Grant Award Details
- To investigate the mechanism of heart regeneration by cardiosphere-derived cells (CDCs)and test the hypothesis that CDCs promote regrowth of normal mammalian heart tissue through induction of adult cardiomyocyte cell cycle re-entry and proliferation.
Progress Reports
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Grant Application Details
- Mechanism of heart regeneration by cardiosphere-derived cells
In the process of a heart attack, clots form suddenly on top of cholesterol-laden plaques, blocking blood flow to heart muscle. As a result, living heart tissue dies and is replaced by scar. The larger the scar, the higher the chance of premature death and disability following the heart attack. While conventional treatments aim to limit the initial injury (by promptly opening the clogged artery) and to prevent further damage (using various drugs), regenerative therapy for heart attacks seeks to regrow healthy heart muscle and to dissolve scar. To date, cell therapy with CDCs is the only intervention which has been shown to be clinically effective in regenerating the injured human heart. However, the cellular origin of the newly-formed heart muscle and the mechanisms underlying its generation remain unknown. The present grant seeks to understand those basic mechanisms in detail, relying upon state-of-the-art scientific methods and preclinical disease models. Our work to date suggests that much of the benefit is due to an indirect effect of transplanted CDCs to stimulate the proliferation of surrounding host heart cells. This represents a major, previously-unrecognized mechanism of cardiac regeneration in response to cell therapy. The proposed project will open up novel mechanistic insights which will hopefully enable us to boost the efficacy of stem cell-based treatments by bolstering the regeneration of injured heart muscle.
Coronary artery disease is the predominant cause of premature death and disability in California. Clots form suddenly on top of cholesterol-laden plaques in the wall of a coronary artery, blocking blood flow to the heart muscle. This leads to a “heart attack”, in which living heart muscle dies and is replaced by scar. The larger the scar, the greater the chance of death and disability following the heart attack. While conventional treatments aim to limit the initial injury (by promptly opening the clogged artery) and to prevent further injury (using various drugs), regenerative therapy for heart attacks seeks to regrow healthy heart muscle and to dissolve scar. To date, cell therapy with CDCs is the only intervention that has been shown to be clinically effective in regenerating the injured human heart. However, the cellular origin of the newly-formed heart muscle and the mechanisms underlying its generation remain unknown. The present grant seeks to understand those basic mechanisms in detail, relying upon state-of-the-art scientific methods and preclinical disease models. The resulting insights will enable more rational development of novel therapeutic approaches, to the benefit of the public health of the citizens of California. Economic benefits may also accrue from licensing of new technology.
Publications
- Circ Heart Fail (2015) Cellular postconditioning: allogeneic cardiosphere-derived cells reduce infarct size and attenuate microvascular obstruction when administered after reperfusion in pigs with acute myocardial infarction. (PubMed: 25587096)
- Eur Heart J (2015) Therapeutic efficacy of cardiosphere-derived cells in a transgenic mouse model of non-ischaemic dilated cardiomyopathy. (PubMed: 24866210)
- Mayo Clin Proc (2014) Breakthroughs in cell therapy for heart disease: focus on cardiosphere-derived cells. (PubMed: 24943699)
- J Am Coll Cardiol (2014) Translating stem cell research to cardiac disease therapies: pitfalls and prospects for improvement. (PubMed: 25169179)
- PLoS One (2014) Allogeneic cardiospheres delivered via percutaneous transendocardial injection increase viable myocardium, decrease scar size, and attenuate cardiac dilatation in porcine ischemic cardiomyopathy. (PubMed: 25460005)
- PLoS One (2014) Angiogenesis, cardiomyocyte proliferation and anti-fibrotic effects underlie structural preservation post-infarction by intramyocardially-injected cardiospheres. (PubMed: 24558402)
- Stem Cells Transl Med (2014) Moving beyond surrogate endpoints in cell therapy trials for heart disease. (PubMed: 24292794)
- Basic Res Cardiol (2014) Cardiospheres reverse adverse remodeling in chronic rat myocardial infarction: roles of soluble endoglin and Tgf-beta signaling. (PubMed: 25245471)
- EMBO Mol Med (2014) Stimulation of endogenous cardioblasts by exogenous cell therapy after myocardial infarction. (PubMed: 24797668)
- Stem Cells (2014) Importance of cell-cell contact in the therapeutic benefits of cardiosphere-derived cells. (PubMed: 24802280)
- JACC Heart Fail (2014) Human cardiosphere-derived cells from advanced heart failure patients exhibit augmented functional potency in myocardial repair. (PubMed: 24511463)
- Circulation (2013) Validation of contrast-enhanced magnetic resonance imaging to monitor regenerative efficacy after cell therapy in a porcine model of convalescent myocardial infarction. (PubMed: 24061088)
- JAMA (2013) Bone marrow-derived cell therapy after myocardial infarction--reply. (PubMed: 23571575)
- EMBO Mol Med (2013) Cardiomyocyte proliferation and progenitor cell recruitment underlie therapeutic regeneration after myocardial infarction in the adult mouse heart. (PubMed: 23255322)
- J Am Coll Cardiol (2013) Allogeneic cardiospheres safely boost cardiac function and attenuate adverse remodeling after myocardial infarction in immunologically mismatched rat strains. (PubMed: 23352785)
- J Regen Med (2013) Targeted MicroRNA Interference Promotes Postnatal Cardiac Cell Cycle Re-Entry. (PubMed: 24910852)
- Stem Cells (2012) Brief report: Mechanism of extravasation of infused stem cells. (PubMed: 23135922)
- JAMA (2012) Mixed results for bone marrow-derived cell therapy for ischemic heart disease. (PubMed: 23117584)