Mesenchymal stem cell‑derived extracellular vesicles prevent neural stem cell hypoxia injury via promoting miR‑210‑3p expression

Li,Fang; Zhang,Jie; Liao,Rui; Duan,Yongchun; Tao,Lili; Xu,Yuwei; Chen,Anbao

doi:10.3892/mmr.2020.11454

Mesenchymal stem cell‑derived extracellular vesicles prevent neural stem cell hypoxia injury via promoting miR‑210‑3p expression

Authors:
- Fang Li
- Jie Zhang
- Rui Liao
- Yongchun Duan
- Lili Tao
- Yuwei Xu
- Anbao Chen
View Affiliations

Affiliations: Department of Emergency Internal Medicine, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650101, P.R. China, Organ Transplantation Center, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, P.R. China
Published online on: August 21, 2020 https://doi.org/10.3892/mmr.2020.11454
Pages: 3813-3821
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Neural stem cells (NSCs) have the potential to give rise to offspring cells and hypoxic injury can impair the function of NSCs. The present study investigated the effects of mesenchymal stem cell (MSC)‑derived extracellular vesicles (EVs) on NSC injury, as well as the underlying mechanisms. MSC‑EVs were isolated and identified via morphological and particle size analysis. Cobalt chloride was used to establish a hypoxic injury model in NSCs. Terminal deoxynucleotidyl transferase dUTP nick end labeling assay was conducted to detect apoptosis. Reverse transcription‑quantitative PCR was performed to detect the expression levels of miR‑210‑3p, and western blotting was used to detect the expression levels of apoptosis‑inducing factor (AIF) and Bcl‑2 19 kDa interacting protein (BNIP3). Compared with the control group, NSC apoptosis, and the expression of miR‑210‑3p, AIF and BNIP3 were significantly higher in the cobalt chloride‑induced hypoxia group. By contrast, treatment with MSC‑EVs further increased miR‑210‑3p expression levels, but reduced NSC apoptosis and the expression levels of AIF and BNIP3 compared with the model group (P<0.05). In addition, miR‑210‑3p inhibitor reduced miR‑210‑3p expression, but promoted hypoxia‑induced apoptosis and the expression levels of AIF and BNIP3 compared with the model group (P<0.05). Collectively, the results suggested that MSC‑EVs prevented NSC hypoxia injury by promoting miR‑210‑3p expression, which might reduce AIF and BNIP3 expression levels and NSC apoptosis.

