Cardiac cell therapy: where we've been, where we are, and where we should be headed

Abstract

Introduction: Stem cell therapy has emerged as a promising strategy for the treatment of ischemic cardiomyopathy.

Sources of data: Multiple candidate cell types have been used in preclinical animal models and in clinical trials to repair or regenerate the injured heart either directly (through formation of new transplanted tissue) or indirectly (through paracrine effects activating endogenous regeneration).

Areas of agreement: (i) Clinical trials examining the safety and efficacy of bone marrow derived cells in patients with heart disease are promising, but results leave much room for improvement. (ii) The safety profile has been quite favorable. (iii) Efficacy has been inconsistent and, overall, modest. (iv) Tissue retention of cells after delivery into the heart is disappointingly low. (v) The beneficial effects of adult stem cell therapy are predominantly mediated by indirect paracrine mechanisms.

Areas of controversy: The cardiogenic potential of bone marrow-derived cells, the mechanism whereby small numbers of poorly-retained cells translate to measurable clinical benefit, and the overall impact on clinical outcomes are hotly debated. GROWING POINTS/AREAS TIMELY FOR DEVELOPING RESEARCH: This overview of the field leaves us with cautious optimism, while motivating a search for more effective delivery methods, better strategies to boost cell engraftment, more apt patient populations, safe and effective 'off the shelf' cell products and more potent cell types.

Fig. 1

Specimen processing for human cardiosphere growth and CDC expansion. Cardiac biopsies (A) are minced into fragments termed explants. Explants are placed in primary culture and spontaneously shed outgrowth cells (B) which upon confluency (C) can be harvested by gentle enzymatic digestion. When placed in suspension culture, these cells self-organized into multicellular spherical clusters, termed cardiospheres (D). CSps are collected and plated onto fibronectin-coated dishes, generating CDCs (E). Flow cytometry experiments demonstrate that CDCs are a naturally heterogeneous population of non-hematologic origin (CD45−), comprising endogenous cardiac stem cells (c-Kit+) and cardiac mesenchymal stem cells (CD90+).

Fig. 2

CDCs and CSps improve cardiac function post-MI in mice, rats and pigs, compared with sham-injected controls (*P < 0.05 compared with controls; in the study by Zakharova et al., CDCs were transplanted as a sheet, while in the study by Takehara et al., CDCs were injected with a basic fibroblast growth factor incorporating hydrogel).

Fig. 3

Excellent safety profile of intracoronary delivery of BMMNCs. Odds ratio of BMMNC infusion therapy with respect to several safety endpoints. Five trials (REPAIR-AMI,^, BOOST, ASTAMI, Janssens et al. and Yao et al.) were included in the meta-analysis. Reproduced from ref. .