ERBB2 drives YAP activation and EMT-like processes during cardiac regeneration

Abstract

Cardiomyocyte (CM) loss after injury results in adverse remodelling and fibrosis, which inevitably lead to heart failure. ERBB2-Neuregulin and Hippo-YAP signaling pathways are key mediators of CM proliferation and regeneration, yet the crosstalk between these pathways is unclear. Here, we demonstrate in adult mice that transient over-expression (OE) of activated ERBB2 in CMs promotes cardiac regeneration in a heart failure model. OE CMs present an EMT-like regenerative response manifested by cytoskeletal remodelling, junction dissolution, migration, and ECM turnover. Molecularly, we identified YAP as a critical mediator of ERBB2 signaling. In OE CMs, YAP interacts with nuclear envelope and cytoskeletal components, reflecting the altered mechanic state elicited by ERBB2. Hippoindependent activating phosphorylation on YAP at S352 and S274 were enriched in OE CMs, peaking during metaphase, and viral overexpression of YAP phospho-mutants dampened the proliferative competence of OE CMs. Taken together, we demonstrate a potent ERBB2mediated YAP mechanosensory signaling, involving EMT-like characteristics, resulting in heart regeneration. Highlights1. ERBB2-driven regeneration of scarred hearts recapitulates core-EMT processes 2. YAP is activated and required downstream to ERBB2 signaling in CMs 3. YAP activity is mechanically driven by cytoskeleton and nuclear envelope remodeling 4. YAP S274 and S352 phosphorylation is essential for CM mitosis

Stimulation of glycolysis promotes cardiomyocyte proliferation after injury in adult zebrafish

“…We then examined CM behavior and found that RNCMs close to the scratch border exhibited membrane protrusions (Fig C). Similar observations have been reported when analyzing zebrafish and mouse regeneration models, where CMs replenish to the injured area (Itou et al , ; Morikawa et al , ; Tahara et al , ; Marin‐Juez et al , ; preprint: Aharonov et al , ). We analyzed the effects of pyruvate metabolism modulation on CM behavior in the scratch assay and found that PDK3 OE led to an increase in the number of CM membrane protrusions (Figs C and EV4C).…”

In vivo proximity labeling identifies cardiomyocyte protein networks during zebrafish heart regeneration

“…Nrg1/ErbB2 signaling can stimulate cardiomyocyte division in adult mice, most notably when ErbB2 is experimentally expressed in the form of a ligand-independent activator (25)(26)(27). ErbB2 signaling was recently reported to work in part through regulation of YAP, a transcriptional activator that can impact cytoskeletal remodeling and cell division in cardiomyocytes during cardiac growth or repair in mice (28)(29)(30)(31). In zebrafish, Nrg1/ErbB2 signals in part by promoting glycolysis versus mitochondrial oxidative phosphorylation, and by reducing Tp53 levels through upregulation of its inhibitor Mdm2 (32)(33)(34).…”

Ischemic tolerance and cardiac repair in the African spiny mouse

“…It is The copyright holder for this preprint this version posted January 8, 2021. ; https://doi.org/10.1101/2021.01.07.425783 doi: bioRxiv preprint including zebrafish, teleost fish, urodele amphibians, and neonatal mice and pigs 19 . While these models have significantly advanced our understanding of regeneration biology, and in some cases have led to marked improvements in cardiomyocyte expansion in adult mice [20][21][22][23] , these models impose restrictions in that they are either of non-mammalian vertebrate (e.g. zebrafish or newts), or neonatal vertebrate (mice or pigs) origin.…”