Background: Myofibroblast differentiation is a key event during wound healing and is triggered primarily by transforming growth factor (TGF-beta). Serum response factor (SRF) is a TGF-beta-inducible transcription factor important for wound healing. We previously demonstrated that injection of SRF expression plasmid into rat gastric ulcers significantly accelerates restoration of epithelium and smooth muscle structures.
Aims: In this study, we sought to determine the role of SRF in esophageal ulcer healing, especially in myofibroblast differentiation.
Subjects: Rats (in vivo), esophageal epithelial cells (Het1A) and fibroblasts (Rat1-R12) (in vitro) were used.
Methods: Esophageal ulcers were induced in rats by acetic acid and subsequently treated by local injection of plasmids expressing either SRF or SRF antisense sequence. Rats were euthanized to collect tissues at 1, 3, 6, 9 and 14 days after treatment. For in vitro studies, both Het1A and Rat1-R12 cells were transfected with the same plasmids used in ulcer treatment.
Results: Up-regulation of SRF increased myofibroblast population in ulcer granulation tissue; knockdown of SRF suppressed this event. In addition, ulceration induced SRF and TGF-beta expressions coordinately. In vitro studies demonstrated that overexpression of SRF in either esophageal epithelial cells or fibroblasts was sufficient to induce myofibroblast phenotype. Furthermore, TGF-beta-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 esophageal ulcer healing and is required for TGF-beta-induced myofibroblast transition from either epithelial cells or fibroblasts. ILK is a mediator in TGF-beta-induced SRF activation and subsequent myofibroblast differentiation.ILK is associated with SRF and TGF-beta enhances this association.
- Integrin-linked kinase
- Serum Response Factor
- cell differentiation
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