Abstract 164: Production of De Novo Cardiomyocytes in Adult Asxl2-/- Hearts
The chromatin-associated protein ASXL2 is highly expressed in the heart, where it critically regulates the levels of two repressive histone marks, trimethylated H3 lysine 27 and ubiquitinated H2A. We have previously observed that Asxl2-/- hearts displayed abnormal growth during adulthood, resulting in disproportionally larger heart from 4 months on. This abnormal growth is not due to cardiomyocyte hypertrophy, as demonstrated by measurement of comprehensive dimensions of isolated cardiomyocytes. BrdU labeling showed an elevation in proliferation index in Asxl2-/- hearts at 3 months. At the time of labeling, with rare exceptions, labeled cells are interstitial non-cardiomyocytes in both wildtype control and Asxl2-/- hearts. The vast majority of labeled cells stained positive for vimentin, a mesenchymal marker, and negative for Nkx2.5, Gata4 or c-kit. EdU pulse-chase experiments were performed to determine the fate of labeled cells. After a 4-week chase, a significant number of EdU+/cTnT+ cardiomyocytes were present in Asxl2-/- hearts but not in wildtype control hearts. Expression of the gap junction protein Cx43 was detected between EdU+ cardiomyocytes and neighboring EdU- cardiomyocytes, suggesting electrical coupling. Cardiomyocytes were isolated from pulsed-chased Asxl2-/- hearts for additional morphological analysis. Isolated EdU+/cTnT+ cardiomyocytes vary greatly in cell size, shape and nucleation status, ranging from small, spindle-shaped and mononuclear to large, rod-shaped and binuclear. Taken together, our data suggest that new cardiomyocytes are produced in adult Asxl2-/- hearts from a population of proliferative interstitial cells that are distinct from c-kit+ cardiac stem cells. This raises intriguing possibilities for cardiac repair and regeneration.
Author Disclosures: R. Brunner: None. M. Gerdes: None. T. Wang: None.
This research has received full or partial funding support from the American Heart Association, Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota & Wisconsin).
- © 2015 by American Heart Association, Inc.