220Ephrin-B1 regulates cell cycle arrest in adult cardiomyocytes: impact on cardiac tissue regeneration

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Abstract

Ephrin-B1 is a member of Eph/Ephrin family, which has been largely studied during central nervous system development. However, expression/function of ephrin-B1 in adult remains unclear. We previously demonstrated that ephrin-B1 is specifically expressed at the lateral membrane of the adult cardiomyocyte (CM) where it regulates stability of the membrane and cardiac tissue architecture (manuscript in revision).

While ephrin-B1 KO mice did not exhibit cardiomyopathy at 2 months of age despite striking alteration of CM structure, our results revealed significant hypertrophy when compared with WT mice after 12 months, with no modification of cardiac function. Interestingly, this hypertrophy is directly correlated with a significant decrease of CM size but increase in CM number, thus indicating cardiac compensation through CM hyperplasia in KO mice. qPCR analyses demonstrated a considerable up-regulation of genes involved in cell cycle progression and mitosis in CMs isolated from 12 month-old KO mice. These results suggest that the lack of ephrin-B1 is associated with CM cell cycle re-entry, thus allowing CM proliferation. Because cell cycle arrest is specific of the CM maturation period time, we examined ephrin-B1 expression during that time. Interestingly, in new-born CMs, ephrin-B1 protein was exclusively expressed within the nucleus. Its expression at the lateral membrane only occurs at the end of the maturation. When analysing nuclei number in CMs from 2 month old KO mice, we measured a significant increase of CM population with 1, 3 and 4 nuclei at the expense of 2 nuclei by opposition with WT mice demonstrating a majority of binucleated CMs. After 12 months, while WT CMs do not exhibit modification of nuclearization, KO mice now demonstrate similar WT profile with a significant reduction of the 1, 3 and 4 nuclei correlating with an increase of the 2 nuclei pool. These results suggest a proliferative capacity of 1, 3 and 4 nuclei CMs from 2 month-old KO mice converted into post-mitotic binucleated cells at 12 months age. To directly assess the proliferative capacity of 2 month-old KO mice, we used an in vivo model of partial cardiac surgical apex resection. Initial histological analysis suggested regeneration of the apex in KO mice as indicating by large CM presence in the resected zone. By opposition, WT mice developed cicatrisation process characterized by a fibrotic and inflammatory area with total lack of CMs.

Our results show that ephrin-B1 plays a crucial role in the anti-proliferative capacity of mature CM. Thus regulation of ephrin-B1 could represent a new target for cardiac regenerative medicine.

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