Copper promotes the migration of bone marrow mesenchymal stem cells via Rnd3‐dependent cytoskeleton remodeling

Abstract

The motility of mesenchymal stem cells (MSCs) is highly related to their homing in vivo, a critical issue in regenerative medicine. Our previous study indicated copper (Cu) might promote the recruitment of endogenous MSCs in canine esophagus defect model. In this study, we investigated the effect of Cu on the motility of bone marrow mesenchymal stem cells (BMSCs) and the underlying mechanism in vitro. Cu supplementation could enhance the motility of BMSCs, and upregulate the expression of hypoxia-inducible factor 1α (Hif1α) at the protein level, and upregulate the expression of rho family GTPase 3 (Rnd3) at messenger RNA and protein level. When Hif1α was silenced by small interfering RNA (siRNA), Cu-induced Rnd3 upregulation was blocked. When Rnd3 was silenced by siRNA, the motility of BMSCs was decreased with or without Cu supplementation, and Cu-induced cytoskeleton remodeling was neutralized. Furthermore, overexpression of Rnd3 also increased the motility of BMSCs and induced cytoskeleton remodeling. Overall, our results demonstrated that Cu enhanced BMSCs migration through, at least in part, cytoskeleton remodeling via Hif1α-dependent upregulation of Rnd3. This study provided an insight into the mechanism of the effect of Cu on the motility of BMSCs, and a theoretical foundation of applying Cu to improve the recruitment of BMSCs in tissue engineering and cytotherapy.

Copper Does Not Induce Tenogenic Differentiation but Promotes Migration and Increases Lysyl Oxidase Activity in Adipose-Derived Mesenchymal Stromal Cells

“…It is probable that this effect was due to higher secretion of CXCL12 as these results are in agreement with the increased secretion of this chemokine after treatment with CuSO 4 (Proteome Profiler analysis, Figure 5). These results find confirmation in the latest findings of Chen et al showing that copper supplementation enhances migration on bone marrow-derived mesenchymal stromal cells [32]. The authors demonstrated that the action of cupric sulfate is associated with the cytoskeleton remodeling induced by hypoxia-inducible factor 1α-(Hif1α-) dependent upregulation of the rho family GTPase 3 (Rnd3).…”

Molecular Insights Into Lysyl Oxidases in Cartilage Regeneration and Rejuvenation

“…Further, emerging evidence has indicated that copper stabilizes the HIF-1α protein through inhibiting prolyl hydroxylases-mediated prolyl hydroxylation in an ironindependent manner, which is required for transcriptional activation of HIF-1 of a series of target genes (Martin et al, 2005;Feng et al, 2009;Himoto et al, 2016;Liu et al, 2018;Chen et al, 2020), suggesting that appropriate copper levels may be required for normal cartilage function through regulation of HIF-1α transcriptional activity. However, detailed mechanisms of transcriptional processes initiating specific target genes expression of HIF-1 require further elucidation.…”

Copper-Lithium-Doped Nanohydroxyapatite Modulates Mesenchymal Stem Cells Homing to Treat Glucocorticoids-Related Osteonecrosis of the Femoral Head

“…HIF-1α regulates SDF-1 expression, and theoretically, Cu also upregulates HIF-1α to increase SDF-1 levels indirectly. Chen found that Cu increased BMSCs motility and recruitment through Rnd3 pathway-dependent cytoskeletal remodeling ( Chen et al, 2020 ). Hence, we designed a composite scaffold by doping Cu into Li-nHA to enhance tissue regeneration potential through the MSCs homing.…”