The Hippo Pathway in the Regulation of Cardiac Cytoskeleton in Cardiac Remodeling and Regeneration

Identification of CM-specific, Newly Synthesized Proteins in Cardiac Remodeling

Cells respond to perturbations or disease by changing their protein expression levels, and measuring these changes is critical to understanding the underlying mechanisms involved. To identify the molecular determinants that regulate CM renewal, I developed a mouse model in which newly synthesized proteins in CMs are labeled and can be used to define proteomic profiles of CMs at different developmental stages and injury conditions. As a proof-of-concept, I have identified differentially expressed proteins in post-MI cardiomyocytes associated with cell signaling, metabolism, cytoskeleton organization, and ion channels. We investigate how these proteins' expression is regulated and their role(s) in cardiac regeneration and remodeling. Hence, these research initiatives will contribute to understanding the proteome dynamics in CMs in different contexts and help us identify potential therapeutic targets to treat patients with various cardiovascular diseases.

Noncanonical Wnt Signaling in Heart Regeneration

In addition to productive cardiomyocyte proliferation during heart regeneration, cardiac fibrosis resolution allows for the recovery of heart pump function. My study has demonstrated that YAP directly regulates the Wls gene in cardiac regeneration. We revealed that (1) Wls-mediated noncanonical Wnt signaling is essential for communication between CMs and cardiac fibroblasts (CFs), and (2) CM-specific noncanonical Wnt ligands suppress CF activation and fibrosis during neonatal heart regeneration (Liu et al. Circ Res. 2021). We also observed that the expression of Wnt receptors is significantly higher in CFs than in other cell types, suggesting that Wnt signaling is tightly regulated in CFs. Bioinformatic analyses of 41 datasets comprising 234 mouse heart samples uncovered injury-response Wnt genes in different cardiac cells and revealed that the expression of noncanonical Wnt genes is significantly increased after MI. We investigate how these secreted Wnt proteins regulate cell-to-cell communication and fibrosis after an injury.