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

Autor: Shakked A; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Petrover Z; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Aharonov A; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Ghiringhelli M; Sohnis Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, Israel., Umansky KB; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Kain D; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Elkahal J; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Divinsky Y; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Nguyen PD; Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, The Netherlands., Miyara S; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Friedlander G; Mantoux Bioinformatics Institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel., Savidor A; De Botton Protein Profiling Institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel., Zhang L; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Perez DE; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Sarig R; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Lendengolts D; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Bueno-Levy H; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel., Kastan N; Howard Hughes Medical Institute and Laboratory of Sensory Neuroscience, The Rockefeller University, New York, NY, USA., Levin Y; De Botton Protein Profiling Institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel., Bakkers J; Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, The Netherlands., Gepstein L; Sohnis Research Laboratory for Cardiac Electrophysiology and Regenerative Medicine Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, Israel., Tzahor E; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
Jazyk: angličtina
Zdroj: Nature cardiovascular research [Nat Cardiovasc Res] 2023 Apr; Vol. 2 (4), pp. 383-398. Date of Electronic Publication: 2023 Mar 08.
DOI: 10.1038/s44161-023-00250-w
Abstrakt: 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.
Competing Interests: Competing interests The authors declare no competing interests.
Databáze: MEDLINE
Externí odkaz: