title: A critical role of serum response factor in myofibroblast differentiation during experimental oesophageal ulcer healing in rats.
abstract: BACKGROUND
  Myofibroblast differentiation is a key event during wound healing and is triggered primarily by transforming growth factor beta (TGFbeta). Serum response factor (SRF) is a TGFbeta-inducible transcription factor that is important for wound healing. Injection of SRF expression plasmid into rat gastric ulcers significantly accelerated restoration of epithelium and smooth muscle structures.
  
  
  OBJECTIVE
  To determine the role of SRF in oesophageal ulcer healing, especially in myofibroblast differentiation.
  
  
  METHODS
  Rats (in vivo), oesophageal epithelial cells (Het1A) and fibroblasts (Rat1-R12) (in vitro) were used.
  
  
  METHODS
  Oesophageal ulcers were induced in rats with acetic acid and subsequently treated by local injection of plasmids expressing either SRF or SRF antisense sequence. Rats were killed at 1, 3, 6, 9 and 14 days after treatment and tissues collected. For in vitro studies, both Het1A and Rat1-R12 cells were transfected with the plasmids used in ulcer treatment.
  
  
  RESULTS
  Upregulation of SRF increased the myofibroblast population in ulcer granulation tissue; knockdown of SRF suppressed this event. In addition, ulceration induced SRF and TGFbeta expression coordinately. In vitro studies showed that overexpression of SRF in either oesophageal epithelial cells or fibroblasts was sufficient to induce myofibroblast phenotype. Furthermore, the TGFbeta-induced myofibroblast phenotype required integrin-linked kinase (ILK)-mediated SRF activation, as either knockdown of SRF or inactivation of ILK prevented this action.
  
  
  CONCLUSIONS
  SRF is indispensable for myofibroblast differentiation during oesophageal ulcer healing and is required for TGFbeta-induced myofibroblast transition from either epithelial cells or fibroblasts. ILK is a mediator in TGFbeta-induced SRF activation and subsequent myofibroblast differentiation. ILK is associated with SRF, and TGFbeta enhances this association.
authors.affiliation: Department of Research (151), VA Long Beach Healthcare System, 5901 E 7th St, Long Beach, CA 90822, USA. jianyuan.chai@med.va.gov
authors.forename: Jianyuan
authors.initials: J
authors.lastname: Chai
authors.forename: Manith
authors.initials: M
authors.lastname: Norng
authors.forename: Andrzej S
authors.initials: AS
authors.lastname: Tarnawski
authors.forename: Justine
authors.initials: J
authors.lastname: Chow
mesh_terms: D019342:Acetic Acid; D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D004935:Esophageal Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D015316:Genetic Therapy / Q000379:methods*; D008297:Male; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D026362:Serum Response Factor / Q000235:genetics / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology; D014456:Ulcer / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D014945:Wound Healing; D000099200:Scaffold Protein ILK
chemical_list: D019342:Acetic Acid; D017346:Protein Serine-Threonine Kinases; D011994:Recombinant Proteins; D026362:Serum Response Factor; D016212:Transforming Growth Factor beta; D000099200:Scaffold Protein ILK