Abstract 18976: Progenitor Cell Ploidy: The Regulator of Regenerative Fate

Abstract

Cellular therapy is an emerging interventional strategy to treat heart failure and has demonstrated tremendous potential in recent years. Use of endogenous stem cells found within the heart, cardiac progenitor cells (CPC), has prompted intense basic research in multiple experimental animal models as well as clinical trials in heart failure patients. Scientifically, the field continues to unravel mechanisms of CPC involvement in remodeling and repair of the heart under both normal and pathologic conditions. Research has been primarily performed in mouse models, which represent the fundamental experimental platform for a vast array of regenerative medicine research. Given the importance of mouse models for stem cell research, understanding fundamental differences between mouse and human stem cell biology are essential. Our findings show that adult murine CPCs contain tetraploid (4n) chromosome content in contrast to the normally expected diploid (2n) chromosome content as found in human CPCs by karyotype analyses. To expand the significance of this finding, CPCs were isolated from standard lab mice (FVB and C57), human telomere-length equivalent mice (CAST and SPRET) and an early onset senescence mouse (SAMP6), which revealed mononuclear tetraploid content as characterized through a combination of flow cytometry and confocal microscopy analysis using antibodies and fluorescence in situ hybridization (FISH) techniques. In comparison, isolated murine ckit+ bone marrow stem cells possess mononuclear diploid content through similar analysis. The ploidy content of endogenous murine and human CPCs was investigated in situ with heart tissue sections with comparable ploidy determinations to that of cultured CPCs. Furthermore, the unique tetraploid content of CPCs within the murine heart is reinforced by comparison with ckit+ progenitor cells of secondary tissues (intestine and bone) that exhibit diploid chromosome content. These studies reveal a fundamental difference between human and murine CPCs that is essential for functional regenerative potential since regenerative tissues commonly are polyploid. Future directions will focus on defining the advantage of polyploidy in mediating regeneration.