Abstract
The role of metabolites produced from stem cell metabolism has been emerged as signaling molecules to regulate stem cell behaviors such as migration. The mitochondrial morphology is closely associated with the metabolic balance and stem cell function. However, the physiological role of succinate on human mesenchymal stem cell (hMSC) migration by regulating the mitochondrial morphology remains unclear. Here, we investigate the effect of succinate on hMSC migration via regulation of mitochondrial dynamics and its related signaling pathway. Succinate (50 μM) significantly accelerates hMSC migration. Succinate increases phosphorylation of pan-PKC, especially the atypical PKCζ level which was blocked by the knockdown of Gαq and Gα12. Activated PKCζ subsequently phosphorylates p38 MAPK. Cytosolic DRP1 is phosphorylated by p38 MAPK and results in DRP1 translocation to the mitochondria outer membrane, eventually inducing mitochondrial fragmentation. Mitochondrial fission-induced mitochondrial function elevates mitochondrial ROS (mtROS) levels and activates Rho GTPases, which then induces F-actin formation. Furthermore, in a skin excisional wound model, we found the effects of succinate-pretreated hMSC enhanced wound closure, vascularization and re-epithelialization and confirmed that DRP1 has a vital role in injured tissue regeneration. Overall, succinate promotes DRP1-mediated mitochondrial fission via GPR91, consequently stimulating the hMSC migration through mtROS-induced F-actin formation.
Highlights
The role of metabolites produced from stem cell metabolism has been emerged as signaling molecules to regulate stem cell behaviors such as migration
Because the dose range of succinate that stimulates the cell function varies on the cell types, we tested the effect of succinate on human mesenchymal stem cell (hMSC) motility in a dose and time dependent manner. hMSCs were treated with various concentrations (0–500 μM) for 24 hr, and it was found that 50 to 500 μM of succinate increased stem cell migration (Fig. 1a)
We clearly demonstrated that succinate promotes hMSC migration through PKCζ/p38-induced dynamin-related protein 1 (DRP1) phosphorylation which upregulates mitochondrial ROS (mtROS) production subsequent to F-actin formation, collectively accelerating the wound repair
Summary
The role of metabolites produced from stem cell metabolism has been emerged as signaling molecules to regulate stem cell behaviors such as migration. The physiological role of succinate on human mesenchymal stem cell (hMSC) migration by regulating the mitochondrial morphology remains unclear. We investigate the effect of succinate on hMSC migration via regulation of mitochondrial dynamics and its related signaling pathway. The comprehensive roles of succinate and its specific receptor in stem cells need to be investigated as a bioactive molecule involved in the activation of stem cell functions facilitating tissue regeneration during the wound repair process. This area of research is burgeoning, still numerous limitations remain, including our incomplete understanding of stem cell metabolite www.nature.com/scientificreports/. Efforts have been made to discover the upstream regulator of mitochondrial dynamics proteins, highlighting the emerging significance of mitochondria in stem cells[26]
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