Re-growth of the adult heart by stem cells?

Abstract

The potential of the human heart to regenerate cells in tissue in adult life by local replacement of cells either by cell division or by differentiation of cardiovascular or mesenchymal progenitor cells (here referred to as stem cells) has been a subject of major controversial discussion in the last 10 years [1]. The debate and studies to understand physiological and pathological regulation of cell turnover in different parts of the heart organ is currently ongoing. Basic science is gradually evolving data on cell turnover and replacement in cardiac tissue with respect to considerable differences between the various cell types of the heart as well as to the generation and turnover of cardiac extracellular matrix components. Different kinetics of cell turnover have been discussed for endothelial cells and myofibroblasts to be at least in part derived from bone marrow stem cells and cardiomyocytes to be potentially derived from resident cardiac stem cells. First reliable human data on cell turnover and cardiomyocyte replacement has been generated by Bergmann et al. [2], observing a slow physiological replacement of cardiomyocytes throughout adult life. The source of supply of new cells either by cell division of cardiac stem cells or by cardiomyocytes is currently under debate in recently published papers. The three possible modes of replacement are (i) cell division of mononuclear cardiomyocytes [3] vs (ii) replacement by resident cardiac (progenitor) stem cells [4, 5] vs (iii) dedifferentiation and proliferation of cardiomyocytes [6]. All three proposed mechanisms remain speculative to be involved in human hearts disease. This is reflected by the divergence of the calculated rate of annual replacement of cardiomyocytes in adult human hearts ranging from 1 [2] to 40% [4]. The potential to stimulate cardiomyocyte growth by periostinbased integrin stimulation discovered by Kuhn et al. [7] fostered research on pathways for therapeutical use. Another interesting advance is coming from cell programming technology, raising prospects for clinical translation. Qian et al. [8] and Song et al. [9] have demonstrated the direct intracardiac programming of fibroblasts to cardiomyocytes by the use of a combination of transcription factors. Actually, this has been complemented by a paper by Eulalio et al. [10], demonstrating the induction by cardiomyocyte proliferation by specific microRNA. The generation of autologous cardiomyocytes from induced pluripotent stem cells (iPS) [11] for myocardial transplantation has been demonstrated to be another promising option for myocardial transplantation of cells or myocardial sheets and to induce cardiac recovery [12]. Thus, a number of tools for cell manipulation and site-directed application in cardiac disease have been discovered and can be developed for preclinical evaluation. Taken together, however, basic science understanding of the mechanism and control of cardiac growth, especially with respect to cardiomyocytes, is still quite limited to open the road for rapid clinical translation in the near future. The use of extracardiac or cardiac stem cells for therapeutic approaches to induce angiogenesis and cardiac growth, however, has gained some early advance in clinical translation, reaching clinical trial level since 2001 [13–15].