Periodic Reporting for period 4 - CardHeal (Novel strategies for mammalian cardiac repair)
Reporting period: 2022-12-01 to 2023-05-31
In Aim 1, we explored the molecular mechanisms underlying ErbB2-mediated cardiomyocyte dedifferentiation and proliferation followed by new vessel formation, scar resolution and functional cardiac repair. Specific objectives included characterising ErbB2-Yap/Hippo signalling during cardiac regeneration; studying transient ErbB2 activation in a chronic heart failure model; investigating an ErbB2- induced regenerative EMT-like process; and characterising cardiomyocyte re-differentiation.
In Aim 2, we investigated the therapeutic effects of agrin, whose administration into injured hearts of mice and pigs elicits a significant regenerative response. Specific objectives included studying matrix-related cardiac regenerative cues, focusing on the role of agrin in modulating the immune response after injury, angiogenesis, and matrix remodelling; developing a preclinical, large animal model to study agrin efficacy for cardiac repair; and, more globally, testing the role of agrin in skeletal muscle regeneration.
Interrogating the differences and similarities between our two regenerative models provided a detailed roadmap for cardiac regenerative medicine by gaining deeper knowledge of the regenerative process in the heart and developing novel targets for cardiac repair in human patients.
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