Stromal cell-derived factor-1/Exendin-4 cotherapy facilitates the proliferation, migration and osteogenic differentiation of human periodontal ligament stem cells in vitro and promotes periodontal bone regeneration in vivo

Cell Prolif. 2021 Mar;54(3):e12997. doi: 10.1111/cpr.12997. Epub 2021 Jan 29.

Abstract

Objectives: Stromal cell-derived factor-1 (SDF-1) actively directs endogenous cell homing. Exendin-4 (EX-4) promotes stem cell osteogenic differentiation. Studies revealed that EX-4 strengthened SDF-1-mediated stem cell migration. However, the effects of SDF-1 and EX-4 on periodontal ligament stem cells (PDLSCs) and bone regeneration have not been investigated. In this study, we aimed to evaluate the effects of SDF-1/EX-4 cotherapy on PDLSCs in vitro and periodontal bone regeneration in vivo.

Methods: Cell-counting kit-8 (CCK8), transwell assay, qRT-PCR and western blot were used to determine the effects and mechanism of SDF-1/EX-4 cotherapy on PDLSCs in vitro. A rat periodontal bone defect model was developed to evaluate the effects of topical application of SDF-1 and systemic injection of EX-4 on endogenous cell recruitment, osteoclastogenesis and bone regeneration in vivo.

Results: SDF-1/EX-4 cotherapy had additive effects on PDLSC proliferation, migration, alkaline phosphatase (ALP) activity, mineral deposition and osteogenesis-related gene expression compared to SDF-1 or EX-4 in vitro. Pretreatment with ERK inhibitor U0126 blocked SDF-1/EX-4 cotherapy induced ERK signal activation and PDLSC proliferation. SDF-1/EX-4 cotherapy significantly promoted new bone formation, recruited more CXCR4+ cells and CD90+ /CD34- stromal cells to the defects, enhanced early-stage osteoclastogenesis and osteogenesis-related markers expression in regenerated bone compared to control, SDF-1 or EX-4 in vivo.

Conclusions: SDF-1/EX-4 cotherapy synergistically regulated PDLSC activities, promoted periodontal bone formation, thereby providing a new strategy for periodontal bone regeneration.

Keywords: exendin-4; osteogenic differentiation; periodontal bone regeneration; periodontal ligament stem cell; stromal cell-derived factor-1.

MeSH terms

  • Bone Regeneration / drug effects*
  • Cell Differentiation / drug effects
  • Cell Movement / drug effects*
  • Cell Proliferation / drug effects
  • Chemokine CXCL12 / metabolism*
  • Exenatide / metabolism
  • Exenatide / pharmacology*
  • Humans
  • Osteogenesis / drug effects
  • Osteogenesis / physiology
  • Periodontal Ligament / cytology*
  • Signal Transduction / drug effects
  • Stem Cells / cytology
  • Stem Cells / drug effects
  • Stromal Cells / drug effects*
  • Stromal Cells / metabolism

Substances

  • Chemokine CXCL12
  • Exenatide