PT - JOURNAL ARTICLE AU - Marie Cauquil AU - Céline Mias AU - Céline Guilbeau-Frugier AU - Clément Karsenty AU - Marie-Hélène Seguelas AU - Gaël Genet AU - Edith Renaud-Gabardos AU - Anne-Catherine Prats AU - Véronique Pons AU - Maxime Branchereau AU - Christophe Heymes AU - Denis Calise AU - Olivier Lairez AU - Danièle Daviaud AU - Benjamin Honton AU - Céline Frongia AU - Bernard Ducommun AU - Marie-Bernadette Delisle AU - Dina N. Arvanitis AU - Atul Pathak AU - Jean-Michel Sénard AU - Céline Galés TI - Ephrin-B1 blocks adult cardiomyocyte proliferation and heart regeneration AID - 10.1101/735571 DP - 2019 Jan 01 TA - bioRxiv PG - 735571 4099 - http://biorxiv.org/content/early/2019/08/15/735571.short 4100 - http://biorxiv.org/content/early/2019/08/15/735571.full AB - Aims Deciphering the innate mechanisms governing the blockade of proliferation in adult cardiomyocytes (CMs) is challenging for mammalian heart regeneration. Despite the exit of CMs from the cell cycle during the postnatal maturation period coincides with their morphological switch to a typical adult rod-shape, whether these two processes are connected is unknown. Here, we examined the role of ephrin-B1, a CM rod-shape stabilizer, in adult CM proliferation and cardiac regeneration.Methods and results Transgenic- or AAV9-based ephrin-B1 repression in adult mouse heart led to substantial proliferation of resident CMs and tissue regeneration to compensate for apex resection, myocardial infarction (MI) and senescence. Interestingly, in the resting state, CMs lacking ephrin-B1 did not constitutively proliferate, indicative of no major cardiac defects. However, they exhibited proliferation-competent signature, as indicated by higher mononucleated state and a dramatic decrease of miR-195 mitotic blocker, which can be mobilized under neuregulin-1 stimulation in vitro and in vivo. Mechanistically, the post-mitotic state of the adult CM relies on ephrin-B1 sequestering of inactive phospho-Yap1, the effector of the Hippo-pathway, at the lateral membrane. Hence, ephrin-B1 repression leads to phospho-Yap1 release in the cytosol but CM quiescence at resting state. Upon cardiac stresses (apectomy, MI, senescence), Yap1 could be activated and translocated to the nucleus to induce proliferation-gene expression and consequent CM proliferationConclusions Our results identified ephrin-B1 as a new natural locker of adult CM proliferation and emphasize that targeting ephrin-B1 may prove a future promising approach in cardiac regenerative medicine for HF treatment.Significance The mammalian adult heart is unable to regenerate due to the inability of cardiomyocytes (CMs) to proliferate and replace cardiac tissue lost. Exploiting CM-specific transgenic mice or AAV9-based gene therapy, this works identifies ephrin-B1, a specific rod-shape stabilizer of the adult CM, as a natural padlock of adult CM proliferation for compensatory adaptation to different cardiac stresses (apectomy, MI, senescence), thus emphasizing a new link between the adult CM morphology and their proliferation potential. Moreover, the study demonstrates proof-of-concept that targeting ephrin-B1 may be an innovative therapeutic approach for ischemic heart failure.