Paracrine interleukin-8 affects mesenchymal stem cells through the Akt pathway and enhances human umbilical vein endothelial cell proliferation and migration.

Lulu Wang,Yongtao Li,Haifeng Jin,Shiyang Shen,Penghui Li,Na Liu,Shizhu Sun,Yang Jiang,Lei Shen,Xiaodong Zhang

doi:10.1042/bsr20210198

Abstract

Interleukin-8 (IL-8) promotes cell homing and angiogenesis, but its effects on activating human bone marrow mesenchymal stem cells (BMSCs) and promoting angiogenesis are unclear. We used bioinformatics to predict these processes. In vitro, BMSCs were stimulated in a high-glucose (HG) environment with 50 or 100 μg/ml IL-8 was used as the IL-8 group. A total of 5 μmol/l Triciribine was added to the two IL-8 groups as the Akt inhibitor group. Cultured human umbilical vein endothelial cells (HUVECs) were cultured in BMSCs conditioned medium (CM). The changes in proliferation, apoptosis, migration ability and levels of VEGF and IL-6 in HUVECs were observed in each group. Seventy processes and 26 pathways were involved in vascular development, through which IL-8 affected BMSCs. Compared with the HG control group, HUVEC proliferation absorbance value (A value), Gap closure rate, and Transwell cell migration rate in the IL-8 50 and IL-8 100 CM groups were significantly increased (P<0.01, n=30). However, HUVEC apoptosis was significantly decreased (P<0.01, n=30). Akt and phospho-Akt (P-Akt) protein contents in lysates of BMSCs treated with IL-8, as well as VEGF and IL-6 protein contents in the supernatant of BMSCs treated with IL-8, were all highly expressed (P<0.01, n=15). These analyses confirmed that IL-8 promoted the expression of 41 core proteins in BMSCs through the PI3K Akt pathway, which could promote the proliferation and migration of vascular endothelial cells. Therefore, in an HG environment, IL-8 activated the Akt signaling pathway, promoted paracrine mechanisms of BMSCs, and improved the proliferation and migration of HUVECs.

Highlights

It is estimated that by 2045, the number of people with diabetes worldwide will increase to 693 million, while the current annual global medical expenditure on diabetes is approximately US$ 850 billion [1]
We found 40 common genes between IL-8 and human bone marrow mesenchymal stem cell (BMSC), including EDNRA, TACR2, CCKAR, GHSR, SSTR2, FNTA, SSTR, ITGA2B, ITGB1, NRP1, SSTR5, NTSR1, NCOR2, HDAC1, AVPR1A, ITGAV, CAPN1, HDAC2, MMP1, MMP2, PPARG, ECE1, MMP7, BACE1, EPHX2, PTGS2, GRB2, ITGA3, MEN1, CTSC, CTSD, MLNR, CASP1, OPRL1, PLG, ITGA4, ITGAL, ITGB2, ICAM1, and ITGB3 (Figure 1)
The multiple cytokines secreted by mesenchymal stem cell (MSC) can promote angiogenesis and have beneficial effects on the IL-6 protein (A) The content of VEGF protein in the supernatant of BMSCs was determined by enzyme-linked immunosorbent assay (ELISA). *P

Summary

Introduction

It is estimated that by 2045, the number of people with diabetes worldwide will increase to 693 million, while the current annual global medical expenditure on diabetes is approximately US$ 850 billion [1]. Hyperglycemic skin ulcer tissues are deficient in cytokines such as interleukin-8 (IL-8), this leads to reduced vascular endothelial cell activity, and a reduced number of peripheral blood vessels, which often promotes issues with the healing of diabetic skin ulcers [3,4]. Homing of host cells to the tissues surrounding a diabetic skin ulcer promotes the repair of ulcers and other injuries [5]. Recent studies have found that MSCs effectively promote angiogenesis of ulcerative tissue and accelerate wound healing of diabetic skin ulcers [7,8]. The use of MSCs to recruit vascular endothelial cells to home the areas of diabetic skin injury is important for accelerating the repair of diabetic skin ulcers and other complications [9]

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Results

Discussion

Conclusion