Bone marrow mesenchymal stem cell-derived exosomes miR-183 target regulation of retinal dehydrogenase 11 to inhibit the development of retinitis pigmentosa_Chinese Journal of Ocular Fundus Diseases

Authors：

Li Yuan ¹ , Qin Tingyu ² , Guo Long ¹ , Li Shuzhen ¹ ,  Hou Xiwu ²

1. Department of Ophthalmology, Shangqiu First People's Hospital, Zhengzhou 476000, China;
2. Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China;

Corresponding author：

Hou Xiwu, Email: 465650322@qq.com

Keywords：

Retinal pigment epithelium; Bone marrow cells; Mesenchymal stem cells; Apoptosis; miR-183; Retinal dehydrogenase 11

DOI：

10.3760/cma.j.cn511434-20201119-00574

Video：

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Objective To observe the expressions of miR-183 and retinal dehydrogenase 11 (RDH11) in exosomes derived from bone marrow mesenchymal stem cells (BMSC), and to preliminarily explore their targeting relationship and their effects on retinal pigment epithelial (RPE) cells. Methods BMSC from C57BL/6 (C57) mice were isolated and cultured, and BMSC-derived exosomes were identified. BMSC were divided into blank group, simulation blank control group (mimic-NC group), miR-183 simulation group (miR-183-mimic group). C57 mice and retinal degeneration 10 (rd10) mouse RPE cells were cultured with reference to literature methods. RPE cells from rd10 mice were transfected with BMSC exosomes and co-cultured and divided into control group, exosome group, mimic-NC-exosome group (mimic-NC-exo group), miR-183-mimic-exosome group (miR-183-mimic-exo group). The relative expression levels of miR-183, RDH11 mRNA and protein in C57 mice, rd10 mice and RPE cells in each group were detected by real-time quantitative polymerase chain reaction and western blotting. The targeting relationship between miR-183 and RDH11 was analyzed by bioinformatics website and dual luciferase reporter. Cell counting kit 8 was used to detect the effect of miR-183 on BMSC exosomes on RPE cell proliferation; in situ labeling end labeling method was used to detect RPE cells apoptosis. One-way ANOVA was used to compare multiple groups. Results Compared with C57 mouse RPE cells, the relative expression of miR-183 in rd10 mouse RPE cells was down-regulated, and the relative expression of RDH11 mRNA was up-regulated, and the differences were statistically significant (t=5.230, 8.548; P=0.006, 0.001). Compared with the blank group and the mimic-NC group, the relative expression of miR-183 mRNA in the exosomes of the miR-183-mimics group was significantly increased (F=60.130, P＜0.05). After 24 h of co-culture, exosomes entered RPE cells. Compared with the mimic-NC-exo group, the relative expression of miR-183 mRNA in RPE cells in the miR-183-mimic-exo group was significantly increased, the proliferation ability was enhanced (t=7.311, P=0.002), and the number of apoptotic cells was decreased (F=10.949, P=0.012), and the differences were statistically significant (t=4.571, P=0.002). Bioinformatics website and dual-luciferase report confirmed that miR-183 has a targeting relationship with RDH11. Compared with the mimic-NC group, the relative expression of RDH11 mRNA and protein in the exosomes of the miR-183-mimic group was decreased, and the difference was statistically significant (t=5.361, 6.591; P=0.006, 0.003). After co-culture, compared with the control group, there was no significant difference in the relative expression of RDH11 mRNA and protein in RPE cells in the exosome group (t=0.169, 1.134; P=0.874, 0.320); The relative expressions of RDH11 mRNA and protein in RPE cells in -183-mimic-exo group were decreased, and the difference was statistically significant (t=5.554, 5.546; P=0.005, 0.005). Conclusion Up-regulation of BMSC-derived exosomal miR-183 promote the proliferation of RPE cells in vitro by targeting the expression of RDH11 and reduce the number of apoptosis.

