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SDF-1 secreted by mesenchymal stem cells promotes the migration of endothelial progenitor cells via CXCR4/PI3K/AKT pathway

Abstract

Cell-based therapeutics bring great hope in areas of unmet medical needs. Mesenchymal stem cells (MSCs) have been suggested to facilitate neovascularization mainly by paracrine action. Endothelial progenitor cells (EPCs) can migrate to ischemic sites and participate in angiogenesis. The combination cell therapy that includes MSCs and EPCs has a favorable effect on ischemic limbs. However, the mechanism of combination cell therapy remains unclear. Herein, we investigate whether stromal cell-derived factor (SDF)-1 secreted by MSCs contributes to EPC migration to ischemic sites via CXCR4/Phosphoinositide 3-Kinases (PI3K)/protein kinase B (termed as AKT) signaling pathway. First, by a “dual-administration” approach, intramuscular MSC injections were supplemented with intravenous Qdot® 525 labeled-EPC injections in the mouse model of hind limb ischemia. Then, the mechanism of MSC effect on EPC migration was detected by the transwell system, tube-like structure formation assays, western blot assays in vitro. Results showed that the combination delivery of MSCs and EPCs enhanced the incorporation of EPCs into the vasculature and increased the capillary density in mouse ischemic hind limb. The numbers of CXCR4-positive EPCs increased after incubation with MSC-conditioned medium (CM). MSCs contributed to EPC migration and tube-like structure formation, both of which were suppressed by AMD3100 and wortmannin. Phospho-AKT induced by MSC-CM was attenuated when EPCs were pretreated with AMD3100 and wortmannin. In conclusion, we confirmed that MSCs contributes to EPC migration, which is mediated via CXCR4/PI3K/AKT signaling pathway.

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Funding

This work was supported by grants from the National Natural Science Foundation of China (No. 81760570, No. 81760371, No. 81703174) and the Project of Young and Middle-aged Scientific and Technological Innovation Leaders in Bingtuan (2018CB017) and the Autonomous Region Graduate Student Scientific Research Innovation Project (XJ2019G081).

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Authors

Contributions

XWW and XC: conceived and designed the experiments. XYW: wrote the manuscript. ZZ and HH: cultured MSCs and EPCs, and critically revised the manuscript. XYW, HJ: performed the establishment of the mouse model of hind limb ischemia. LG and QZ: performed immunohistochemistry and immunofluorescence staining, analysed the data. LW and LX: prepared MSC-CM, performed flow cytometry and analysed the data. SW: performed the migration assay and analysed the data. WC: performed tube-like structure formation assay and analysed the data. XY: performed western blot assay and analysed the data. All the authors read and approved the final version of the manuscript.

Corresponding authors

Correspondence to Xueling Chen or Xiangwei Wu.

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All authors declare that they have no conflict of interest.

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All mice were conducted in accordance with the Xinjiang Medical University Guide for Laboratory Animals and approved by the Shihezi University Ethics Committee.

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Wang, X., Jiang, H., Guo, L. et al. SDF-1 secreted by mesenchymal stem cells promotes the migration of endothelial progenitor cells via CXCR4/PI3K/AKT pathway. J Mol Histol 52, 1155–1164 (2021). https://doi.org/10.1007/s10735-021-10008-y

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Keywords

  • Mesenchymal stem cells
  • Endothelial progenitor cells
  • Stromal cell-derived factor-1
  • CXCR4
  • AKT
  • Mouse model of hind limb ischemia