FNDC5 overexpression promotes the survival rate of bone marrow mesenchymal stem cells after transplantation in a rat cerebral infarction model

Abstract

Background: Most bone marrow mesenchymal stem cell (BMSC) death is caused by the harsh ischemia and hypoxic microenvironment, which impacts the therapeutic effects of transplanted BMSCs. Fibronectin type III domain-containing protein 5 (FNDC5) and its cleaved product, irisin, are reportedly involved in cerebral protective effect. Research into whether FNDC5 plays a key role in the survival rate of BMSCs and cerebral infarction (CI) remains inadequate. The present study aimed to clarify the protective role of FNDC5 on the low viability of transplanted BMSCs and improve CI treatment outcomes. Methods: A lentivirus vector, which drives the expression of FNDC5, was constructed and used to transfect BMSCs. Cell Counting Kit-8 (CCK8), flow cytometry, immunofluorescence, and western blot were performed to evaluate the function of FNDC5-overexpressing BMSCs (BMSCs-OE-FNDC5) exposed to hypoxic and serum deprivation (H/SD) stress. Transmission electron microscopy (TEM) was used to monitor autophagy. In addition, BMSCs were engrafted into a middle cerebral artery occlusion (MCAO) rat model with or without FNDC5-overexpression (OE-FNDC5). The survival rate of transplanted BMSCs was evaluated by 5-ethynyl-2'-deoxyuridine (EdU) labeling. The CI volume was assessed by 2,3,5-triphenyl tetrazolium chloride (TTC) staining.Results: H/SD stress caused increased cell autophagy, apoptosis, and decreased cell viability of BMSCs, while OE-FNDC5 alleviated these injuries. The in vivo results showed that transplantation of BMSCs-OE-FNDC5 reduced the infarct volume in the rat MCAO model. Furthermore, OE-FNDC5 decreased neuronal apoptosis. The improved therapeutic efficacy of BMSCs-OE-FNDC5 may be attributable to the obviously increased cell survival number after transplantation.Conclusions: These results indicated that FNDC5 overexpression promotes BMSC survival in a CI model, which might provide a potential therapeutic target.

mir-150-5p inhibits the osteogenic differentiation of bone marrow-derived mesenchymal stem cells by targeting irisin to regulate the p38/MAPK signaling pathway

“…In vitro studies have shown that irisin increases osteoblast and mineralization, and inhibits nuclear factor-kB ligand (RANKL)-induced receptor activation in osteoclasts [ 34 ]. Importantly, FNDC5 / irisin has been found to play a therapeutic role in myocardial infarction [ 35 ] and cerebral infarction [ 17 ] by regulating the function of BMSCs.…”

“…However, the detailed mechanism of miR-150-5p on the osteogenic differentiation of BMSCs has not been further studied by Geng Y, et al, but miR-150-5p has been found to inhibit the osteogenic differentiation of ankylosing spondylitis fibroblasts [ 14 ] and adipose-derived stem cells [ 15 ]. At the same time, it is well known that the protein encoded by the FNDC5 gene (iris) has been found to regulate the differentiation of BMSCs [ 16 , 17 ], including promoting the osteogenic differentiation of BMSCs [ 18 ]. Therefore, miR-150-5p may be involved in the regulation of osteogenic differentiation of BMSCs by regulating the expression of FNDC5.…”

hBcl2 overexpression in BMSCs enhances resistance to myelin debris-induced apoptosis and facilitates neuroprotection after spinal cord injury in rats

“…Chizuka Ide et al proved that the beneficial effects of BMSC transplantation on tissue repair, axonal outgrowth, and locomotor improvement in SCI rats 7 – 9 . However, a significant limitation of BMSCs transplantation in SCI treatment is the low survival rate of transplanted BMSCs at the injury site 10 , 11 . We propose that BMSCs are prone to apoptosis after transplantation, which may be influenced by the presence of myelin debris.…”

FNDC5 inhibits autophagy of bone marrow mesenchymal stem cells and promotes their survival after transplantation by downregulating Sp1

“…The glycosylated transmembrane precursor protein, Fibronectin type III domain protein 5 (FNDC5), and its extracellular cleavage product of 112 amino acids, named Irisin, have been implicated in numerous processes, including energy metabolism, oxidative stress, anti-aging, and synapse rebuilding [ 19 , 20 ], making it a promising target for modulating autophagy [ 21 ]. Exercise-induced FNDC5/Irisin can protect nucleus pulposus cells against senescence by modulating autophagy [ 22 ] and we have previously shown that overexpression of FNDC5 (OE-FNDC5) can ameliorate autophagy and promote cell proliferation in bone marrow MSCs (BMSCs) upon hypoxia and serum deprivation (H/SD) [ 23 ]. However, the molecular pathways by which FNDC5 modulates BMSCs autophagy are undetermined and the protective effect of FNDC5 after BMSC transplantation for treatment of cerebral infarction needs further elucidation.…”