FNDC5 Overexpression Promotes the Survival Rate of Bone Marrow Mesenchymal Stem Cells After Transplantation in a Rat Cerebral Infarction Model

Overview

Journal Ann Transl Med

Publisher AME Publishing Company

Date 2022 Mar 14

PMID 35282127

Authors

Huan Wei

Kangmei Liu

Tingting Wang

Yanping Li

Shaolei Guo

Ling Li

Affiliations

Soon will be listed here.

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 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.

Citing Articles

FNDC5 prevents oxidative stress and neuronal apoptosis after traumatic brain injury through SIRT3-dependent regulation of mitochondrial quality control.

Ge Y, Wu X, Cai Y, Hu Q, Wang J, Zhang S Cell Death Dis. 2024; 15(5):364.

PMID: 38802337 PMC: 11130144. DOI: 10.1038/s41419-024-06748-w.

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

Qi J, Zhang Z, Dong Z, Shan T, Yin Z J Orthop Surg Res. 2024; 19(1):190.

PMID: 38500202 PMC: 10949585. DOI: 10.1186/s13018-024-04671-6.

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

Tian D, You X, Ye J, Chen G, Yu H, Lv J Sci Rep. 2024; 14(1):1830.

PMID: 38246980 PMC: 10800342. DOI: 10.1038/s41598-024-52167-4.

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

Wei H, Liu S, Wang T, Li Y, Liu K, Guo Q Cell Death Discov. 2023; 9(1):336.

PMID: 37673870 PMC: 10482879. DOI: 10.1038/s41420-023-01634-4.

References

Liu C, Liu A, Zhong D, Wang C, Yu M, Zhang H . Circular RNA AFF4 modulates osteogenic differentiation in BM-MSCs by activating SMAD1/5 pathway through miR-135a-5p/FNDC5/Irisin axis. Cell Death Dis. 2021; 12(7):631. PMC: 8213698. DOI: 10.1038/s41419-021-03877-4. View

Bostrom P, Wu J, Jedrychowski M, Korde A, Ye L, Lo J . A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature. 2012; 481(7382):463-8. PMC: 3522098. DOI: 10.1038/nature10777. View

Hu C, Zhao L, Wu D, Li L . Modulating autophagy in mesenchymal stem cells effectively protects against hypoxia- or ischemia-induced injury. Stem Cell Res Ther. 2019; 10(1):120. PMC: 6471960. DOI: 10.1186/s13287-019-1225-x. View

Rajbhandari S, Beppu M, Takagi T, Nakano-Doi A, Nakagomi N, Matsuyama T . Ischemia-Induced Multipotent Stem Cells Isolated from Stroke Patients Exhibit Higher Neurogenic Differentiation Potential than Bone Marrow-Derived Mesenchymal Stem Cells. Stem Cells Dev. 2020; 29(15):994-1006. DOI: 10.1089/scd.2020.0031. View

Mizushima N, Levine B, Cuervo A, Klionsky D . Autophagy fights disease through cellular self-digestion. Nature. 2008; 451(7182):1069-75. PMC: 2670399. DOI: 10.1038/nature06639. View

Dong Y, Zhang S, Tao J, Zhang X, Zhang J, Yang J . Fibronectin type III domain-containing protein 5 promotes proliferation and differentiation of goat adipose-derived stem cells. Res Vet Sci. 2019; 125:351-359. DOI: 10.1016/j.rvsc.2019.07.011. View

Wu H, Guo P, Jin Z, Li X, Yang X, Tang C . Serum levels of irisin predict short-term outcomes in ischemic stroke. Cytokine. 2018; 122:154303. DOI: 10.1016/j.cyto.2018.02.017. View

Yuan X, Wang X, Chen C, Zhou J, Han M . Bone mesenchymal stem cells ameliorate ischemia/reperfusion-induced damage in renal epithelial cells via microRNA-223. Stem Cell Res Ther. 2017; 8(1):146. PMC: 5472974. DOI: 10.1186/s13287-017-0599-x. View

Xiao C, Wang K, Xu Y, Hu H, Zhang N, Wang Y . Transplanted Mesenchymal Stem Cells Reduce Autophagic Flux in Infarcted Hearts via the Exosomal Transfer of miR-125b. Circ Res. 2018; 123(5):564-578. DOI: 10.1161/CIRCRESAHA.118.312758. View

10.

Bagheri-Mohammadi S . Protective effects of mesenchymal stem cells on ischemic brain injury: therapeutic perspectives of regenerative medicine. Cell Tissue Bank. 2020; 22(2):249-262. DOI: 10.1007/s10561-020-09885-6. View

11.

Levine B, Kroemer G . Autophagy in the pathogenesis of disease. Cell. 2008; 132(1):27-42. PMC: 2696814. DOI: 10.1016/j.cell.2007.12.018. View

12.

Liu T, Xiong X, Ren X, Zhao M, Shi C, Wang J . FNDC5 Alleviates Hepatosteatosis by Restoring AMPK/mTOR-Mediated Autophagy, Fatty Acid Oxidation, and Lipogenesis in Mice. Diabetes. 2016; 65(11):3262-3275. DOI: 10.2337/db16-0356. View

13.

Borlongan C . Concise Review: Stem Cell Therapy for Stroke Patients: Are We There Yet?. Stem Cells Transl Med. 2019; 8(9):983-988. PMC: 6708064. DOI: 10.1002/sctm.19-0076. View

14.

Rabiee F, Lachinani L, Ghaedi S, Nasr-Esfahani M, Megraw T, Ghaedi K . New insights into the cellular activities of Fndc5/Irisin and its signaling pathways. Cell Biosci. 2020; 10:51. PMC: 7106581. DOI: 10.1186/s13578-020-00413-3. View

15.

Chung J, Chang W, Bang O, Moon G, Kim S, Kim S . Efficacy and Safety of Intravenous Mesenchymal Stem Cells for Ischemic Stroke. Neurology. 2021; 96(7):e1012-e1023. DOI: 10.1212/WNL.0000000000011440. View

16.

Roh J, Jung K, Chu K . Adult stem cell transplantation in stroke: its limitations and prospects. Curr Stem Cell Res Ther. 2008; 3(3):185-96. DOI: 10.2174/157488808785740352. View

17.

Longa E, Weinstein P, Carlson S, Cummins R . Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke. 1989; 20(1):84-91. DOI: 10.1161/01.str.20.1.84. View

18.

Park K, Zaichenko L, Brinkoetter M, Thakkar B, Sahin-Efe A, Joung K . Circulating irisin in relation to insulin resistance and the metabolic syndrome. J Clin Endocrinol Metab. 2013; 98(12):4899-907. PMC: 3849667. DOI: 10.1210/jc.2013-2373. View

19.

Soleimani M, Nadri S . A protocol for isolation and culture of mesenchymal stem cells from mouse bone marrow. Nat Protoc. 2009; 4(1):102-6. DOI: 10.1038/nprot.2008.221. View

20.

He H, Zeng Q, Huang G, Lin Y, Lin H, Liu W . Bone marrow mesenchymal stem cell transplantation exerts neuroprotective effects following cerebral ischemia/reperfusion injury by inhibiting autophagy via the PI3K/Akt pathway. Brain Res. 2018; 1707:124-132. DOI: 10.1016/j.brainres.2018.11.018. View