TY - JOUR
T1 - Redifferentiated cardiomyocytes retain residual dedifferentiation signatures and are protected against ischemic injury
AU - Shakked, Avraham
AU - Petrover, Zachary
AU - Aharonov, Alla
AU - Ghiringhelli, Matteo
AU - Umansky, Kfir Baruch
AU - Kain, David
AU - Elkahal, Jacob
AU - Divinsky, Yalin
AU - Nguyen, Phong Dang
AU - Miyara, Shoval
AU - Friedlander, Gilgi
AU - Savidor, Alon
AU - Zhang, Lingling
AU - Perez, Dahlia E.
AU - Sarig, Rachel
AU - Lendengolts, Daria
AU - Bueno-Levy, Hanna
AU - Kastan, Nathaniel
AU - Levin, Yishai
AU - Bakkers, Jeroen
AU - Gepstein, Lior
AU - Tzahor, Eldad
N1 - Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2023/4
Y1 - 2023/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85165093334&partnerID=8YFLogxK
U2 - 10.1038/s44161-023-00250-w
DO - 10.1038/s44161-023-00250-w
M3 - Article
AN - SCOPUS:85165093334
SN - 2731-0590
VL - 2
SP - 383
EP - 398
JO - Nature Cardiovascular Research
JF - Nature Cardiovascular Research
IS - 4
ER -