Egr1 regulates regenerative senescence and cardiac repair

Lingling Zhang, Jacob Elkahal, Tianzhen Wang, Racheli Rimmer, Alexander Genzelinakh, Elad Bassat, Jingkui Wang, Dahlia Perez, David Kain, Daria Lendengolts, Roni Winkler, Hanna Bueno-levy, Kfir Baruch Umansky, David Mishaly, Avraham Shakked, Shoval Miyara, Avital Sarusi-Portuguez, Naomi Goldfinger, Amir Prior, David MorgensternYishai Levin, Yoseph Addadi, Baoguo Li, Varda Rotter, Uriel Katz, Elly M. Tanaka, Valery Krizhanovsky, Rachel Sarig, Eldad Tzahor

Research output: Contribution to journalArticlepeer-review

Abstract

Senescence plays a key role in various physiological and pathological processes. We reported that injury-induced transient senescence correlates with heart regeneration, yet the multi-omics profile and molecular underpinnings of regenerative senescence remain obscure. Using proteomics and single-cell RNA sequencing, here we report the regenerative senescence multi-omic signature in the adult mouse heart and establish its role in neonatal heart regeneration and agrin-mediated cardiac repair in adult mice. We identified early growth response protein 1 (Egr1) as a regulator of regenerative senescence in both models. In the neonatal heart, Egr1 facilitates angiogenesis and cardiomyocyte proliferation. In adult hearts, agrin-induced senescence and repair require Egr1, activated by the integrin–FAK–ERK–Akt1 axis in cardiac fibroblasts. We also identified cathepsins as injury-induced senescence-associated secretory phenotype components that promote extracellular matrix degradation and potentially assist in reducing fibrosis. Altogether, we uncovered the molecular signature and functional benefits of regenerative senescence during heart regeneration, with Egr1 orchestrating the process.

Original languageEnglish
JournalNature Cardiovascular Research
StateAccepted/In press - 2024
Externally publishedYes

Bibliographical note

Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature Limited 2024.

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