Thymosin beta-4 regulates activation of hepatic stellate cells via hedgehog signaling

Abstract The molecular mechanisms of thymosin beta-4 (TB4) involved in regulating hepatic stellate cell (HSC) functions remain unclear. Therefore, we hypothesize that TB4 influences HSC activation through hedgehog (Hh) pathway. HSC functions declined in a TB4 siRNA-treated LX-2. TB4 suppression down...

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Autores principales:	Jieun Kim, Jeongeun Hyun, Sihyung Wang, Chanbin Lee, Jae-Wook Lee, Eun-Yi Moon, Heejae Cha, Anna Mae Diehl, Youngmi Jung
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/de1193bb16be4930b317ead645d89755
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spelling	oai:doaj.org-article:de1193bb16be4930b317ead645d897552021-12-02T11:53:05ZThymosin beta-4 regulates activation of hepatic stellate cells via hedgehog signaling10.1038/s41598-017-03782-x2045-2322https://doaj.org/article/de1193bb16be4930b317ead645d897552017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03782-xhttps://doaj.org/toc/2045-2322Abstract The molecular mechanisms of thymosin beta-4 (TB4) involved in regulating hepatic stellate cell (HSC) functions remain unclear. Therefore, we hypothesize that TB4 influences HSC activation through hedgehog (Hh) pathway. HSC functions declined in a TB4 siRNA-treated LX-2. TB4 suppression down-regulated both integrin linked kinase (ILK), an activator of smoothened, and phosphorylated glycogen synthase kinase 3 beta (pGSK-3B), an inactive form of GSK-3B degrading glioblastoma 2 (GLI2), followed by the decreased expression of both smoothened and GLI2. A TB4 CRISPR also blocked the activation of primary HSCs, with decreased expression of smoothened, GLI2 and ILK compared with cells transfected with nontargeting control CRISPR. Double immunostaining and an immunoprecipitation assay revealed that TB4 interacted with either smoothened at the cytoplasm or GLI2 at the nucleus in LX-2. Smoothened suppression in primary HSCs using a Hh antagonist or adenovirus transduction decreased TB4 expression with the reduced activation of HSCs. Tb4-overexpressing transgenic mice treated with CCl4 were susceptible to the development hepatic fibrosis with higher levels of ILK, pGSK3b, and Hh activity, as compared with wild-type mice. These findings demonstrate that TB4 regulates HSC activation by influencing the activity of Smoothened and GLI2, suggesting TB4 as a novel therapeutic target in liver disease.Jieun KimJeongeun HyunSihyung WangChanbin LeeJae-Wook LeeEun-Yi MoonHeejae ChaAnna Mae DiehlYoungmi JungNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-16 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jieun Kim Jeongeun Hyun Sihyung Wang Chanbin Lee Jae-Wook Lee Eun-Yi Moon Heejae Cha Anna Mae Diehl Youngmi Jung Thymosin beta-4 regulates activation of hepatic stellate cells via hedgehog signaling
description	Abstract The molecular mechanisms of thymosin beta-4 (TB4) involved in regulating hepatic stellate cell (HSC) functions remain unclear. Therefore, we hypothesize that TB4 influences HSC activation through hedgehog (Hh) pathway. HSC functions declined in a TB4 siRNA-treated LX-2. TB4 suppression down-regulated both integrin linked kinase (ILK), an activator of smoothened, and phosphorylated glycogen synthase kinase 3 beta (pGSK-3B), an inactive form of GSK-3B degrading glioblastoma 2 (GLI2), followed by the decreased expression of both smoothened and GLI2. A TB4 CRISPR also blocked the activation of primary HSCs, with decreased expression of smoothened, GLI2 and ILK compared with cells transfected with nontargeting control CRISPR. Double immunostaining and an immunoprecipitation assay revealed that TB4 interacted with either smoothened at the cytoplasm or GLI2 at the nucleus in LX-2. Smoothened suppression in primary HSCs using a Hh antagonist or adenovirus transduction decreased TB4 expression with the reduced activation of HSCs. Tb4-overexpressing transgenic mice treated with CCl4 were susceptible to the development hepatic fibrosis with higher levels of ILK, pGSK3b, and Hh activity, as compared with wild-type mice. These findings demonstrate that TB4 regulates HSC activation by influencing the activity of Smoothened and GLI2, suggesting TB4 as a novel therapeutic target in liver disease.
format	article
author	Jieun Kim Jeongeun Hyun Sihyung Wang Chanbin Lee Jae-Wook Lee Eun-Yi Moon Heejae Cha Anna Mae Diehl Youngmi Jung
author_facet	Jieun Kim Jeongeun Hyun Sihyung Wang Chanbin Lee Jae-Wook Lee Eun-Yi Moon Heejae Cha Anna Mae Diehl Youngmi Jung
author_sort	Jieun Kim
title	Thymosin beta-4 regulates activation of hepatic stellate cells via hedgehog signaling
title_short	Thymosin beta-4 regulates activation of hepatic stellate cells via hedgehog signaling
title_full	Thymosin beta-4 regulates activation of hepatic stellate cells via hedgehog signaling
title_fullStr	Thymosin beta-4 regulates activation of hepatic stellate cells via hedgehog signaling
title_full_unstemmed	Thymosin beta-4 regulates activation of hepatic stellate cells via hedgehog signaling
title_sort	thymosin beta-4 regulates activation of hepatic stellate cells via hedgehog signaling
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/de1193bb16be4930b317ead645d89755
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Thymosin beta-4 regulates activation of hepatic stellate cells via hedgehog signaling

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