Transforming growth factor-β promotes recruitment of bone marrow cells and bone marrow-derived mesenchymal stem cells through stimulation of MCP-1 production in vascular smooth muscle cells

Fan Zhang, Shirling Tsai, Kaori Kato, Dai Yamanouchi, Chunjie Wang, Shahin Rafii, Bo Liu, K. Craig Kent

Research output: Contribution to journalArticle

93 Citations (Scopus)

Abstract

Bone marrow-derived progenitor cells have recently been shown to be involved in the development of intimal hyperplasia after vascular injury. Transforming growth factor-β (TGF-β) has profound stimulatory effects on intimal hyperplasia, but it is unknown whether these effects involve progenitor cell recruitment. In this study we found that although TGF-β had no direct effect on progenitor cell recruitment, conditioned media derived from vascular smooth muscle cells (VSMC) stimulated with TGF-β induced migration of both total bone marrow (BM) cells and BM-mesenchymal stem cells (MSC) and also induced MSC differentiation into smooth muscle like cells. Furthermore, overexpression of the signaling molecule Smad3 in VSCM via adenovirus-mediated gene transfer (AdSmad3) enhanced the TGF-β's chemotactic effect. Microarray analysis of VSMC stimulated by TGF-β/ AdSmad3 revealed monocyte chemoattractant protein-1 (MCP-1) as a likely factor responsible for progenitor cell recruitment. We then demonstrated that TGF-β through Smad3 phosphorylation induced a robust expression of MCP-1 in VSMC. Recombinant MCP-1 mimicked the stimulatory effect of conditioned media on BM and MSC migration. In the rat carotid injury model, Smad3 overexpression significantly increased MCP-1 expression after vascular injury, consistent with our in vitro results. Interestingly, TGF-β/Smad3-induced MCP-1 was completely blocked by both Ro-32-0432 and rotterlin, suggesting protein kinase C-δ (PKCδ) may play a role in TGF-β/Smad3-induced MCP-1 expression. In summary, our data demonstrate that TGF-β, through Smad3 and PKCδ, stimulates VSMC production of MCP-1, which is a chemoattractant for bone marrow-derived cells, specifically MSC. Manipulation of this signaling system may provide a novel approach to inhibition of intimal hyperplasia.

Original languageEnglish (US)
Pages (from-to)17564-17574
Number of pages11
JournalJournal of Biological Chemistry
Volume284
Issue number26
DOIs
StatePublished - Jun 26 2009

Fingerprint

Chemokine CCL2
Transforming Growth Factors
Stem cells
Mesenchymal Stromal Cells
Vascular Smooth Muscle
Bone Marrow Cells
Smooth Muscle Myocytes
Muscle
Bone
Bone Marrow
Cells
Bone and Bones
Tunica Intima
Stem Cells
Hyperplasia
Vascular System Injuries
Conditioned Culture Medium
Protein Kinase C
Smad3 Protein
Gene transfer

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Transforming growth factor-β promotes recruitment of bone marrow cells and bone marrow-derived mesenchymal stem cells through stimulation of MCP-1 production in vascular smooth muscle cells. / Zhang, Fan; Tsai, Shirling; Kato, Kaori; Yamanouchi, Dai; Wang, Chunjie; Rafii, Shahin; Liu, Bo; Kent, K. Craig.

In: Journal of Biological Chemistry, Vol. 284, No. 26, 26.06.2009, p. 17564-17574.

Research output: Contribution to journalArticle

@article{646c16c33ea9494984b5dece0b1eba58,
title = "Transforming growth factor-β promotes recruitment of bone marrow cells and bone marrow-derived mesenchymal stem cells through stimulation of MCP-1 production in vascular smooth muscle cells",
abstract = "Bone marrow-derived progenitor cells have recently been shown to be involved in the development of intimal hyperplasia after vascular injury. Transforming growth factor-β (TGF-β) has profound stimulatory effects on intimal hyperplasia, but it is unknown whether these effects involve progenitor cell recruitment. In this study we found that although TGF-β had no direct effect on progenitor cell recruitment, conditioned media derived from vascular smooth muscle cells (VSMC) stimulated with TGF-β induced migration of both total bone marrow (BM) cells and BM-mesenchymal stem cells (MSC) and also induced MSC differentiation into smooth muscle like cells. Furthermore, overexpression of the signaling molecule Smad3 in VSCM via adenovirus-mediated gene transfer (AdSmad3) enhanced the TGF-β's chemotactic effect. Microarray analysis of VSMC stimulated by TGF-β/ AdSmad3 revealed monocyte chemoattractant protein-1 (MCP-1) as a likely factor responsible for progenitor cell recruitment. We then demonstrated that TGF-β through Smad3 phosphorylation induced a robust expression of MCP-1 in VSMC. Recombinant MCP-1 mimicked the stimulatory effect of conditioned media on BM and MSC migration. In the rat carotid injury model, Smad3 overexpression significantly increased MCP-1 expression after vascular injury, consistent with our in vitro results. Interestingly, TGF-β/Smad3-induced MCP-1 was completely blocked by both Ro-32-0432 and rotterlin, suggesting protein kinase C-δ (PKCδ) may play a role in TGF-β/Smad3-induced MCP-1 expression. In summary, our data demonstrate that TGF-β, through Smad3 and PKCδ, stimulates VSMC production of MCP-1, which is a chemoattractant for bone marrow-derived cells, specifically MSC. Manipulation of this signaling system may provide a novel approach to inhibition of intimal hyperplasia.",
author = "Fan Zhang and Shirling Tsai and Kaori Kato and Dai Yamanouchi and Chunjie Wang and Shahin Rafii and Bo Liu and Kent, {K. Craig}",
year = "2009",
month = "6",
day = "26",
doi = "10.1074/jbc.M109.013987",
language = "English (US)",
volume = "284",
pages = "17564--17574",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "26",

