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A critical role of serum response factor in myofibroblast differentiation during experimental oesophageal ulcer healing in rats

Department of Research, VA Long Beach Healthcare System, Long Beach, CA, USA

Correspondence to:
Correspondence to:
Dr Chai
Department of Research (151), VA Long Beach Healthcare System, 5901 E 7th St, Long Beach, CA 90822, USA; jianyuan.chai{at}med.va.gov

Background: Myofibroblast differentiation is a key event during wound healing and is triggered primarily by transforming growth factor ß (TGFß). Serum response factor (SRF) is a TGFß-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.

Aim: To determine the role of SRF in oesophageal ulcer healing, especially in myofibroblast differentiation.

Subjects: 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 TGFß 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 TGFß-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 TGFß-induced myofibroblast transition from either epithelial cells or fibroblasts. ILK is a mediator in TGFß-induced SRF activation and subsequent myofibroblast differentiation. ILK is associated with SRF, and TGFß enhances this association.

Abbreviations: EMT, epithelial–mesenchymal transition; ILK, integrin-linked kinase; ILK(–), inactivation of ILK; MBP, myelin basic protein; SM -actin, smooth muscle -actin; SRE, serum response element; SRF, serum response factor; SRF(+), overexpression of SRF; SRF(–), knockdown of SRF; TGFß1, transforming growth factor ß1

Keywords: serum response factor; integrin-linked kinase; transforming growth factor ß; cell differentiation; ulcer