Setd4 controlled quiescent c-Kit+ cells contribute to cardiac neovascularization of capillaries beyond activation

Abstract Blood vessels in the adult mammal exist in a highly organized and stable state. In the ischemic heart, limited expansion capacity of the myocardial vascular bed cannot satisfy demands for oxygen supply and the myocardium eventually undergoes irreversible damage. The predominant contribution...

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Autores principales:	Sheng Xing, Jin-Ze Tian, Shu-Hua Yang, Xue-Ting Huang, Yan-Fu Ding, Qian-Yun Lu, Jin-Shu Yang, Wei-Jun Yang
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/40699a78a74244c4b1ca0c38fd7b22d1
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spelling	oai:doaj.org-article:40699a78a74244c4b1ca0c38fd7b22d12021-12-02T15:56:49ZSetd4 controlled quiescent c-Kit+ cells contribute to cardiac neovascularization of capillaries beyond activation10.1038/s41598-021-91105-62045-2322https://doaj.org/article/40699a78a74244c4b1ca0c38fd7b22d12021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-91105-6https://doaj.org/toc/2045-2322Abstract Blood vessels in the adult mammal exist in a highly organized and stable state. In the ischemic heart, limited expansion capacity of the myocardial vascular bed cannot satisfy demands for oxygen supply and the myocardium eventually undergoes irreversible damage. The predominant contribution of endogenous c-Kit+ cells is understood to be in the development and homeostasis of cardiac endothelial cells, which suggests potential for their targeting in treatments for cardiac ischemic injury. Quiescent cells in other tissues are known to contribute to the long-term maintenance of a cell pool, preserve proliferation capacity and, upon activation, facilitate tissue homeostasis and regeneration in response to tissue injury. Here, we present evidence of a Setd4-expressing quiescent c-Kit+ cell population in the adult mouse heart originating from embryonic stages. Conditional knock-out of Setd4 in c-Kit-CreER T2 ;Setd4 f/f ;Rosa26 TdTomato mice induced an increase in vascular endothelial cells of capillaries in both neonatal and adult mice. We show that Setd4 regulates quiescence of c-Kit+ cells by the PI3K-Akt-mTOR signaling pathway via H4K20me3 catalysis. In myocardial infarction injured mice, Setd4 knock-out resulted in attenuated cardiomyocyte apoptosis, decreased infarction size and improved cardiac function. Lineage tracing in Setd4-Cre;Rosa26 mT/mG mice showed that Setd4+ cells contribute to each cardiac lineage. Overall, Setd4 epigenetically controls c-Kit+ cell quiescence in the adult heart by facilitating heterochromatin formation via H4K20me3. Beyond activation, endogenous quiescent c-Kit+ cells were able to improve cardiac function in myocardial infarction injured mice via the neovascularization of capillaries.Sheng XingJin-Ze TianShu-Hua YangXue-Ting HuangYan-Fu DingQian-Yun LuJin-Shu YangWei-Jun YangNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sheng Xing Jin-Ze Tian Shu-Hua Yang Xue-Ting Huang Yan-Fu Ding Qian-Yun Lu Jin-Shu Yang Wei-Jun Yang Setd4 controlled quiescent c-Kit+ cells contribute to cardiac neovascularization of capillaries beyond activation
description	Abstract Blood vessels in the adult mammal exist in a highly organized and stable state. In the ischemic heart, limited expansion capacity of the myocardial vascular bed cannot satisfy demands for oxygen supply and the myocardium eventually undergoes irreversible damage. The predominant contribution of endogenous c-Kit+ cells is understood to be in the development and homeostasis of cardiac endothelial cells, which suggests potential for their targeting in treatments for cardiac ischemic injury. Quiescent cells in other tissues are known to contribute to the long-term maintenance of a cell pool, preserve proliferation capacity and, upon activation, facilitate tissue homeostasis and regeneration in response to tissue injury. Here, we present evidence of a Setd4-expressing quiescent c-Kit+ cell population in the adult mouse heart originating from embryonic stages. Conditional knock-out of Setd4 in c-Kit-CreER T2 ;Setd4 f/f ;Rosa26 TdTomato mice induced an increase in vascular endothelial cells of capillaries in both neonatal and adult mice. We show that Setd4 regulates quiescence of c-Kit+ cells by the PI3K-Akt-mTOR signaling pathway via H4K20me3 catalysis. In myocardial infarction injured mice, Setd4 knock-out resulted in attenuated cardiomyocyte apoptosis, decreased infarction size and improved cardiac function. Lineage tracing in Setd4-Cre;Rosa26 mT/mG mice showed that Setd4+ cells contribute to each cardiac lineage. Overall, Setd4 epigenetically controls c-Kit+ cell quiescence in the adult heart by facilitating heterochromatin formation via H4K20me3. Beyond activation, endogenous quiescent c-Kit+ cells were able to improve cardiac function in myocardial infarction injured mice via the neovascularization of capillaries.
format	article
author	Sheng Xing Jin-Ze Tian Shu-Hua Yang Xue-Ting Huang Yan-Fu Ding Qian-Yun Lu Jin-Shu Yang Wei-Jun Yang
author_facet	Sheng Xing Jin-Ze Tian Shu-Hua Yang Xue-Ting Huang Yan-Fu Ding Qian-Yun Lu Jin-Shu Yang Wei-Jun Yang
author_sort	Sheng Xing
title	Setd4 controlled quiescent c-Kit+ cells contribute to cardiac neovascularization of capillaries beyond activation
title_short	Setd4 controlled quiescent c-Kit+ cells contribute to cardiac neovascularization of capillaries beyond activation
title_full	Setd4 controlled quiescent c-Kit+ cells contribute to cardiac neovascularization of capillaries beyond activation
title_fullStr	Setd4 controlled quiescent c-Kit+ cells contribute to cardiac neovascularization of capillaries beyond activation
title_full_unstemmed	Setd4 controlled quiescent c-Kit+ cells contribute to cardiac neovascularization of capillaries beyond activation
title_sort	setd4 controlled quiescent c-kit+ cells contribute to cardiac neovascularization of capillaries beyond activation
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/40699a78a74244c4b1ca0c38fd7b22d1
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Setd4 controlled quiescent c-Kit+ cells contribute to cardiac neovascularization of capillaries beyond activation

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