Redifferentiated cardiomyocytes retain residual dedifferentiation signatures and are protected against ischemic injury

Avraham Shakked, Zachary Petrover, Alla Aharonov, Matteo Ghiringhelli, Kfir-Baruch Umansky, David Kain, Jacob Elkahal, Yalin Divinsky, Phong Dang Nguyen, Shoval Miyara, Gilgi Friedlander, Alon Savidor, Lingling Zhang, Dahlia E Perez, Rachel Sarig, Daria Lendengolts, Hanna Bueno-Levy, Nathaniel Kastan, Yishai Levin, Jeroen BakkersLior Gepstein, Eldad Tzahor

Research output: Contribution to journal/periodicalArticleScientificpeer-review

1 Citation (Scopus)


Cardiomyocyte proliferation and dedifferentiation have fueled the field of regenerative cardiology in recent years, whereas the reverse process of redifferentiation remains largely unexplored. Redifferentiation is characterized by the restoration of function lost during dedifferentiation. Previously, we showed that ERBB2-mediated heart regeneration has these two distinct phases: transient dedifferentiation and redifferentiation. Here we survey the temporal transcriptomic and proteomic landscape of dedifferentiation-redifferentiation in adult mouse hearts and reveal that well-characterized dedifferentiation features largely return to normal, although elements of residual dedifferentiation remain, even after the contractile function is restored. These hearts appear rejuvenated and show robust resistance to ischemic injury, even 5 months after redifferentiation initiation. Cardiomyocyte redifferentiation is driven by negative feedback signaling and requires LATS1/2 Hippo pathway activity. Our data reveal the importance of cardiomyocyte redifferentiation in functional restoration during regeneration but also protection against future insult, in what could lead to a potential prophylactic treatment against ischemic heart disease for at-risk patients.

Original languageEnglish
Pages (from-to)383-398
Number of pages16
JournalNature cardiovascular research
Issue number4
Publication statusPublished - Apr 2023


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