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Complex epithelial-mesenchymal interactions modulate transforming growth factor-beta expression in keloid-derived
Wei Xia1, Toan-Thang Phan, Ivor J Lim
1Department of Surgery, Stanford University Medical School, 257 Campus Drive, Stanford, CA 94305, USA.
Summary
Keloid formation involves complex cell interactions. Transforming growth factor-beta (TGF-beta) plays a key role, with both keloid keratinocytes and fibroblasts showing altered TGF-beta signaling, contributing to abnormal wound healing.
Area of Science:
- Dermatology
- Wound Healing
- Cell Biology
- Molecular Biology
Background:
- Keloids are pathological dermal growths resulting from abnormal wound healing.
- Previous studies showed keloid fibroblasts proliferate more with keloid keratinocytes.
- The role of transforming growth factor-beta (TGF-beta) in this interaction was investigated.
Purpose of the Study:
- To examine the contribution of TGF-beta to the enhanced proliferation of fibroblasts when cocultured with keloid keratinocytes.
- To investigate the expression and activation of TGF-beta signaling pathways in keloid-derived cells.
Main Methods:
- Utilized a two-chamber coculture system with keloid and normal skin-derived fibroblasts and keratinocytes.
- Measured fibroblast proliferation rates with and without a pan-TGF-beta neutralizing antibody.
- Assessed mRNA expression of TGF-beta isoforms, receptors, and downstream signaling molecules (Smad2).
- Quantified the production of extracellular matrix proteins (collagen type I, CTGF, IGF-II/M6PR).
Main Results:
- Fibroblast proliferation was reduced by the addition of a TGF-beta neutralizing antibody.
- Keloid keratinocytes showed increased expression of TGF-beta1, TGF-beta3, and TGF-beta receptor 1 compared to normal keratinocytes.
- Keloid fibroblasts cocultured with keloid keratinocytes exhibited higher mRNA levels for TGF-beta1, TGF-beta2, TGF-beta receptor 1, and Smad2.
- Keloid fibroblasts produced more collagen type I, connective tissue growth factor, and IGF-II/M6PR when cocultured with keloid keratinocytes.
- Total and activated TGF-beta activity increased in cocultures, correlating with TGF-beta transcriptional activity.
Conclusions:
- A complex paracrine interaction between keratinocytes and fibroblasts regulates TGF-beta mRNA expression and activation.
- Keloid pathogenesis may involve increased TGF-beta production and activation by keloid keratinocytes.
- Elevated TGF-beta expression, utilization, and signaling in keloid fibroblasts also contribute to keloid formation.