et al.

    Intracoronary injection of in situ forming alginate hydrogel reverses left ventricular remodeling after myocardial infarction in Swine

    J Am Coll Cardiol

    (2009)
  • TP Kraehenbuehl et al.

    Human embryonic stem cell-derived microvascular grafts for cardiac tissue preservation after myocardial infarction

    Biomaterials

    (2011)
  • AL Bui et al.

    Epidemiology and risk profile of heart failure

    Nat Rev Cardiol

    (2011)
  • TA Gaziano

    Reducing the growing burden of cardiovascular disease in the developing world

    Health Aff (Millwood)

    (2007)
  • RS Whelan et al.

    Cell death in the pathogenesis of heart disease: mechanisms and significance

    Annu Rev Physiol

    (2010)
  • R Taub

    Liver regeneration: from myth to mechanism

    Nat Rev Mol Cell Biol

    (2004)
  • AW Neff et al.

    Heart development and regeneration in urodeles

    Int J Dev Biol

    (1996)
  • KD Poss et al.

    Heart regeneration in zebrafish

    Science

    (2002)
  • ER Porrello et al.

    Transient regenerative potential of the neonatal mouse heart

    Science

    (2011)
  • MH Soonpaa et al.

    Survey of studies examining mammalian cardiomyocyte DNA synthesis

    Circ Res

    (1998)
  • O Bergmann et al.

    Evidence for cardiomyocyte renewal in humans

    Science

    (2009)
  • AP Beltrami et al.

    Evidence that human cardiac myocytes divide after myocardial infarction

    N Engl J Med

    (2001)
  • PC Hsieh et al.

    Evidence from a genetic fate-mapping study that stem cells refresh adult mammalian cardiomyocytes after injury

    Nat Med

    (2007)
  • DA Taylor et al.

    Regenerating functional myocardium: improved performance after skeletal myoblast transplantation

    Nat Med

    (1998)
  • P Menasché et al.

    The Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC) trial: first randomized placebo-controlled study of myoblast transplantation

    Circulation

    (2008)
  • D Orlic et al.

    Bone marrow cells regenerate infarcted myocardium

    Nature

    (2001)
  • F Quaini et al.

    Chimerism of the transplanted heart

    N Engl J Med

    (2002)
  • 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)
  • K Lunde et al.

    Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction

    N Engl J Med

    (2006)
  • Cited by (194)

    • Engineering stem cell therapeutics for cardiac repair

      2022, Journal of Molecular and Cellular Cardiology
    • Umbilical cord mesenchymal stromal cells engraft and transdifferentiate into cardiomyocyte-like cells following acute myocardial ischemia⋆

      2020, Acta Histochemica
      Citation Excerpt :

      In this study, we tested the efficacy of intramyocardial cell administration following an acute MI intervention, after which the animals were followed up for 3 weeks. We directly transplanted cells around the ischemic region, a more direct route of delivery, which noticeably inhibited the cell loss after transplantation since many transplanted cells either diffuse throughout the body with the circulatory system as immunologically rejected, do not find a proper microenvironment and become trapped in the pulmonary vasculature (Ptaszek et al., 2012). Yannarelli et al. recorded that cardiac function improved when hUC-perivascular cells (PVCs) were administered intramyocardially, whereas observed no improvement in cardiac function when the same type and number of cells were given by IV (intravenous) infusion (Yannarelli et al., 2013).

    View all citing articles on Scopus
    View full text