Basic fibroblast growth factor reduces scar by inhibiting the differentiation of epidermal stem cells to myofibroblasts via the Notch1/Jagged1 pathway

Stem Cell Res Ther. 2017 May 16;8(1):114. doi: 10.1186/s13287-017-0549-7.

Abstract

Background: Basic fibroblast growth factor (bFGF) plays an important role in promoting wound healing and reducing scar, but the possible molecular mechanisms are still unclear. Our previous studies have found that activating the Notch1/Jagged1 pathway can inhibit the differentiation of epidermal stem cells (ESCs) to myofibroblasts (MFB). Herein, we document that bFGF reduces scar by inhibiting the differentiation of ESCs to MFB via activating the Notch1/Jagged1 pathway.

Methods: In in-vitro study, ESCs were isolated from 10 neonatal SD rats (1-3 days old), cultured in keratinocyte serum-free medium, and divided into six groups: bFGF group, bFGF + SU5402 group, bFGF + DAPT group, siJagged1 group, bFGF + siJagged1 group, and control group. Jagged1 of the ESCs in the siJagged1 group and bFGF + siJagged1 group was knocked down by small-interfering RNA transfection. Expression of ESC markers (CK15/CK10), MFB markers (α-SMA, Collagen I, Collagen III), and Notch1/Jagged1 components (Jagged1, Notch1, Hes1) was detected by FCM, qRT-PCR, and western blot analysis to study the relationships of bFGF, ESCs, and Notch1/Jagged1 pathway. In in-vivo study, the wound healing time and scar hyperplasia were observed on rabbit ear scar models. The quality of wound healing was estimated by hematoxylin and eosin staining and Masson staining. Expression of ESC markers, MFB markers and Notch1/Jagged1 components was elucidated by immunohistochemistry, immunofluorescence, and western blot analysis.

Results: The in-vitro study showed that bFGF could significantly upregulate the expression of ESC markers and Notch1/Jagged1 components, while downregulating the expression of MFB markers at the same time. However, these effects could be obviously decreased when we knocked down Jagged1 or added DAPT. Similarly, in in-vivo study, bFGF also exhibited its functions in inhibiting the differentiation of rabbit ESCs to MFB by activating the Notch1/Jagged1 pathway, which improved the wound healing quality and alleviated scar significantly.

Conclusion: These results provide evidence that bFGF can reduce scar by inhibiting the differentiation of ESCs to MFB via the Notch1/Jagged1 pathway, and present a new promising potential direction for the treatment of scar.

Keywords: Basic fibroblast growth factor; Epidermal stem cells; Myofibroblasts; Notch1/Jagged1 pathway; Scar.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Cell Differentiation / drug effects*
  • Cell Proliferation / drug effects
  • Cicatrix / pathology*
  • Collagen Type I / metabolism
  • Dipeptides / pharmacology
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / drug effects
  • Epidermis / pathology*
  • Female
  • Fibroblast Growth Factor 2 / pharmacology*
  • Jagged-1 Protein / metabolism*
  • Myofibroblasts / drug effects
  • Myofibroblasts / pathology*
  • Rabbits
  • Rats, Sprague-Dawley
  • Re-Epithelialization / drug effects
  • Receptors, Notch / metabolism*
  • Regeneration / drug effects
  • Signal Transduction / drug effects
  • Stem Cells / drug effects
  • Stem Cells / pathology*
  • Transforming Growth Factor beta1 / pharmacology

Substances

  • Collagen Type I
  • Dipeptides
  • Jagged-1 Protein
  • N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester
  • Receptors, Notch
  • Transforming Growth Factor beta1
  • Fibroblast Growth Factor 2