View Figures

View References

1	Ma DK, Bonaguidi MA, Ming GL and Song H: Adult neural stem cells in the mammalian central nervous system. Cell Res. 19:672–682. 2009. View Article : Google Scholar : PubMed/NCBI
2	Vishwakarma SK, Bardia A, Tiwari SK, Paspala SA and Khan AA: Current concept in neural regeneration research: NSCs isolation, characterization and transplantation in various neurodegenerative diseases and stroke: A review. J Adv Res. 5:277–294. 2014. View Article : Google Scholar : PubMed/NCBI
3	Babenko VA, Silachev DN, Popkov VA, Zorova LD, Pevzner IB, Plotnikov EY, Sukhikh GT and Zorov DB: Miro1 enhances mitochondria transfer from multipotent mesenchymal stem cells (mmsc) to neural cells and improves the efficacy of cell recovery. Molecules. 23:6872018. View Article : Google Scholar
4	Zahr SK, Yang G, Kazan H, Borrett MJ, Yuzwa SA, Voronova A, Kaplan DR and Miller FD: A Translational repression complex in developing mammalian neural stem cells that regulates neuronal specification. Neuron. 97:520–537 e6. 2018. View Article : Google Scholar : PubMed/NCBI
5	Xu X, Warrington AE, Bieber AJ and Rodriguez M: Enhancing CNS repair in neurological disease: Challenges arising from neurodegeneration and rewiring of the network. CNS Drugs. 25:555–573. 2011. View Article : Google Scholar : PubMed/NCBI
6	Ullah I, Subbarao RB and Rho GJ: Human mesenchymal stem cells-current trends and future prospective. Biosci Rep. 35:e001912015. View Article : Google Scholar : PubMed/NCBI
7	Zhang X, Sai B, Wang F, Wang L, Wang Y, Zheng L, Li G, Tang J and Xiang J: Hypoxic BMSC-derived exosomal miRNAs promote metastasis of lung cancer cells via STAT3-induced EMT. Mol Cancer. 18:402019. View Article : Google Scholar : PubMed/NCBI
8	Lee KW, Kim DH, Lee JH and Youn YN: The effect of pulsatile flow on bmsc-derived endothelial-like cells in a small-sized artificial vessel made by 3-dimensional bioprinting. Stem Cells Int. 2018:78238302018. View Article : Google Scholar : PubMed/NCBI
9	Chen L, Lu FB, Chen DZ, Wu JL, Hu ED, Xu LM, Zheng MH, Li H, Huang Y, Jin XY, et al: BMSCs-derived miR-223-containing exosomes contribute to liver protection in experimental autoimmune hepatitis. Mol Immunol. 93:38–46. 2018. View Article : Google Scholar : PubMed/NCBI
10	Wang Y, Zhao R, Liu D, Deng W, Xu G, Liu W, Rong J, Long X, Ge J and Shi B: Exosomes derived from miR-214-enriched bone marrow-derived mesenchymal stem cells regulate oxidative damage in cardiac stem cells by targeting caMKII. Oxid Med Cell Longev. 2018:49712612018. View Article : Google Scholar : PubMed/NCBI
11	Baglio SR, Rooijers K, Koppers-Lalic D, Verweij FJ, Pérez Lanzón M, Zini N, Naaijkens B, Perut F, Niessen HW, Baldini N and Pegtel DM: Human bone marrow- and adipose-mesenchymal stem cells secrete exosomes enriched in distinctive miRNA and tRNA species. Stem Cell Res Ther. 6:1272015. View Article : Google Scholar : PubMed/NCBI
12	Su T, Xiao Y, Xiao Y, Guo Q, Li C, Huang Y, Deng Q, Wen J, Zhou F and Luo XH: Bone amesenchymal stem cells-derived exosomal MiR-29b-3p regulates Aging-associated insulin resistance. ACS Nano. 13:2450–2462. 2019.PubMed/NCBI
13	Mead B and Tomarev S: Bone marrow-derived mesenchymal stem cells-derived exosomes promote survival of retinal ganglion cells through miRNA-Dependent mechanisms. Stem cells Transl Med. 6:1273–1285. 2017. View Article : Google Scholar : PubMed/NCBI
14	Santos JC, Lima NDS, Sarian LO, Matheu A, Ribeiro ML and Derchain SFM: Exosome-mediated breast cancer chemoresistance via miR-155 transfer. Sci Rep. 8:8292018. View Article : Google Scholar : PubMed/NCBI
