Cardiac progenitor cells (CPCs) in the adult mammalian heart are identified by stem cell-related antigens, multipotency, and by their ability to regenerate myocardium endogenously and iatrogenically. CPCs, when injected into the heart after ischemic injury, produce limited multilineage differentiation (cardiomyocytes, endothelial cells, vascular smooth muscle cells) and functional benefits. The origin of CPCs is as-yet unclear. Some if not most CPCs are likely of innate embryonic origin within the heart;exogenous bloodborne precursor cells can also seed the heart after injury. Another potential mechanism of origin that has been overlooked is that of dedifferentiation, a process whereby mature, specialized cells regain proliferative ability and augmented plasticity. The established paradigm for cardiomyocyte development posits a one-way transit from precursor cells through neonatal cardiomyocytes on to mature heart cells, which can no longer divide and proliferate. Adult zebrafish cardiomyocytes, in contrast, re-enter the cell cycle with alacrity, but even they have not been demonstrated to dedifferentiate to a state of multipotency. The major discovery in the initial grant period of this R01 was the recognition of the ability of postnatal mammalian cardiomyocytes to dedifferentiate and acquire features of CPCs. Preliminary data supporting this claim are presented in the progress report. The proposed ability of dedifferentiated cardiomyocytes to become CPCs, if verified by the work proposed here, would change fundamentally our view of the adult heart and its potential plasticity. For this reason, we seek to demonstrate cardiomyocyte dedifferentiation to CPCs by multiple complementary experimental approaches;to characterize the underlying molecular and cellular mechanisms;and to establish the pathophysiological relevance of dedifferentiation. We will test the idea that cell culture promotes dedifferentiation, cell cycle re- entry, and acquisition of "stemness". Genetic cell fate mapping will be utilized to establish that confirmed cardiomyocytes dedifferentiate, express c-kit, and are capable of differentiating into at least two cardiac lineages. Specific questions to be addressed include: How often and under what conditions do dedifferentiating cardiomyocytes re-enter the cell cycle? What changes in gene expression, microRNAs, and cell cycle regulatory proteins underlie the dedifferentiation process? Are autocrine/paracrine factors in conditioned media important in cardiomyocyte dedifferentiation? Do dedifferentiated cardiomyocytes express stem cell antigens? Are they pluripotent? Can they be clonally proliferated? Can dedifferentiated cardiomyocytes re-differentiate and transdifferentiate in vitro? When injected into injured hearts, do dedifferentiated cardiomyocytes engraft, differentiate and improve function? Do genetically-defined cardiomyocytes dedifferentiate in situ in response to injury? Does endogenous myocardial regeneration after infarction reflect dedifferentiation and subsequent multilineage differentiation of cardiomyocytes? The work tests the idea that CPCs may arise from dedifferentiation as well as embryogenesis or bloodborne seeding.

Public Health Relevance

The proposed work focuses on the heart's innate ability to regenerate, and how that ability might be tapped to improve therapies for heart disease. We seek to understand the mechanism of origin of innate progenitor cells in the heart that normally function to repair the wear and tear of daily life. We will test the idea that mature heart cells can go backwards and regain the features of innate progenitor cells, an idea which has important biological, pathophysiological and therapeutic implications.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL083109-08
Application #
8223163
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Wong, Renee P
Project Start
2006-03-01
Project End
2015-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
8
Fiscal Year
2012
Total Cost
$417,500
Indirect Cost
$167,500
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
Cheng, Ke; Shen, Deliang; Hensley, M Taylor et al. (2014) Magnetic antibody-linked nanomatchmakers for therapeutic cell targeting. Nat Commun 5:4880
Cheng, Ke; Ibrahim, Ahmed; Hensley, M Taylor et al. (2014) Relative roles of CD90 and c-kit to the regenerative efficacy of cardiosphere-derived cells in humans and in a mouse model of myocardial infarction. J Am Heart Assoc 3:e001260
Malliaras, Konstantinos; Ibrahim, Ahmed; Tseliou, Eleni et al. (2014) Stimulation of endogenous cardioblasts by exogenous cell therapy after myocardial infarction. EMBO Mol Med 6:760-77
Xie, Yucai; Ibrahim, Ahmed; Cheng, Ke et al. (2014) Importance of cell-cell contact in the therapeutic benefits of cardiosphere-derived cells. Stem Cells 32:2397-406
Cheng, Ke; Malliaras, Konstantinos; Smith, Rachel Ruckdeschel et al. (2014) Human cardiosphere-derived cells from advanced heart failure patients exhibit augmented functional potency in myocardial repair. JACC Heart Fail 2:49-61
Ibrahim, Ahmed Gamal-Eldin; Cheng, Ke; Marbán, Eduardo (2014) Exosomes as critical agents of cardiac regeneration triggered by cell therapy. Stem Cell Reports 2:606-19
Malliaras, Konstantinos; Zhang, Yiqiang; Seinfeld, Jeffrey et al. (2013) Cardiomyocyte proliferation and progenitor cell recruitment underlie therapeutic regeneration after myocardial infarction in the adult mouse heart. EMBO Mol Med 5:191-209
Malliaras, Konstantinos; Li, Tao-Sheng; Luthringer, Daniel et al. (2012) Safety and efficacy of allogeneic cell therapy in infarcted rats transplanted with mismatched cardiosphere-derived cells. Circulation 125:100-12
Li, Tao-Sheng; Cheng, Ke; Malliaras, Konstantinos et al. (2011) Expansion of human cardiac stem cells in physiological oxygen improves cell production efficiency and potency for myocardial repair. Cardiovasc Res 89:157-65
Cheng, Ke; Li, Tao-Sheng; Malliaras, Konstantinos et al. (2010) Magnetic targeting enhances engraftment and functional benefit of iron-labeled cardiosphere-derived cells in myocardial infarction. Circ Res 106:1570-81

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