Citation： Li Yuan, Qin Tingyu, Guo Long, Li Shuzhen, Hou Xiwu. Bone marrow mesenchymal stem cell-derived exosomes miR-183 target regulation of retinal dehydrogenase 11 to inhibit the development of retinitis pigmentosa. Chinese Journal of Ocular Fundus Diseases, 2022, 38(8): 688-695. doi: 10.3760/cma.j.cn511434-20201119-00574 Copy

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1. 蒋鹏飞, 彭俊, 欧晨, 等. 视网膜色素变性的实验研究进展[J]. 国际眼科杂志, 2020, 20(6): 970-973. DOI: 10.3980/j.issn.1672-5123.2020.6.09.Jiang PF, Peng J, Ou C, et al. Progress in experimental research of retinitis pigmentosa[J]. Int Eye Sci, 2020, 20(6): 970-973. DOI: 10.3980/j.issn.1672-5123.2020.6.09.
2. Tsang SH, Sharma T. Autosomal dominant retinitis pigmentosa[J]. Adv Exp Med Biol, 2018, 1085: 69-77. DOI: 10.1007/978-3-319-95046-4_15.
3. Donato L, Scimone C, Alibrandi S, et al. Discovery of GLO1 new related genes and pathways by RNA-Seq on A2E-stressed retinal epithelial cells could improve knowledge on retinitis pigmentosa[J/OL]. Antioxidants (Basel), 2020, 9(5): 416[2020-5-13]. https://pubmed.ncbi.nlm.nih.gov/32413970/. DOI: 10.3390/antiox9050416.
4. Kanan Y, Wicker LD, Al-Ubaidi MR, et al. Retinol dehydrogenases RDH11 and RDH12 in the mouse retina: expression levels during development and regulation by oxidative stress[J]. Invest Ophthalmol Vis Sci, 2008, 49(3): 1071-1078. DOI: 10.1167/iovs.07-1207.
5. Donato L, Bramanti P, Scimone C, et al. MiRNA expression profile of retinal pigment epithelial cells under oxidative stress conditions[J]. FEBS Open Bio, 2018, 8(2): 219-233. DOI: 10.1002/2211-5463.12360.
6. Deng CL, Hu CB, Wang BY, et al. Bone progeria diminished the therapeutic effects of bone-marrow mesenchymal stem cells on retinal degeneration[J]. Biochem Biophys Res Commun, 2020, 531(2): 180-186. DOI: 10.1016/j.bbrc.2020.07.007.
7. 杨晓英, 徐国兴. 间充质干细胞来源外泌体对视网膜新生血管影响的研究进展[J]. 国际眼科杂志, 2020, 20(6): 974-976. DOI: 10.3980/j.issn.1672-5123.2020.6.10.Yang XY, Xu GX. Research progress on the effect of exosomes derived from mesenchymal stem cells on retinal neovascularization[J]. Int Eye Sci, 2020, 20(6): 974-976. DOI: 10.3980/j.issn.1672-5123.2020.6.10.
8. Mahmoudian-Sani MR, Forouzanfar F, Asgharzade S, et al. Overexpression of mir-183/96/182 triggers retina-like fate in human bone marrow-derived mesenchymal stem cells (hBMSCs) in culture[J/OL]. J Ophthalmol, 2019, 2019: 2454362[2019-12-11]. https://pubmed.ncbi.nlm.nih.gov/31885884/. DOI: 10.1155/2019/2454362.
9. Davis C, Dukes A, Drewry M, et al. MicroRNA-183-5p increases with age in bone-derived extracellular vesicles, suppresses bone marrow stromal (stem) cell proliferation, and induces stem cell senescence[J]. Tissue Eng Part A, 2017, 23(21-22): 1231-1240. DOI: 10.1089/ten.TEA.2016.0525.
10. Xin-Zhao Wang C, Zhang K, Aredo B, et al. Novel method for the rapid isolation of RPE cells specifically for RNA extraction and analysis[J]. Exp Eye Res, 2012, 102: 1-9. DOI: 10.1016/j.exer.2012.06.003.
11. 王悦, 徐国兴. 视网膜色素变性研究新进展[J]. 国际眼科杂志, 2020, 20(4): 628-630. DOI: 10.3980/j.issn.1672-5123.2020.4.10.Wang Y, Xu GX. New progress in the study of retinitis pigmentosa[J]. Int Eye Sci, 2020, 20(4): 628-630. DOI: 10.3980/j.issn.1672-5123.2020.4.10.