15	Lin Y, Wu J, Gu W, Huang Y, Tong Z, Huang L and Tan J: Exosome-Liposome hybrid nanoparticles deliver CRISPR/Cas9 System in MSCs. Adv Sci (Weinh). 5:17006112018. View Article : Google Scholar : PubMed/NCBI
16	Michlewski G and Cáceres JF: Post-transcriptional control of miRNA biogenesis. RNA. 25:1–16. 2019. View Article : Google Scholar : PubMed/NCBI
17	Yang S, Mi X, Chen Y, Feng C, Hou Z, Hui R and Zhang W: MicroRNA-216a induces endothelial senescence and inflammation via Smad3/IkappaBα pathway. J Cell Mol Med. 22:2739–2749. 2018. View Article : Google Scholar : PubMed/NCBI
18	Huang X, Le QT and Giaccia AJ: MiR-210-micromanager of the hypoxia pathway. Trends Mol Med. 16:230–237. 2010. View Article : Google Scholar : PubMed/NCBI
19	Ma X, Wang J, Li J, Ma C, Chen S, Lei W, Yang Y, Liu S, Bihl J and Chen C: Loading MiR-210 in endothelial progenitor cells derived exosomes boosts their beneficial effects on hypoxia/reoxygeneation-injured human endothelial cells via protecting mitochondrial function. Cell Physiol Biochem. 46:664–675. 2018. View Article : Google Scholar : PubMed/NCBI
20	Bavelloni A, Ramazzotti G, Poli A, Piazzi M, Focaccia E, Blalock W and Faenza I: MiRNA-210: A current overview. Anticancer Res. 37:6511–6521. 2017.PubMed/NCBI
21	Yu J, Yang H, Fang B, Zhang Z, Wang Y and Dai Y: Mfat-1 transgene protects cultured adult neural stem cells against cobalt chloride-mediated hypoxic injury by activating Nrf2/ARE pathways. J Neurosci Res. 96:87–102. 2018. View Article : Google Scholar : PubMed/NCBI
22	Walls KC, Ghosh AP, Ballestas ME, Klocke BJ and Roth KA: Bcl-2/Adenovirus E1B 19-kd interacting protein 3 (BNIP3) regulates hypoxia-induced neural precursor cell death. J Neuropathol Exp Neurol. 68:1326–1338. 2009. View Article : Google Scholar : PubMed/NCBI
23	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
24	Song Z, Chen H, Xu W, Wu S and Zhu G: Basolateral amygdala calpain is required for extinction of contextual fear-memory. Neurobiol Learn Mem. 155:180–188. 2018. View Article : Google Scholar : PubMed/NCBI
25	Zuo R, Liu M, Wang Y, Li J, Wang W, Wu J, Sun C, Li B, Wang Z, Lan W, et al: BM-MSC-derived exosomes alleviate radiation-induced bone loss by restoring the function of recipient BM-MSCs and activating Wnt/β-catenin signaling. Stem Cell Res Ther. 10:302019. View Article : Google Scholar : PubMed/NCBI
26	Xu T, Xu M, Bai J, Lin J, Yu B, Liu Y, Guo X, Shen J, Sun H, Hao Y and Geng D: Tenocyte-derived exosomes induce the tenogenic differentiation of mesenchymal stem cells through TGF-β. Cytotechnology. 71:57–65. 2019. View Article : Google Scholar : PubMed/NCBI
27	Yu B, Shao H, Su C, Jiang Y, Xiteng Y, Bai L, Zhang Y, Li Q, Zhang X and Li X: Exosomes derived from MSCs ameliorate retinal laser injury partially by inhibition of MCP-1. Sci Rep. 6:345622016. View Article : Google Scholar : PubMed/NCBI
28	Lu Y, Zhou Y, Zhang R, Wen L, Wu K, Li Y, Yao Y, Duan R and Jia Y: Bone mesenchymal stem cell-derived extracellular vesicles promote recovery following spinal cord injury via improvement of the integrity of the blood-spinal cord barrier. Front Neurosci. 13:2092019. View Article : Google Scholar : PubMed/NCBI
29	Gilligan KE and Dwyer RM: Engineering exosomes for cancer therapy. Int J Mol Sci. 18:11222017. View Article : Google Scholar
30	Lou G, Song X, Yang F, Wu S, Wang J, Chen Z and Liu Y: Exosomes derived from miR-122-modified adipose tissue-derived MSCs increase chemosensitivity of hepatocellular carcinoma. J Hematol Oncol. 8:1222015. View Article : Google Scholar : PubMed/NCBI
