Activation of MRTF-A-dependent gene expression with a small molecule promotes myofibroblast differentiation and wound healing

Lissette S. Velasquez, Lillian B. Sutherland, Zhenan Liu, Frederick Grinnell, Kristine E. Kamm, Jay W. Schneider, Eric N. Olson, Eric M. Small

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

Myocardin-related transcription factors (MRTFs) regulate cellular contractility and motility by associating with serum response factor (SRF) and activating genes involved in cytoskeletal dynamics. We reported previously that MRTF-A contributes to pathological cardiac remodeling by promoting differentiation of fibroblasts to myofibroblasts following myocardial infarction. Here, we show that forced expression of MRTF-A in dermal fibroblasts stimulates contraction of a collagen matrix, whereas contractility of MRTF-A null fibroblasts is impaired under basal conditions and in response to TGF-β1 stimulation.We also identify an isoxazole ring-containing small molecule, previously shown to induce smooth muscle α-actin gene expression in cardiac progenitor cells, as an agonist of myofibroblast differentiation. Isoxazole stimulates myofibroblast differentiation via induction of MRTF-A-dependent gene expression. The MRTF-SRF signaling axis is activated in response to skin injury, and treatment of dermal wounds with isoxazole accelerates wound closure and suppresses the inflammatory response. These results reveal an important role forMRTF-SRF signaling in dermal myofibroblast differentiation and wound healing and suggest that targeting MRTFs pharmacologically may prove useful in treating diseases associated with inappropriate myofibroblast activity.

Original languageEnglish (US)
Pages (from-to)16850-16855
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number42
DOIs
StatePublished - Oct 15 2013

Fingerprint

Myofibroblasts
Wound Healing
Transcription Factors
Gene Expression
Serum Response Factor
Isoxazoles
Skin
Fibroblasts
Wounds and Injuries
myocardin
Smooth Muscle
Actins
Collagen
Stem Cells
Myocardial Infarction
Genes

Keywords

  • Dermal injury
  • Fibrosis
  • Granulation tissue
  • MAP kinase signaling

ASJC Scopus subject areas

  • General

Cite this

@article{ea5322cdded4460db3a16cc6f860b0f2,
title = "Activation of MRTF-A-dependent gene expression with a small molecule promotes myofibroblast differentiation and wound healing",
abstract = "Myocardin-related transcription factors (MRTFs) regulate cellular contractility and motility by associating with serum response factor (SRF) and activating genes involved in cytoskeletal dynamics. We reported previously that MRTF-A contributes to pathological cardiac remodeling by promoting differentiation of fibroblasts to myofibroblasts following myocardial infarction. Here, we show that forced expression of MRTF-A in dermal fibroblasts stimulates contraction of a collagen matrix, whereas contractility of MRTF-A null fibroblasts is impaired under basal conditions and in response to TGF-β1 stimulation.We also identify an isoxazole ring-containing small molecule, previously shown to induce smooth muscle α-actin gene expression in cardiac progenitor cells, as an agonist of myofibroblast differentiation. Isoxazole stimulates myofibroblast differentiation via induction of MRTF-A-dependent gene expression. The MRTF-SRF signaling axis is activated in response to skin injury, and treatment of dermal wounds with isoxazole accelerates wound closure and suppresses the inflammatory response. These results reveal an important role forMRTF-SRF signaling in dermal myofibroblast differentiation and wound healing and suggest that targeting MRTFs pharmacologically may prove useful in treating diseases associated with inappropriate myofibroblast activity.",
keywords = "Dermal injury, Fibrosis, Granulation tissue, MAP kinase signaling",
author = "Velasquez, {Lissette S.} and Sutherland, {Lillian B.} and Zhenan Liu and Frederick Grinnell and Kamm, {Kristine E.} and Schneider, {Jay W.} and Olson, {Eric N.} and Small, {Eric M.}",
year = "2013",
month = "10",
day = "15",
doi = "10.1073/pnas.1316764110",
language = "English (US)",
volume = "110",
pages = "16850--16855",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "42",

}

TY - JOUR

T1 - Activation of MRTF-A-dependent gene expression with a small molecule promotes myofibroblast differentiation and wound healing

AU - Velasquez, Lissette S.

AU - Sutherland, Lillian B.

AU - Liu, Zhenan

AU - Grinnell, Frederick

AU - Kamm, Kristine E.

AU - Schneider, Jay W.

AU - Olson, Eric N.

AU - Small, Eric M.

PY - 2013/10/15

Y1 - 2013/10/15

N2 - Myocardin-related transcription factors (MRTFs) regulate cellular contractility and motility by associating with serum response factor (SRF) and activating genes involved in cytoskeletal dynamics. We reported previously that MRTF-A contributes to pathological cardiac remodeling by promoting differentiation of fibroblasts to myofibroblasts following myocardial infarction. Here, we show that forced expression of MRTF-A in dermal fibroblasts stimulates contraction of a collagen matrix, whereas contractility of MRTF-A null fibroblasts is impaired under basal conditions and in response to TGF-β1 stimulation.We also identify an isoxazole ring-containing small molecule, previously shown to induce smooth muscle α-actin gene expression in cardiac progenitor cells, as an agonist of myofibroblast differentiation. Isoxazole stimulates myofibroblast differentiation via induction of MRTF-A-dependent gene expression. The MRTF-SRF signaling axis is activated in response to skin injury, and treatment of dermal wounds with isoxazole accelerates wound closure and suppresses the inflammatory response. These results reveal an important role forMRTF-SRF signaling in dermal myofibroblast differentiation and wound healing and suggest that targeting MRTFs pharmacologically may prove useful in treating diseases associated with inappropriate myofibroblast activity.

AB - Myocardin-related transcription factors (MRTFs) regulate cellular contractility and motility by associating with serum response factor (SRF) and activating genes involved in cytoskeletal dynamics. We reported previously that MRTF-A contributes to pathological cardiac remodeling by promoting differentiation of fibroblasts to myofibroblasts following myocardial infarction. Here, we show that forced expression of MRTF-A in dermal fibroblasts stimulates contraction of a collagen matrix, whereas contractility of MRTF-A null fibroblasts is impaired under basal conditions and in response to TGF-β1 stimulation.We also identify an isoxazole ring-containing small molecule, previously shown to induce smooth muscle α-actin gene expression in cardiac progenitor cells, as an agonist of myofibroblast differentiation. Isoxazole stimulates myofibroblast differentiation via induction of MRTF-A-dependent gene expression. The MRTF-SRF signaling axis is activated in response to skin injury, and treatment of dermal wounds with isoxazole accelerates wound closure and suppresses the inflammatory response. These results reveal an important role forMRTF-SRF signaling in dermal myofibroblast differentiation and wound healing and suggest that targeting MRTFs pharmacologically may prove useful in treating diseases associated with inappropriate myofibroblast activity.

KW - Dermal injury

KW - Fibrosis

KW - Granulation tissue

KW - MAP kinase signaling

UR - http://www.scopus.com/inward/record.url?scp=84885710467&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84885710467&partnerID=8YFLogxK

U2 - 10.1073/pnas.1316764110

DO - 10.1073/pnas.1316764110

M3 - Article

C2 - 24082095

AN - SCOPUS:84885710467

VL - 110

SP - 16850

EP - 16855

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 42

ER -