TGF-β/Smad3 stimulates stem cell/developmental gene expression and vascular smooth muscle cell de-differentiation.

Atherosclerotic-associated diseases are the leading cause of death in the United States. Despite recent progress, interventional treatments for atherosclerosis can be complicated by restenosis resulting from neo-intimal hyperplasia. We have previously demonstrated that TGF-β and its downstream signa...

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Autores principales:	Xudong Shi, Daniel DiRenzo, Lian-Wang Guo, Sarah R Franco, Bowen Wang, Stephen Seedial, K Craig Kent
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e55f5cce489b4a9bbf8942696144e134
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spelling	oai:doaj.org-article:e55f5cce489b4a9bbf8942696144e1342021-11-18T08:24:13ZTGF-β/Smad3 stimulates stem cell/developmental gene expression and vascular smooth muscle cell de-differentiation.1932-620310.1371/journal.pone.0093995https://doaj.org/article/e55f5cce489b4a9bbf8942696144e1342014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24718260/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Atherosclerotic-associated diseases are the leading cause of death in the United States. Despite recent progress, interventional treatments for atherosclerosis can be complicated by restenosis resulting from neo-intimal hyperplasia. We have previously demonstrated that TGF-β and its downstream signaling protein Smad3 ∶ 1) are up-regulated following vascular injury, 2) together drive smooth muscle cell (SMC) proliferation and migration and 3) enhance the development of intimal hyperplasia. In order to determine a mechanism through which TGF-β/Smad3 promote these effects, Affymetrix gene expression arrays were performed on primary rat SMCs infected with Smad3 and stimulated with TGF-β or infected with GFP alone. More than 200 genes were differentially expressed (>2.0 fold change, p<0.05) in TGF-β/Smad3 stimulated SMCs. We then performed GO term enrichment analysis using the DAVID bioinformatics database and found that TGF-β/Smad3 activated the expression of multiple genes related to either development or cell differentiation, several of which have been shown to be associated with multipotent stem or progenitor cells. Quantitative real-time PCR confirmed up-regulation of several developmental genes including FGF1, NGF, and Wnt11 (by 2.5, 6 and 7 fold, respectively) as well as stem/progenitor cell associated genes CD34 and CXCR4 (by 10 and 45 fold, respectively). In addition, up-regulation of these factors at protein levels were also confirmed by Western blotting, or by immunocytochemistry (performed for CXCR4 and NGF). Finally, TGF-β/Smad3 down regulated transcription of SMC contractile genes as well as protein production of smooth muscle alpha actin, calponin, and smooth muscle myosin heavy chain. These combined results suggest that TGF-β/Smad3 stimulation drives SMCs to a phenotypically altered state of de-differentiation through the up-regulation of developmental related genes.Xudong ShiDaniel DiRenzoLian-Wang GuoSarah R FrancoBowen WangStephen SeedialK Craig KentPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 4, p e93995 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Xudong Shi Daniel DiRenzo Lian-Wang Guo Sarah R Franco Bowen Wang Stephen Seedial K Craig Kent TGF-β/Smad3 stimulates stem cell/developmental gene expression and vascular smooth muscle cell de-differentiation.
description	Atherosclerotic-associated diseases are the leading cause of death in the United States. Despite recent progress, interventional treatments for atherosclerosis can be complicated by restenosis resulting from neo-intimal hyperplasia. We have previously demonstrated that TGF-β and its downstream signaling protein Smad3 ∶ 1) are up-regulated following vascular injury, 2) together drive smooth muscle cell (SMC) proliferation and migration and 3) enhance the development of intimal hyperplasia. In order to determine a mechanism through which TGF-β/Smad3 promote these effects, Affymetrix gene expression arrays were performed on primary rat SMCs infected with Smad3 and stimulated with TGF-β or infected with GFP alone. More than 200 genes were differentially expressed (>2.0 fold change, p<0.05) in TGF-β/Smad3 stimulated SMCs. We then performed GO term enrichment analysis using the DAVID bioinformatics database and found that TGF-β/Smad3 activated the expression of multiple genes related to either development or cell differentiation, several of which have been shown to be associated with multipotent stem or progenitor cells. Quantitative real-time PCR confirmed up-regulation of several developmental genes including FGF1, NGF, and Wnt11 (by 2.5, 6 and 7 fold, respectively) as well as stem/progenitor cell associated genes CD34 and CXCR4 (by 10 and 45 fold, respectively). In addition, up-regulation of these factors at protein levels were also confirmed by Western blotting, or by immunocytochemistry (performed for CXCR4 and NGF). Finally, TGF-β/Smad3 down regulated transcription of SMC contractile genes as well as protein production of smooth muscle alpha actin, calponin, and smooth muscle myosin heavy chain. These combined results suggest that TGF-β/Smad3 stimulation drives SMCs to a phenotypically altered state of de-differentiation through the up-regulation of developmental related genes.
format	article
author	Xudong Shi Daniel DiRenzo Lian-Wang Guo Sarah R Franco Bowen Wang Stephen Seedial K Craig Kent
author_facet	Xudong Shi Daniel DiRenzo Lian-Wang Guo Sarah R Franco Bowen Wang Stephen Seedial K Craig Kent
author_sort	Xudong Shi
title	TGF-β/Smad3 stimulates stem cell/developmental gene expression and vascular smooth muscle cell de-differentiation.
title_short	TGF-β/Smad3 stimulates stem cell/developmental gene expression and vascular smooth muscle cell de-differentiation.
title_full	TGF-β/Smad3 stimulates stem cell/developmental gene expression and vascular smooth muscle cell de-differentiation.
title_fullStr	TGF-β/Smad3 stimulates stem cell/developmental gene expression and vascular smooth muscle cell de-differentiation.
title_full_unstemmed	TGF-β/Smad3 stimulates stem cell/developmental gene expression and vascular smooth muscle cell de-differentiation.
title_sort	tgf-β/smad3 stimulates stem cell/developmental gene expression and vascular smooth muscle cell de-differentiation.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/e55f5cce489b4a9bbf8942696144e134
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TGF-β/Smad3 stimulates stem cell/developmental gene expression and vascular smooth muscle cell de-differentiation.

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