The work performed during the project included two major discoveries. The first was the discovery of ERBB2 and YAP activation and the induction of EMT-like processes during cardiac regeneration. ERBB2-Neuregulin and Hippo-YAP signaling pathways are key mediators of heart regeneration, yet the crosstalk between them is unclear. We demonstrated 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 remodeling, junction dissolution, migration, and ECM turnover. We identified YAP as a critical mediator of ERBB2 signaling. In OE CMs, YAP interacts with nuclear envelope and cytoskeletal components, reflecting an altered mechanic state elicited by ERBB2. We identified two YAP activating phosphorylation on S352 and S274 in OE CMs, peaking during metaphase and are ERK-dependent and Hippo-independent. Viral overexpression of YAP phospho-mutants dampened the proliferative competence of OE CMs. Taken together, we revealed a potent ERBB2-mediated YAP mechanotransduction signaling, involving EMT-like characteristics, resulting in robust heart regeneration. This work was published in NCB:
Alla Aharonov, Avraham Shakked, Kfir Baruch Umansky, Alon Savidor , David Kain, Daria Lendengolts, Or-Yam Revach, Yuka Morikawa, Jiuli Zhou, Jixin Dong, Yishai Levin, Benjamin Geiger, James F. Martin and Eldad Tzahor
• NCB 2020 DOI: 10.1038/s41556-020-00588-4
The second discovery identified the coordinated therapeutic processes induced by Agrin that result in improved cardiac repair in pigs. We have recently reported that a fragment of the extracellular matrix (ECM) protein Agrin promotes cardiac regeneration following MI in adult mice. Here, we tested the therapeutic potential of Agrin in a preclinical porcine model, comprising either 3 or 28 days reperfusion period. We first demonstrated that local (antegrade) delivery of recombinant human Agrin (rhAgrin) to the infarcted pig heart can target the affected regions in an efficient and clinically-relevant manner. A single dose of rhAgrin resulted in significant improvement in heart function, infarct size, fibrosis and adverse remodeling parameters 28 days post-MI. Short-term MI experiments along with complementary murine MI studies revealed myocardial protection, improved angiogenesis, inflammatory suppression and cell cycle re-entry, as Agrin’s mechanisms of action. We conclude that a single dose of Agrin is capable of reducing ischemia-reperfusion injury and improving cardiac function, demonstrating that Agrin could serve as a therapy for patients with acute MI and potentially heart failure. This work was published in Circulation:
Andrea Baehr†, Kfir-Baruch Umansky†, Elad Bassat, Katharina Klett, Victoria Jurisch, Tarik Bozoglu, Nadja Hornaschewitz, Olga Solyanik, David Kain, Bartolo Ferrero, Renee Cohen-Rabi, Markus Krane, Clemens Cyran, Oliver Soehnlein, Karl Ludwig Laugwitz, Rabea Hinkel, Christian Kupatt,*, Eldad Tzahor*
• Circulation 2020 DOI: 10.1161/CIRCULATIONAHA.119.045116