31	Li X, Wang S, Zhu R, Li H, Han Q and Zhao RC: Lung tumor exosomes induce a Pro-inflammatory phenotype in mesenchymal stem cells via NFκB-TLR signaling pathway. J Hematol Oncol. 9:422016. View Article : Google Scholar : PubMed/NCBI
32	Kong FL, Wang XP, Li YN and Wang HX: The role of exosomes derived from cerebrospinal fluid of spinal cord injury in neuron proliferation in vitro. Artif Cells Nanomed Biotechnol. 46:200–205. 2018. View Article : Google Scholar : PubMed/NCBI
33	Wang Z, Deng M, Liu Z and Wu S: Hypoxia-induced miR-210 promoter demethylation enhances proliferation, autophagy and angiogenesis of schwannoma cells. Oncol Rep. 37:3010–3018. 2017. View Article : Google Scholar : PubMed/NCBI
34	Liu LL, Li D, He YL, Zhou YZ, Gong SH, Wu LY, Zhao YQ, Huang X, Zhao T, Xu L, et al: miR-210 protects renal cell against hypoxia-induced apoptosis by targeting HIF-1 alpha. Mol Med. 23:258–271. 2017. View Article : Google Scholar : PubMed/NCBI
35	Costales MG, Haga CL, Velagapudi SP, Childs-Disney JL, Phinney DG and Disney MD: Small Molecule inhibition of microRNA-210 reprograms an oncogenic hypoxic circuit. J Am Chem Soc. 139:3446–3455. 2017. View Article : Google Scholar : PubMed/NCBI
36	Sun LL, Li WD, Lei FR and Li XQ: The regulatory role of microRNAs in angiogenesis-related diseases. J Cell Mol Med. 22:4568–4587. 2018. View Article : Google Scholar : PubMed/NCBI
37	Tsujimoto Y: Role of Bcl-2 family proteins in apoptosis: Apoptosomes or mitochondria? Genes Cells. 3:697–707. 1998. View Article : Google Scholar : PubMed/NCBI
38	Burton TR and Gibson SB: The role of Bcl-2 family member BNIP3 in cell death and disease: NIPping at the heels of cell death. Cell Death Differ. 16:515–523. 2009. View Article : Google Scholar : PubMed/NCBI
39	Jin Q, Li R, Hu N, Xin T, Zhu P, Hu S, Ma S, Zhu H, Ren J and Zhou H: DUSP1 alleviates cardiac ischemia/reperfusion injury by suppressing the Mff-required mitochondrial fission and Bnip3-related mitophagy via the JNK pathways. Redox Biol. 14:576–587. 2018. View Article : Google Scholar : PubMed/NCBI
40	Bano D and Prehn JHM: Apoptosis-Inducing factor (AIF) in physiology and disease: The tale of a repented natural born killer. EBioMedicine. 30:29–37. 2018. View Article : Google Scholar : PubMed/NCBI
41	Liu J, Yuan C, Pu L and Wang J: Nutrient deprivation induces apoptosis of nucleus pulposus cells via activation of the BNIP3/AIF signalling pathway. Mol Med Rep. 16:7253–7260. 2017. View Article : Google Scholar : PubMed/NCBI
42	Benitez-Guzman A, Arriaga-Pizano L, Moran J and Gutierrez-Pabello JA: Endonuclease G takes part in AIF-mediated caspase-independent apoptosis in Mycobacterium bovis-infected bovine macrophages. Veterinary Res. 49:692018. View Article : Google Scholar
43	Luan Y, Zhang X, Zhang Y and Dong Y: MicroRNA-210 protects PC-12 cells against hypoxia-induced injury by targeting BNIP3. Front Cell Neurosci. 11:2852017. View Article : Google Scholar : PubMed/NCBI
44	Ren J, Li X, Dong H, Suo L and Zhang J, Zhang L and Zhang J: miR-210-3p regulates the proliferation and apoptosis of non-small cell lung cancer cells by targeting SIN3A. Exp Ther Med. 18:2565–2573. 2019.PubMed/NCBI
45	Lu WJ, Liang HB, Li YF, Tu XQ, He JR, Ding KQ, Yang GY, Xin XY and Zeng LL: MicroRNA-210-3p targets RGMA to enhance the angiogenic functions of endothelial progenitor cells under hypoxic conditions. Front Cell Neurosci. 13:2232019. View Article : Google Scholar : PubMed/NCBI
46	Keshtkar S, Azarpira N and Ghahremani MH: Mesenchymal stem cell-derived extracellular vesicles: Novel frontiers in regenerative medicine. Stem Cell Res Ther. 9:632018. View Article : Google Scholar : PubMed/NCBI