Promotion of Epithelial Healing in Oral Mucositis by hESC-derived Mesenchymal Stem Cells via the PI3K/AKT Pathway.

Abstract

Introduction: Oral mucositis (OM) is a common and debilitating side effect of cancer therapies such as radiotherapy, chemotherapy, hematopoietic cell transplant, or their combinations. This study focused on the reparative effects of human embryonic stem cell-derived mesenchymal stem cells(hESC-MSCs) in OM and possible mechanisms.

Methods: An ulcer model was created in the rat buccal mucosa to mimic an in vivo animal model of OM mucosal injury, and hESC-MSCs were injected 48h later to assess their reparative effects. In vitro, the efficacy of hESC-MSCs in regulating apoptosis and proliferation in LPS- or 5-fluorouracil (5-FU)-injured HaCaT cells was studied using a transwell coculture system. Subsequently, the PI3K inhibitor LY24002 was used to assess whether hESC-MSCs regulated injured HaCaT cells through the PI3K/AKT pathway.

Results: In vivo, we found that hESC-MSCs injection promoted OM healing in rats through the acceleration of re-epithelialization and a decrease in apoptosis. In vitro, our findings revealed that the hESC-MSCs treatment led to a reduction in the quantity of HaCaT cells undergoing apoptosis. Western blot analysis revealed that hESC-MSCs activated AKT, resulting in increased protein levels of PCNA and BCL-2 and decreased protein levels of Bax and Caspase-3. Whereas LY294002 reversed these changes.

Conclusion: These findings suggest that hESC-MSCs promoted OM wound healing by stimulating the proliferation of epithelial cells and inhibiting their apoptosis in rat models. Furthermore, hESC-MSCs might mediate the PI3K/AKT pathway to modulate apoptosis/proliferation injured by LPS or 5-FU in HaCaT cells.