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 Morgenstern; Yishai Levin; Yoseph Addadi; Baoguo Li; Varda Rotter; Uriel Katz; Elly M. Tanaka; Valery Krizhanovsky; Rachel Sarig; Eldad Tzahor

doi:10.1038/s44161-024-00493-1

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

17 Citations (Scopus)

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 language	English
Pages (from-to)	915-932
Number of pages	18
Journal	Nature Cardiovascular Research
Volume	3
Issue number	8
Early online date	14 Jun 2024
DOIs	https://doi.org/10.1038/s44161-024-00493-1
Publication status	Published - Aug 2024

Funding

This work was supported by grants to E.T. from the European Research Council (ERC AdG grant no. 788194, CardHeal), ERA-CVD CARDIO-PRO, the Israel Science Foundation (ISF, grant no. 2214/22), the Yotam project and the Weizmann institute sustainability and energy research initiative (grant no. 142735), the Minerva Center on ‘Aging, from physical materials to human tissues’, the Israel Ministry of Science and Technology, the EU Horizon 2020 research innovation programme REANIMA (providing grants to E.T. and E.M.T., grant no. 874764), the Estate of Caroline Cancelmo, the Erica Drake Fund, the Weizmann UK Building for Biocomplexity Research (GG 2016), the Aharon and Tova (Buena) Cohen Memorial Fund, the Horwitz Research Fund, the Yacov Chaoul Kapczuk Fund, the Estate of Elizabeth Wachsman, Seed for Peace. Inc., the Jacques Asseoff Trust, the Gurwin Family Fund for Scientific Research and the Midwest Electron Microscope Project. We thank T. Eigler-Hirsh, S. Cheng, A. Aharonov, W. Li, G. Aviel, Y. Divinsky, Z. Petrover, E. Amzallag, E. Spector, L. Roitman, A. Agrawal, J.-M. Majewska, Z. Porat and N. Halevi for their suggestions. We thank M. Cohen from the Histology Unit, Department of Veterinary Resources, Weizmann Institute of Science, for histological processing and staining. We thank T. Moshe and S. Ulman for animal husbandry. We thank R. Ronen and R. Blecher from the Crown Genomics Institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine for single-cell sample processing (library preparation and data sequencing). We thank M. Yehudi, H. David, G. Attias, S. Vishner and Z. Dobrish for technical laboratory assistance. Illustrations in Fig. 7 were created with BioRender. Publisher Copyright: © The Author(s), under exclusive licence to Springer Nature Limited 2024.

All Science Journal Classification (ASJC) codes

Biochemistry, Genetics and Molecular Biology (miscellaneous)
Cell Biology
Medicine (miscellaneous)
Cardiology and Cardiovascular Medicine

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Zhang, L., Elkahal, J., Wang, T., Rimmer, R., Genzelinakh, A., Bassat, E., Wang, J., Perez, D., Kain, D., Lendengolts, D., Winkler, R., Bueno-levy, H., Umansky, K. B., Mishaly, D., Shakked, A., Miyara, S., Sarusi-Portuguez, A., Goldfinger, N., Prior, A., ... Tzahor, E. (2024). Egr1 regulates regenerative senescence and cardiac repair. Nature Cardiovascular Research, 3(8), 915-932. https://doi.org/10.1038/s44161-024-00493-1

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title = "Egr1 regulates regenerative senescence and cardiac repair",

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.",

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

year = "2024",

month = aug,

doi = "10.1038/s44161-024-00493-1",

language = "English",

volume = "3",

pages = "915--932",

journal = "Nature Cardiovascular Research",

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Zhang, L , Elkahal, J , Wang, T, Rimmer, R, Genzelinakh, A, Bassat, E, Wang, J, Perez, D, Kain, D, Lendengolts, D , Winkler, R, Bueno-levy, H, Umansky, KB, Mishaly, D, Shakked, A, Miyara, S, Sarusi-Portuguez, A, Goldfinger, N, Prior, A, Morgenstern, D , Levin, Y , Addadi, Y, Li, B, Rotter, V, Katz, U, Tanaka, EM, Krizhanovsky, V , Sarig, R & Tzahor, E 2024, 'Egr1 regulates regenerative senescence and cardiac repair', Nature Cardiovascular Research, vol. 3, no. 8, pp. 915-932. https://doi.org/10.1038/s44161-024-00493-1

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T1 - Egr1 regulates regenerative senescence and cardiac repair

AU - Zhang, Lingling

AU - Elkahal, Jacob

AU - Wang, Tianzhen

AU - Rimmer, Racheli

AU - Genzelinakh, Alexander

AU - Bassat, Elad

AU - Wang, Jingkui

AU - Perez, Dahlia

AU - Kain, David

AU - Lendengolts, Daria

AU - Winkler, Roni

AU - Bueno-levy, Hanna

AU - Umansky, Kfir Baruch

AU - Mishaly, David

AU - Shakked, Avraham

AU - Miyara, Shoval

AU - Sarusi-Portuguez, Avital

AU - Goldfinger, Naomi

AU - Prior, Amir

AU - Morgenstern, David

AU - Levin, Yishai

AU - Addadi, Yoseph

AU - Li, Baoguo

AU - Rotter, Varda

AU - Katz, Uriel

AU - Tanaka, Elly M.

AU - Krizhanovsky, Valery

AU - Sarig, Rachel

AU - Tzahor, Eldad

PY - 2024/8

Y1 - 2024/8

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85195960327

U2 - 10.1038/s44161-024-00493-1

DO - 10.1038/s44161-024-00493-1

M3 - Article

AN - SCOPUS:85195960327

SN - 2731-0590

VL - 3

SP - 915

EP - 932

JO - Nature Cardiovascular Research

JF - Nature Cardiovascular Research

IS - 8

ER -

Egr1 regulates regenerative senescence and cardiac repair

Abstract

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