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Partially Digested Adult Cardiac Extracellular Matrix Promotes Cardiomyocyte Proliferation In Vitro.

ABSTRACT: Stimulating or maintaining the proliferative capacity of postnatal mammalian cardiomyocytes is a major challenge to cardiac regeneration. Previously, it is found that fetal cardiac extracellular matrix (ECM) can promote neonatal rat cardiomyocyte proliferation in vitro better than neonatal or adult ECM. It is hypothesized that partial digestion of adult ECM (PD-ECM) would liberate less crosslinked components that promote cardiomyocyte proliferation, similar to fetal ECM. Neonatal rat cardiac cells are seeded onto substrates coated with adult rat cardiac ECM that has been solubilized in pepsin-HCl for 1, 3, 6, 12, 24, or 48 h. Cardiomyocyte proliferation and fold-change in numbers from 1 to 5 d are highest on 1 and 3 h PD-ECM compared to other conditions. Sarcomeres tend to mature on 24 and 48 h PD-ECM where low proliferation is observed. 3 h PD-ECM is primarily composed of Fibrillin-1, Fibrinogen, and Laminins while 48 h PD-ECM is dominated by Collagen I. Our results suggest that adult ECM retains regenerative cues that may be masked by more abundant, mature ECM components. PD-ECM provides a simple yet powerful approach to promoting cardiomyocyte proliferation.

SUBMITTER: Williams C

PROVIDER: S-EPMC4504755 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Partially Digested Adult Cardiac Extracellular Matrix Promotes Cardiomyocyte Proliferation In Vitro.

Williams Corin C Sullivan Kelly K Black Lauren D LD

Advanced healthcare materials 20150518 10

Stimulating or maintaining the proliferative capacity of postnatal mammalian cardiomyocytes is a major challenge to cardiac regeneration. Previously, it is found that fetal cardiac extracellular matrix (ECM) can promote neonatal rat cardiomyocyte proliferation in vitro better than neonatal or adult ECM. It is hypothesized that partial digestion of adult ECM (PD-ECM) would liberate less crosslinked components that promote cardiomyocyte proliferation, similar to fetal ECM. Neonatal rat cardiac cel ...[more]

PMID: 25988681

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Project description:BackgroundNeonatal mouse cardiomyocytes undergo a metabolic switch from glycolysis to oxidative phosphorylation, which results in a significant increase in reactive oxygen species production that induces DNA damage. These cellular changes contribute to cardiomyocyte cell cycle exit and loss of the capacity for cardiac regeneration. The mechanisms that regulate this metabolic switch and the increase in reactive oxygen species production have been relatively unexplored. Current evidence suggests that elevated reactive oxygen species production in ischemic tissues occurs as a result of accumulation of the mitochondrial metabolite succinate during ischemia via succinate dehydrogenase (SDH), and this succinate is rapidly oxidized at reperfusion. Mutations in SDH in familial cancer syndromes have been demonstrated to promote a metabolic shift into glycolytic metabolism, suggesting a potential role for SDH in regulating cellular metabolism. Whether succinate and SDH regulate cardiomyocyte cell cycle activity and the cardiac metabolic state remains unclear.MethodsHere, we investigated the role of succinate and SDH inhibition in regulation of postnatal cardiomyocyte cell cycle activity and heart regeneration.ResultsOur results demonstrate that injection of succinate into neonatal mice results in inhibition of cardiomyocyte proliferation and regeneration. Our evidence also shows that inhibition of SDH by malonate treatment after birth extends the window of cardiomyocyte proliferation and regeneration in juvenile mice. Remarkably, extending malonate treatment to the adult mouse heart after myocardial infarction injury results in a robust regenerative response within 4 weeks after injury via promoting adult cardiomyocyte proliferation and revascularization. Our metabolite analysis after SDH inhibition by malonate induces dynamic changes in adult cardiac metabolism.ConclusionsInhibition of SDH by malonate promotes adult cardiomyocyte proliferation, revascularization, and heart regeneration via metabolic reprogramming. These findings support a potentially important new therapeutic approach for human heart failure.

Dataset Information

Partially Digested Adult Cardiac Extracellular Matrix Promotes Cardiomyocyte Proliferation In Vitro.

Publications

Partially Digested Adult Cardiac Extracellular Matrix Promotes Cardiomyocyte Proliferation In Vitro.

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