Cellular Cardiomyoplasty: Improvement of Left Ventricular Function Correlates with the Release of Cardioactive Cytokines

Abstract

A growing number of studies are reporting beneficial effects of the transplantation of alleged cardiac stem cells into diseased hearts after myocardial infarction. However, the mechanisms by which transplanted cells might help to promote repair of cardiac tissue are not understood and might involve processes different from the differentiation of transplanted cells into cardiomyocytes. We have compared the effects exerted by skeletal myoblasts (which are not able to form new cardiomyocytes) and ESC-derived cardiomyocytes after implantation into infarcted mouse hearts by echocardiographic follow-up and histological analysis and related these effects to the release of cardioactive cytokines. We found that both cell types led to a long-lasting improvement of left ventricle function and to an improvement of tissue architecture. Since no relevant amounts of myoblastderived cells were present in infarcted hearts 28 days after transplantation, we investigated the release of cytokines from implanted cells both before and after transplantation into infarcted hearts. ESC-derived cardiomyocytes and myoblasts secreted substantial amounts of interleukin (IL)-1␣, IL-6, tumor necrosis factor-␤, and oncostatin M, which strongly supported survival and protein synthesis of cultured cardiomyocytes. We postulate that the beneficial effects of the transplantation of myoblasts and cardiomyocytes on heart function and morphology only partially (if at all) depend on the integration of transplanted cells into the myocardium but do depend on the release of a complex blend of cardioactive cytokines. STEM CELLS 2007;25:236 -244

Characterization of the paracrine effects of human skeletal myoblasts transplanted in infarcted myocardium

“…Nevertheless, with the exception of the recently described skeletal precursors of cardiomyocyte cells (Spoc) isolated from mouse muscle, which have demonstrated their potential to differentiate into beating and functional cardiomyocytes both in vitro an in vivo [27], the general consensus is that SM do not differentiate into cardiomyocytes [6]. Therefore, the paracrine hypothesis looks like a sound mechanism to explain the experimentally-demonstrated improvement of function in myoblast-grafted failing hearts independently of true cardiac regeneration [9,26,[28][29][30][31][32]. Overall, our microarray data, more directly validated by Q-RT-PCR measurements, suggests that injected SM, differentiated myotubes expected to result from their in vivo fusion and fibroblastlike cells that contaminate myoblast injections, release important factors involved in angiogenesis, remodelling and apoptosis inhibition pathways that can ultimately lead to enhanced cardiac tissue protection.…”

Non-canonical Wnt signaling enhances differentiation of Sca1+/c-kit+ adipose-derived murine stromal vascular cells into spontaneously beating cardiac myocytes

“…Although research has been performed on the in vivo role of cytokines in cell therapies and heart repair (Ebelt et al, 2007), no research has been performed on the role of cytokines on in vitro stem cell differentiation along the cardiac lineage. We tested the hypothesis that cytokines would enhance the cardiac differentiation potential of SVCs in vitro.…”

Genomic profiling of developing cardiomyocytes from recombinant murine embryonic stem cells reveals regulation of transcription factor clusters

“…They are capable of self-renewing and can differentiate into a variety of cell lineages in vitro, including cardiomyocytes (50), which is manifested by the appearance of spontaneously and rhythmically contracting cell clusters. Cardiac myocytes derived from ESC were also used for experimental cell therapy and transplanted into infarcted mouse ventricular myocardium (7,16,36). However, ESC-derived cardiomyocytes have not been used in clinical trials yet due to an increased tumor risk, immunological issues, and ethical concerns.…”