Abstract 18947: Clonal C-kit-Positive Bone Marrow Cells and Cardiomyogenesis

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Conflicting results have been reported concerning the ability of c-kit-positive bone marrow cells (c-kit-BMCs) to transdifferentiate into cardiomyocytes. We have raised the possibility that c-kit-BMCs may constitute a functionally heterogeneous pool, containing cells with different cardiomyogenic potential. To test this hypothesis, multicellular clones derived from individual c-kit-BMCs were obtained and transplanted in acutely infarcted mice. Only a limited fraction of clonal c-kit-BMCs was found to be able to form cardiomyocytes and promote myocardial regeneration. On this basis, c-kit-BMC-derived clones were classified as myogenic or non-myogenic. The gene profile of these two categories of cells was studied by RNA-sequencing. Genes that showed a significant (p<0.05) expression difference among cell groups were included in the analysis; 35 genes were uniquely upregulated in myogenic c-kit-BMCs. These results were subjected to functional annotation using gene ontology for the identification of molecular pathways showing different state of activation or repression in myogenic c-kit-BMCs. The 35 upregulated transcripts in myogenic c-kit-BMCs involved signal transduction and cell differentiation pathways. Similarly, a set of genes implicated in the response to stress were more represented in myogenic c-kit-BMCs, possibly reflecting the proficiency of this cell class to engraft in the microenvironment of the infarcted heart. A subset of these genes was found to be highly expressed in adult c-kit-positive resident cardiac stem cells. They included sequestosome1 and phosphodiesterase1C, which are highly expressed during cardiac development. Moreover, cathepsin D, which favors angiotensin II formation, sarcomeric accumulation, and myocyte hypertrophy, was more represented in myogenic c-kit-BMCs. With respect to the whole pool of freshly isolated c-kit-BMCs, 105 genes were downregulated in myogenic c-kit-BMCs, indicating that transdifferentation into cardiomyocytes requires the suppression of hematopoietic factors. In conclusion, c-kit-BMCs are functionally heterogeneous, containing cells with different cardiomyogenic potential.