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Context-Dependent Regulation of Epithelial Cell Behaviour by Palatal Connective Tissue Graft-Derived Fibroblasts via
Xiaoqing Song1,2,3,4, Cristina Nica2, Alexandra Stähli2
1Laboratory of Oral Cell Biology, Dental Research Center, School of Dental Medicine, University of Bern, Bern, Switzerland.
Aim:
To investigate how human palatal fibroblasts (HPFs) from anterior (A) or posterior (P) subepithelial connective tissue grafts (CTGs) regulate oral epithelial cell behaviour, focusing on epidermal growth factor (EGF) and heparin-binding EGF-like growth factor (HB-EGF).
Materials And Methods:
Oral epithelial cells were cocultured with either A-HPFs or P-HPFs under indirect and direct conditions. Proliferation and differentiation were assessed by BrdU, qRT-PCR and immunofluorescence. Growth factor signalling was analysed by ELISA, inhibition/neutralisation experiments, siRNA knockdown and immunoblotting.
Results:
A-HPFs promoted epithelial proliferation but not differentiation under indirect conditions. In contrast, direct contact triggered epithelial differentiation and AP-1 gene induction. EGF mediated proliferation via the EGF receptor (EGFR), whereas HB-EGF induced differentiation via the ErbB4 receptor. HB-EGF knockdown selectively impaired expression of differentiation-associated and AP-1 genes without affecting proliferation. Distinct intracellular signalling was observed, with Erk1/2 activation predominating in indirect coculture and Akt and Stat5 activation in direct coculture.
Conclusion:
This mechanistic in vitro study supports a model in which A-CTG-derived fibroblasts regulate epithelial responses through a transition from paracrine EGF-EGFR to juxtacrine HB-EGF-ErbB4 signalling during wound healing. These findings provide a biological basis for personalised strategies to optimise graft selection and biomaterial functionalisation in periodontal and peri-implant therapy.