Dissecting the mechanisms of epicardium-guided heart regeneration
Description: The adult human heart shows minimal regeneration of cardiac muscle after myocardial infarction (MI). There remains no regenerative therapy for human heart disease; thus, continued basic research and diverse approaches are necessary. Zebrafish possess a remarkable capacity for cardiac regeneration. Understanding how natural heart repair is regulated in zebrafish will help to shape strategies for human heart repair. The epicardium covers all vertebrate hearts and has received recent attention as a target in cardiac repair strategies. In zebrafish, the epicardium is activated by cardiac injury and enables muscle regeneration through paracrine effects and as a multipotent cell source. Our recent work revealed that the presence of epicardium is required for muscle regeneration. However, how the epicardium is activated by injury and further exerts effects on muscle regeneration is poorly understood. In a recent publication, I found that the epicardial injury response involves spatiotemporally regulated cell cycle behavior and identified a pharmacological mitogen for the epicardial cell. Preliminary data indicates that this mitogen greatly augments epicardial cell activation and proliferation, suggesting a potential for enhancing heart regeneration. Transcriptional profiling has derived putative mitogenic genes targeted by this mitogen. Additionally, I generated chromatin accessibility profiles of epicardial cells during heart regeneration, identifying regulatory sequences for the putative mitogenic genes, the corresponding transcription factors, and pathways such as the Tgf-beta pathway. I hypothesize that enhancing epicardial cell activation and proliferation will promote heart muscle regeneration. To test this hypothesis, I will first define the mechanisms underlying the effects of the new mitogen through in situ hybridization and genetic reporter and mutation assays, and explore the effect on heart muscle regeneration. Second, I will characterize transcriptional regulation of the mitogenic genes by defining the regulatory elements and transcription factor bindings through transgenic assays. I will also manipulate Tgf-beta signaling in epicardial cells to define its effects on mitogen expression and heart regeneration. This work will provide a detailed understanding of epicardial cell activation and proliferation during heart regeneration, which will inform new approaches for enhancing the limited regenerative capacity of the human heart after MI.
Funder: American Heart Association
Amount: $266,000
Funding type: fellowship
Funder scheme: Career Development Award
Start date: 2018-10-01
End date: 2021-09-30
Investigators: Jingli Cao, Jingli Cao
Institution: Weill Medical College of Cornell University
Funded outputs count: 7
Funder award ID: 18CDA34110108
OpenAlex ID: G3136787507