12. Limoli PG, Vingolo EM, Limoli C, et al. Antioxidant and biological properties of mesenchymal cells used for therapy in retinitis pigmentosa[J/OL]. Antioxidants (Basel), 2020, 9(10): E983[2020-10-13]. https://pubmed.ncbi.nlm.nih.gov/33066211/. DOI: 10.3390/antiox9100983.
13. 陈瑾, 徐国兴. 干细胞诱导分化为视网膜色素上皮细胞的途径探讨[J]. 国际眼科杂志, 2020, 20(10): 1722-1725. DOI: 10.3980/j.issn.1672-5123.2020.10.12.Chen J, Xu GX. Approach discussion of the differentiation of stem cells induced to retinal pigment epithelial cells[J]. Int Eye Sci, 2020, 20(10): 1722-1725. DOI: 10.3980/j.issn.1672-5123.2020.10.12.
14. Novoseletskaya E, Grigorieva O, Nimiritsky P, et al. Mesenchymal stromal cell-produced components of extracellular matrix potentiate multipotent stem cell response to differentiation stimuli[J/OL]. Front Cell Dev Biol, 2020, 8: 555378[2020-09-22]. https://pubmed.ncbi.nlm.nih.gov/33072743/. DOI: 10.3389/fcell.2020.555378.
15. Ma QQ, Liu FY, Shi M, et al. Bone marrow mesenchymal stem cells modified by angiogenin-1 promotes tissue repair in mice with oxygen-induced retinopathy of prematurity by promoting retinal stem cell proliferation and differentiation[J]. J Cell Physiol, 2019, 234(11): 21027-21038. DOI: 10.1002/jcp.28706.
16. Pegtel DM, Gould SJ. Exosomes[J]. Annu Rev Biochem, 2019, 88: 487-514. DOI: 10.1146/annurev-biochem-013118-111902.
17. Correia de Sousa M, Gjorgjieva M, Dolicka D, et al. Deciphering miRNAs' action through miRNA editing[J/OL]. Int J Mol Sci, 2019, 20(24): 6249[2019-12-11]. https://pubmed.ncbi.nlm.nih.gov/31835747/. DOI: 10.3390/ijms20246249.
18. Kinoshita J, Fujita K, Yasuno K, et al. Outer retinal involvement in N-methyl-D-aspartate-induced inner retinal injury in rabbits assessed by optical coherence tomography[J]. J Toxicol Sci, 2020, 45(5): 261-269. DOI: 10.2131/jts.45.261.
19. Zhao W, Qin P, Zhang D, et al. Long non-coding RNA PVT1 encapsulated in bone marrow mesenchymal stem cell-derived exosomes promotes osteosarcoma growth and metastasis by stabilizing ERG and sponging miR-183-5p[J]. Aging (Albany NY), 2019, 11(21): 9581-9596. DOI: 10.18632/aging.102406.
20. Park J, Jeong S, Park K, et al. Expression profile of microRNAs following bone marrow-derived mesenchymal stem cell treatment in lipopolysaccharide-induced acute lung injury[J]. Exp Ther Med, 2018, 15(6): 5495-5502. DOI: 10.3892/etm.2018.6118.
21. Choi EW, Lee M, Song JW, et al. Mesenchymal stem cell transplantation can restore lupus disease-associated miRNA expression and Th1/Th2 ratios in a murine model of SLE[J/OL]. Sci Rep, 2016, 6: 38237[2016-12-07]. https://pubmed.ncbi.nlm.nih.gov/27924862/. DOI: 10.1038/srep38237.
22. Xie YA, Lee W, Cai C, et al. New syndrome with retinitis pigmentosa is caused by nonsense mutations in retinol dehydrogenase RDH11[J]. Hum Mol Genet, 2014, 23(21): 5774-5780. DOI: 10.1093/hmg/ddu291.

Chinese Journal of Ocular Fundus Diseases

Bone marrow mesenchymal stem cell-derived exosomes miR-183 target regulation of retinal dehydrogenase 11 to inhibit the development of retinitis pigmentosa

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