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 Bakkers; Lior Gepstein; Eldad Tzahor

doi:10.1038/s44161-023-00250-w

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

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

3 Citations (Scopus)

Abstract

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 language	English
Pages (from-to)	383-398
Number of pages	16
Journal	Nature cardiovascular research
Volume	2
Issue number	4
DOIs	https://doi.org/10.1038/s44161-023-00250-w
Publication status	Published - Apr 2023

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Shakked, A., Petrover, Z., Aharonov, A., Ghiringhelli, M., Umansky, K.-B., Kain, D., Elkahal, J., Divinsky, Y., Nguyen, P. D., Miyara, S., Friedlander, G., Savidor, A., Zhang, L., Perez, D. E., Sarig, R., Lendengolts, D., Bueno-Levy, H., Kastan, N., Levin, Y., ... Tzahor, E. (2023). Redifferentiated cardiomyocytes retain residual dedifferentiation signatures and are protected against ischemic injury. Nature cardiovascular research, 2(4), 383-398. https://doi.org/10.1038/s44161-023-00250-w

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title = "Redifferentiated cardiomyocytes retain residual dedifferentiation signatures and are protected against ischemic injury",

abstract = "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.",

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

year = "2023",

month = apr,

doi = "10.1038/s44161-023-00250-w",

language = "English",

volume = "2",

pages = "383--398",

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Shakked, A, Petrover, Z, Aharonov, A, Ghiringhelli, M, Umansky, K-B, Kain, D, Elkahal, J, Divinsky, Y, Nguyen, PD, Miyara, S, Friedlander, G, Savidor, A, Zhang, L, Perez, DE, Sarig, R, Lendengolts, D, Bueno-Levy, H, Kastan, N, Levin, Y, Bakkers, J, Gepstein, L & Tzahor, E 2023, 'Redifferentiated cardiomyocytes retain residual dedifferentiation signatures and are protected against ischemic injury', Nature cardiovascular research, vol. 2, no. 4, pp. 383-398. https://doi.org/10.1038/s44161-023-00250-w

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

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.

U2 - 10.1038/s44161-023-00250-w

DO - 10.1038/s44161-023-00250-w

M3 - Article

C2 - 37974970

SN - 2731-0590

VL - 2

SP - 383

EP - 398

JO - Nature cardiovascular research

JF - Nature cardiovascular research

IS - 4

ER -

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

Abstract

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