Basic Biology IV
$1 367 604
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 (in Dr. Marbán’s CADUCEUS trial). 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.
Statement of Benefit to California:
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 (in Dr. Marbán’s CADUCEUS trial, recently spotlighted by CIRM; see http://www.cirm.ca.gov/Video/stem-cell-clinical-trial-heart-failure-eduardo-marb%C3%A1n-cirm-spotlight-disease). 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.
In this proposal, the applicant challenges the predominant view that mature cardiomyocytes are incapable of cell cycle re-entry and explores the possibility that renewed cardiomyocyte proliferation may be the basis of a novel therapeutic approach to heart disease. The proposed research is focused on determining whether cardiosphere-derived cells (CDCs) can induce adult cardiomyocyte proliferation, leading to the regrowth of myocardium. The proposed research will further investigate molecular mechanisms underlying this process. To achieve this goal, the applicant will first determine whether CDCs induce proliferation of post-mitotic (non-dividing, mature) cardiomyocytes through rigorous study of CDC fates and will investigate the mechanisms through which certain cardiomyocytes re-enter the cell cycle. The applicant will then compare the extent of proliferation induced by CDCs to that induced by other cell types both in vivo and in vitro. Finally, the applicant will define quantitatively the relative importance of various mechanisms that contribute to CDC-induced cardiac regeneration. Significance and Innovation - Reviewers appreciated the project’s approach and focus on mechanisms by which endogenous cardiomyocyte populations may be induced to proliferate to create new myocardium. - The CDCs represent a novel cell population with therapeutic potential, as well as possible utility in the development of small molecule-based therapies. - Although the use of CDCs is an innovative approach, reviewers expressed minor concerns that the applicant did not properly acknowledge existing data in the literature and overstated some of the novelty of the proposed experiments. Feasibility and Experimental Design - The preliminary data provided very strong evidence for the potential therapeutic efficacy of CDCs. - Reviewers viewed the project as largely feasible and judged the overall experimental design as appropriate. However, important experimental details were lacking for some of the proposed studies, such as the investigation of mechanisms by which cardiomyocytes resume proliferation. Principal Investigator (PI) and Research Team - The PI is an outstanding clinical investigator with a significant track record of contributions to cardiovascular research. - The research team has appropriate expertise to carryout the proposed studies. Responsiveness to the RFA - The reviewers commented that despite the heavy use of preclinical models, there is no way to perform the described studies in purely human system. Also, reviewers considered the application to be potentially groundbreaking. Thus, the application was considered responsive to the RFA.