The concept of stimulating cardiomyocyte mitotic divisions has dramatic implications for cardiac regeneration and hence, cardiovascular disease. We previously demonstrated for the first time that mammalian cardiomyocyte mitoses can occur postnatally if cyclin A2 is constitutively expressed in cardiomyocytes in a transgenic mouse model. Our more recent results demonstrate that cyclin A2 mediates cardiomyocyte mitoses in the transgenic hearts after myocardial infarction (Ml) is induced, thus repairing the heart with significant recovery of cardiac function when compared with nontransgenic littermate controls. To explore potential clinical translation of these results, we administered cDNA encoding cyclin A2 via de-activated adenovirus to infarcted rats and noted that the rats receiving adeno-cyclin A2 undergo cellular regeneration at the sites of injection and have preserved cardiac output when compared to controls which received empty adenovirus. We hypothesize that there are two potential mechanisms mediating the regeneration we have observed. First, side population (SP) stem cells appear to differentiate into cardiomyocytes in our mouse infarction model, but mitoses in these immature cardiomyocytes are only noted in the transgenic mice, thus possibly uncovering a novel mechanism to induce hyperproliferative progenitor cells. Second, we note a significant increase in expression of phosphohistone H3 and uptake of BrdU in the peri-infarct zone of transgenic mice compared to nontransgenic controls, implicating dedifferentiation and division of adult cardiomyocytes. Utilizing SP cells from transgenic and nontransgenic mice, we propose to explore the first mechanism via in vitro studies of proliferation of SP cell-derived progenitor cells and in vivo studies of SP cell transplantation into a mouse infarction model. Additionally, we will use novel engineered cardiac tissues to evaluate both mechanisms by testing the response to injury of both SP cell-derived progenitors and adult cardiomyocytes from transgenic and nontransgenic mice. The second mechanism will also be examined using viral transfer of cyclin A2 cDNA into adult cardiomyocytes in vitro and the utilization of video microscopy to monitor mitosis and cytokinesis of these cells. These studies are proposed in order to elucidate a more directed path to clinical therapy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL088255-04
Application #
7903998
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Buxton, Denis B
Project Start
2007-04-15
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
4
Fiscal Year
2010
Total Cost
$423,750
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Shapiro, Scott D; Ranjan, Amaresh K; Kawase, Yoshiaki et al. (2014) Cyclin A2 induces cardiac regeneration after myocardial infarction through cytokinesis of adult cardiomyocytes. Sci Transl Med 6:224ra27
Bolli, P; Vardabasso, C; Bernstein, E et al. (2013) Chromatin immunoprecipitation of adult murine cardiomyocytes. Curr Protoc Cell Biol Chapter 17:Unit17.14
Gajzer, David C; Balbin, Jerome; Chaudhry, Hina W (2013) Thymosin ?4 and cardiac regeneration: are we missing a beat? Stem Cell Rev 9:303-12
Kara, Rina J; Bolli, Paola; Matsunaga, Iwao et al. (2012) A mouse model for fetal maternal stem cell transfer during ischemic cardiac injury. Clin Transl Sci 5:321-8
Kara, Rina J; Bolli, Paola; Karakikes, Ioannis et al. (2012) Fetal cells traffic to injured maternal myocardium and undergo cardiac differentiation. Circ Res 110:82-93
Bolli, Paola; Chaudhry, Hina W (2010) Molecular physiology of cardiac regeneration. Ann N Y Acad Sci 1211:113-26