Peptide hormone ELABELA promotes rat bone marrow-derived mesenchymal stem cell proliferation and migration by manipulating the cell cycle through the PI3K/AKT pathway under the hypoxia and ischemia microenvironment

Abstract

Background Mesenchymal stem cells (MSCs) are emerging as a potential candidate for stem cell transplantation to repair myocardial tissue in myocardial infarctions (MI). However, there are some pivotal limitations such as poor survival and low migration capacity of MSCs in hypoxic and ischemic microenvironments of MI. Our previous work verified that ELABELA (also abbreviated as ELA), a peptide hormone, could play a role as a growth factor and prolong the life span of rat bone marrow-derived mesenchymal stem cells (RAT BM-MSCs) under hypoxic and ischemic conditions. Nevertheless, the influence of ELA on the cell cycle, proliferation, and migration remains elusive. This study will further explore the improvement of the biological functions of ELA-treated RAT BM-MSCs, so as to provide a reference for improving the efficacy of RAT BM-MSCs in MI. Methods Rat BM-MSCs were isolated from 80 to 120 g Sprague Dawley rats by flushing femurs and tibias under the aseptic condition. RAT BM-MSCs of the third passage were divided into control group, hypoxic/ischemic (H/I) group, ELA group, ELA-LY group and LY group. RAT BM-MSCs were cultured under normoxia in control group. In H/I group, RAT BM-MSCs were exposed to hypoxia (1% O2) and serum deprivation for 24 h. RAT BM-MSCs in ELA group were treated with 5 µM ELA prior to the H/I exposure for 24 h. The PI3K/AKT inhibitor, LY294002 (50 µM), was used in ELA-LY group and LY group to observe the effect of ELA on PI3K/AKT activation. Cell proliferation ability was examined by CCK-8. Cell cycle was assessed with flow cytometry. Cell migration was evaluated by Transwell assay. Expression levels of total-AKT, phosphorylated-AKT, and cell cycle-associated proteins were examined by Western blotting. Results ELA-treated RAT BM-MSCs exhibited significantly higher proliferation ability, cell viability, and migration under H/I conditions. The cell cycle analysis showed that an increased proportion of cells in the S and G2/M phases of the cell cycle were observed in ELA-treated RAT BM-MSCs. The addition of ELA activated the PI3K/AKT signaling pathway. Additionally, upon treating with the inhibitor of the PI3K/AKT signaling pathway, ELA-triggered proliferation, cell viability, and migration were abrogated. Conclusions ELA can be used to enhance the proliferation ability, cell viability, and migration of RAT BM-MSCs through the PI3K/AKT signaling pathway and alleviate cell cycle arrest at the G0/G1 phase under hypoxic and ischemic injury. Thus, this study provides a promising strategy that ELA may help to optimize the mesenchymal stem cell-based therapy in MI.

Astragalus Polysaccharides Augment BMSCs Homing via SDF-1/CXCR4 Modulation: A Novel Approach to Counteract Peritoneal Mesenchymal Transformation and Fibrosis

“…Our study further demonstrates that APS promotes the activity and migration of BMSCs by upregulating the expression of CXCR4. The activation of the SDF-1/CXCR4 binding activates downstream signaling pathways including MAPK and Akt, participating in cell homing, migration, apoptosis, and gene expression 40,41 . In the presence of SDF-1, our study shows that APS can further enhance the increased phosphorylation levels downstream, partially reversing the inhibitory effect of AMD3100 on SDF-1/CXCR4 phosphorylation, which may be achieved by increasing the expression of CXCR4 on the surface of BMSCs.…”

Astragalus polysaccharides augment BMSC homing via SDF-1/CXCR4 modulation: a novel approach to counteract peritoneal mesenchymal transformation and fibrosis

“…The interaction between SDF-1 and CXCR4 triggers the activation of downstream signaling pathways, including MAPK and Akt, which are pivotal in regulating cell homing, migration, apoptosis, and gene expression [44][45][46]. A 2022 study demonstrated that using the CXCR4 blocker AMD3100, indirectly suppressed the PI3K/Akt signaling pathway and significantly reduced the recruitment of transplanted MSCs to the ovary [47].…”

Cellular microenvironment: a key for tuning mesenchymal stem cell senescence

“…Moreover, BMSCs cultured in hypoxic ischemic (HI) environments exhibited reduced cell migration capacity compared to the normal controls. These cells also showed impaired cell proliferation, possibly due to the inhibition of the PI3K/AKT pathway ( Chen Xuxiang et al, 2022 ).…”