Lost and found: cardiac stem cell therapy revisited

Abstract

Several clinical trials of bone marrow stem cell therapy for myocardial infarction are ongoing, but the mechanistic basis for any potential therapeutic effect is currently unclear. A growing body of evidence suggests that the potential improvement in cardiac function is largely independent of cardiac muscle regeneration. A study by Fazel et al. in this issue of the JCI provides evidence that bone marrow-derived c-kit+ cells can lead to an improvement in cardiac function in mutant hypomorphic c-kit mice that is independent of transdifferentiation into either cardiac muscle or endothelial cells, but rather is associated with the release of angiogenic cytokines and associated neovascularization in the infarct border zone (see the related article beginning on page 1865). These findings suggest the potential therapeutic effect of specific paracrine pathways for angiogenesis in improving cardiac function in the injured heart.

Figure 1. Bone marrow transplantation of mutant c-kit mice partially rescues dilated cardiomyopathy following acute myocardial infarction via neovascularization (16).

(A) Compound heterozygote mutant Kit^W/Kit^W-v mice are irradiated and the bone marrow reconstituted with GFP-tagged bone marrow precursors derived from wild-type mice. (B) A small number of the wild-type c-kit⁺ GFP-tagged bone marrow–derived cells migrate into the heart of the mutant c-kit⁺ mice. (C) Coronary ligation results in an acute myocardial infarction in the mutant mice, with the marked migration of the wild-type GFP-tagged c-kit⁺ cells into the infarct border zone. Compared with mutant c-kit mice that have not had reconstitution with wild-type bone marrow precursors, there is a markedly smaller extent of chamber dilation and associated dysfunction in the wild-type transplanted mutant c-kit mice. The beneficial effect is not associated with transdifferentiation into cardiac myocytes or vascular cells but rather is associated with the release of angiogenic cytokines and an increase in neovascularization.