[R01] Mechanisms controlling epicardial-dependent promotion of heart regeneration in zebrafish.
Ente: National Heart Lung and Blood Institute
Scadenza: 2030-06-30
Importo max: 828.860 EUR
Paese: US
Descrizione
Abstract
Unlike adult mammals, zebrafish possess a remarkable ability to regenerate their hearts through cardiomyocyte
(CM) proliferation, a process supported by the epicardium. While the mammalian epicardium activates post-
injury, it fails to provide adequate regenerative support. Enhancing epicardial activation could be key to improving
heart repair in humans. In the previous funding period, we identified epicardial-specific regeneration enhancers
and discovered a transiently activated epicardial progenitor cell (aEPC) population. These progenitors
differentiate into mural and mesenchymal cells, facilitating coronary angiogenesis and CM regeneration.
However, the molecular mechanisms governing aEPC differentiation into distinct cell types and their interaction
with other cardiac cells remain unclear. Using spatial transcriptomics and genetic lineage tracing, we identified
an aEPC-CM interaction that promotes CM dedifferentiation, and identified three aEPC subtypes (scxa+, rgmb+,
and col11a1a+) with distinct roles in development and regeneration. scxa+ aEPCs form scaffolds for endothelial
tip cell migration and differentiate into a novel col18a1a+ perivascular mesenchymal cell type (Epi-PMC), while
rgmb+ aEPCs give rise to mural cells and col11a1a+ aEPCs represent an injury-specific subtype transiently
activated during regeneration. We hypothesize that distinct signaling and transcriptional networks govern
epicardial differentiation and paracrine functions that drive CM proliferation and vascularization in development
and regeneration. To test this in zebrafish heart development and regeneration, we propose to 1) investigate
how Scxa regulates aEPC differentiation by analyzing upstream and downstream regulation through genetic and
transcriptional approaches; 2) characterize the role of col18a1a+ Epi-PMC in coronary vessel formation; and 3)
define the contributions of rgmb+ mural precursors and col11a1a+ injury-specific cells to heart regeneration. We
will also incorporate a human pluripotent stem cell-derived cardioid model as a complementary platform to test
gene functions in organoid formation and injury responses. This study will elucidate the molecular and cellular
mechanisms by which the epicardium coordinates vascular formation and CM regeneration, providing a
framework for translational strategies to enhance epicardial-driven repair in the injured mammalian heart.
Istituzione: WEILL MEDICAL COLL OF CORNELL UNIV
PI: Jingli Cao
Progetto: 2R01HL155607-06A1
Settori: National Heart Lung and Blood Institute
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