Abstract 48: Clonal Analysis of Cardiac Cell Generation During Cardiac Development and Injury
Accumulating evidence supports limited regenerative potential of the mammalian heart. However, this endogenous regenerative capacity significantly decreases with age and it is not sufficient to replenish the lost myocardium following injury in the adult. Both resident cardiac stem/progenitor cells and mature cardiomyocytes have been proposed to contribute to cardiac tissue generation. Understanding the molecular and cellular mechanisms governing cardiac cell formation is imperative towards the development of novel therapeutic strategies for cardiac regeneration. Hypothesis: Cardiac growth occurs primarily through progenitor cells and to a lesser extent through cardiomyocyte proliferation. Nkx2.5+ cells are the predominant population driving cardiac growth during development and may represent candidate progenitors for cardiac regeneration. Moreover, a subset of “proliferating” αMHC+ cardiomyocytes may also contribute to cardiac growth during early embryonic development and the first week of life. Materials and methods: We performed clonal analysis using a multicolor reporter system (Rainbow) that allows labeling of single cells with one of three fluorescent proteins and retrospective analysis of their progeny. Rainbow mice were crossed to βactinCreER, αMHCCreER, Nkx2.5CreER and Rosa26CreER mice. Tamoxifen was administered at E9.5 or E12.5 and analysis was performed at P1, P7, P15 and P30. Results: We observed significant clonal expansion in βactinCreER;Rainbow and Nkx2.5CreER;Rainbow hearts while αMHCCreER;Rainbow hearts exhibited clones comprising of smaller cell number. We also found that αMHC positive cells lose their proliferative capacity from E9.5 to E12.5, whereas cells expressing Nkx2.5 continue to clonally expand during that same time period. Finally, we demonstrated that αMHC+ cardiomyocyte proliferation is reactivated following myocardial injury soon after birth. Conclusion: Our data support that clonal dominance of progenitor cells promotes cardiac development, while cardiomyocyte proliferation contributes to a lesser extent early in development and postnatally.
Author Disclosures: K. Sereti: None. P. Kamran: None. P. Zhao: None. S. Ranjbarvaziri: None. J. Engel: None. H. Mikkola: None. R. Ardehali: None.
- © 2015 by American Heart Association, Inc.