Friday, December 6, 2024
12/6/2024
PROJECT SUMMARY Adult ischemic heart injury causes significant loss of cardiomyocytes (CMs) which, over time, leads to heart failure. Developing methods to therapeutically stimulate cardiomyogenesis promises to improve the lives and survival of these patients. However, cardiomyogenesis in the adult mammalian heart is challenging due to the limited proliferative capacity of adult CMs. Cardiomyocyte proliferation, as determined by complete cell division and daughter cell generation, occurs during embryogenesis and early postnatal maturation, and requires the CMs to enter the cell cycle and progress through mitosis. However, during postnatal maturation, despite active entrance into the cell cycle, mitosis is either bypassed or aborted, termed endoreplication, leading to polyploidy and failure to expand CM numbers. Thus, upon ischemic injury, the mouse heart is regenerative within the first postnatal week via proliferation of pre-existing CMs but becomes non-regenerative after the first postnatal week due to incomplete CM division. The process and regulators that decide division versus endoreplication in CMs are poorly understood. Their elucidation is essential to achieve successful heart regeneration. Thus, our overarching goal is to elucidate molecular and cellular mechanisms that regulate CM mitosis as a means to ultimately achieve cardiac regeneration after ischemic injury. To prepare for and progress through mitosis, cells undergo an extensive reorganization of cytoskeleton to accurately guide chromosome segregation and give rise to daughter cells. We have discovered that Lmnb2, which encodes the nuclear lamina protein Lamin B2, functions as a novel mitotic regulator, which becomes significantly repressed during the transition of postnatal CMs to the non-regenerative state. Our preliminary data showed that depletion of Lamin B2 blocks CM division and activates endoreplication by inhibiting reorganization of the mitotic cytoskeleton. However, the regulatory mechanisms of Lamin B2 function in controlling the switch from division to endoreplication during postnatal development remain elusive. Our recent work suggests that Lmnb2 inhibition, and therefore the switch to endoreplication is regulated by the transcriptional repressors, E2F7 and E2F8. We hypothesize that repression of Lmnb2 by E2F7/8 prevents completion of mitosis in non- regenerative CMs by inhibiting reorganization of the mitotic apparatus in cycling CMs, and therefore gain of Lmnb2 function will promote mitotic division resulting in proliferation and heart regeneration after ischemic injury. We propose two Specific Aims. Aim 1 will elucidate the mechanisms of mitotic cytoskeletal reorganization that are mediated by Lamin B2, and its effect on adult heart regeneration after ischemic injury. Aim 2 will assess the impact of CM-specific depletion of E2F7/8 on Lmnb2 expression and CM proliferation in the ischemic adult heart. Our incomplete understanding of how CM division is repressed in postnatal CMs constitutes an enormous obstacle to designing heart regeneration strategies. This research will help elucidate the mechanistic basis of mitotic regulation at key developmental stages, and after cardiac injury.
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