}

TY - JOUR

T1 - Transforming growth factor-β promotes recruitment of bone marrow cells and bone marrow-derived mesenchymal stem cells through stimulation of MCP-1 production in vascular smooth muscle cells

AU - Zhang, Fan

AU - Tsai, Shirling

AU - Kato, Kaori

AU - Yamanouchi, Dai

AU - Wang, Chunjie

AU - Rafii, Shahin

AU - Liu, Bo

AU - Kent, K. Craig

PY - 2009/6/26

Y1 - 2009/6/26

N2 - Bone marrow-derived progenitor cells have recently been shown to be involved in the development of intimal hyperplasia after vascular injury. Transforming growth factor-β (TGF-β) has profound stimulatory effects on intimal hyperplasia, but it is unknown whether these effects involve progenitor cell recruitment. In this study we found that although TGF-β had no direct effect on progenitor cell recruitment, conditioned media derived from vascular smooth muscle cells (VSMC) stimulated with TGF-β induced migration of both total bone marrow (BM) cells and BM-mesenchymal stem cells (MSC) and also induced MSC differentiation into smooth muscle like cells. Furthermore, overexpression of the signaling molecule Smad3 in VSCM via adenovirus-mediated gene transfer (AdSmad3) enhanced the TGF-β's chemotactic effect. Microarray analysis of VSMC stimulated by TGF-β/ AdSmad3 revealed monocyte chemoattractant protein-1 (MCP-1) as a likely factor responsible for progenitor cell recruitment. We then demonstrated that TGF-β through Smad3 phosphorylation induced a robust expression of MCP-1 in VSMC. Recombinant MCP-1 mimicked the stimulatory effect of conditioned media on BM and MSC migration. In the rat carotid injury model, Smad3 overexpression significantly increased MCP-1 expression after vascular injury, consistent with our in vitro results. Interestingly, TGF-β/Smad3-induced MCP-1 was completely blocked by both Ro-32-0432 and rotterlin, suggesting protein kinase C-δ (PKCδ) may play a role in TGF-β/Smad3-induced MCP-1 expression. In summary, our data demonstrate that TGF-β, through Smad3 and PKCδ, stimulates VSMC production of MCP-1, which is a chemoattractant for bone marrow-derived cells, specifically MSC. Manipulation of this signaling system may provide a novel approach to inhibition of intimal hyperplasia.

AB - Bone marrow-derived progenitor cells have recently been shown to be involved in the development of intimal hyperplasia after vascular injury. Transforming growth factor-β (TGF-β) has profound stimulatory effects on intimal hyperplasia, but it is unknown whether these effects involve progenitor cell recruitment. In this study we found that although TGF-β had no direct effect on progenitor cell recruitment, conditioned media derived from vascular smooth muscle cells (VSMC) stimulated with TGF-β induced migration of both total bone marrow (BM) cells and BM-mesenchymal stem cells (MSC) and also induced MSC differentiation into smooth muscle like cells. Furthermore, overexpression of the signaling molecule Smad3 in VSCM via adenovirus-mediated gene transfer (AdSmad3) enhanced the TGF-β's chemotactic effect. Microarray analysis of VSMC stimulated by TGF-β/ AdSmad3 revealed monocyte chemoattractant protein-1 (MCP-1) as a likely factor responsible for progenitor cell recruitment. We then demonstrated that TGF-β through Smad3 phosphorylation induced a robust expression of MCP-1 in VSMC. Recombinant MCP-1 mimicked the stimulatory effect of conditioned media on BM and MSC migration. In the rat carotid injury model, Smad3 overexpression significantly increased MCP-1 expression after vascular injury, consistent with our in vitro results. Interestingly, TGF-β/Smad3-induced MCP-1 was completely blocked by both Ro-32-0432 and rotterlin, suggesting protein kinase C-δ (PKCδ) may play a role in TGF-β/Smad3-induced MCP-1 expression. In summary, our data demonstrate that TGF-β, through Smad3 and PKCδ, stimulates VSMC production of MCP-1, which is a chemoattractant for bone marrow-derived cells, specifically MSC. Manipulation of this signaling system may provide a novel approach to inhibition of intimal hyperplasia.

UR - http://www.scopus.com/inward/record.url?scp=67650538040&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67650538040&partnerID=8YFLogxK

U2 - 10.1074/jbc.M109.013987

DO - 10.1074/jbc.M109.013987

M3 - Article

VL - 284

SP - 17564

EP - 17574

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 26

ER -