Abstract
Retinal degenerative diseases such as glaucoma, retinitis pigmentosa, and age-related macular degeneration pose serious threats to human visual health due to lack of effective therapeutic approaches. In recent years, the transplantation of retinal progenitor cells (RPCs) has shown increasing promise in the treatment of these diseases; however, the application of RPC transplantation is limited by both their poor proliferation and their differentiation capabilities. Previous studies have shown that microRNAs (miRNA) act as essential mediators in the fate determination of stem/progenitor cells. In this study, we hypothesized that miR-124-3p plays a regulatory role in the fate of RPC determination by targeting Septin10 (SEPT10) in vitro. We observed that the overexpression of miR124-3p downregulates SEPT10 expression in RPCs, leading to reduced RPC proliferation and increased differentiation, specifically towards both neurons and ganglion cells. Conversely, antisense knockdown of miR-124-3p was shown to boost SEPT10 expression, enhance RPC proliferation, and attenuate differentiation. Moreover, overexpression of SEPT10 rescued miR-124-3p-caused proliferation deficiency while weakening the enhancement of miR-124-3p-induced-RPC differentiation. Results from this study show that miR-124-3p regulates RPC proliferation and differentiation by targeting SEPT10. Furthermore, our findings enable a more comprehensive understanding into the mechanisms of proliferation and differentiation of RPC fate determination. Ultimately, this study may be useful for helping researchers and clinicians to develop more promising and effective approaches to optimize the use of RPCs in treating retinal degeneration diseases.
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Data availability
The data that support the findings of this study are available on request from the corresponding author, Yisheng Zhong, upon reasonable request.
Abbreviations
- RPC:
-
Retinal progenitor cells
- SEPT10:
-
Septin10
- miRNA:
-
MicroRNA
- RP:
-
Retinitis pigmentosa
- AMD:
-
Central nervous system
- RGCs:
-
Retinal ganglion cells
- siRNA:
-
Small interfering RNA
- 3′-UTR:
-
Three prime untranslated region
- RT-PCR:
-
Reverse transcriptase polymerase chain reaction
References
Ageta-Ishihara N, Yamakado H, Morita T, Hattori S, Takao K, Miyakawa T, Takahashi R, Kinoshita M (2013) Chronic overload of SEPT4, a parkin substrate that aggregates in Parkinson’s disease, causes behavioral alterations but not neurodegeneration in mice. Mol Brain 6:35. https://doi.org/10.1186/1756-6606-6-35
Ambros V (2004) The functions of animal microRNAs. Nature 431:350–355. https://doi.org/10.1038/nature02871
Barnstable CJ, Blum AS, Devoto SH, Hicks D, Morabito MA, Sparrow JR, Treisman JE (1988) Cell differentiation and pattern formation in the developing mammalian retina. Neurosci Res Suppl 8:S27-41. https://doi.org/10.1016/0921-8696(88)90005-9
Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297. https://doi.org/10.1016/s0092-8674(04)00045-5
Bourne RR, Stevens GA, White RA, Smith JL, Flaxman SR, Price H, Jonas JB, Keeffe J, Leasher J, Naidoo K et al (2013) Causes of vision loss worldwide, 1990–2010: a systematic analysis. Lancet Glob Health 1:e339-349. https://doi.org/10.1016/S2214-109X(13)70113-X
Carthew RW, Sontheimer EJ (2009) Origins and mechanisms of miRNAs and siRNAs. Cell 136:642–655. https://doi.org/10.1016/j.cell.2009.01.035
Cheng LC, Pastrana E, Tavazoie M, Doetsch F (2009) miR-124 regulates adult neurogenesis in the subventricular zone stem cell niche. Nat Neurosci 12:399–408. https://doi.org/10.1038/nn.2294
Covey MV, Streb JW, Spektor R, Ballas N (2012) REST regulates the pool size of the different neural lineages by restricting the generation of neurons and oligodendrocytes from neural stem/progenitor cells. Development 139:2878–2890. https://doi.org/10.1242/dev.074765
Estey MP, Di Ciano-Oliveira C, Froese CD, Bejide MT, Trimble WS (2010) Distinct roles of septins in cytokinesis: SEPT9 mediates midbody abscission. J Cell Biol 191:741–749. https://doi.org/10.1083/jcb.201006031
Gao H, Ni N, Zhang D, Wang Y, Tang Z, Sun N, Ju Y, Dai X, Zhang Y, Liu Y, Gu P (2020) miR-762 regulates the proliferation and differentiation of retinal progenitor cells by targeting NPDC1. Cell Cycle 19:1754–1767. https://doi.org/10.1080/15384101.2020.1777805
Goureau O, Orieux G (2020) Photoreceptor cell transplantation for future treatment of retinitis pigmentosa. Med Sci (Paris) 36:600–606. https://doi.org/10.1051/medsci/2020097
Gu X, Meng S, Liu S, Jia C, Fang Y, Li S, Fu C, Song Q, Lin L, Wang X (2014) miR-124 represses ROCK1 expression to promote neurite elongation through activation of the PI3K/Akt signal pathway. J Mol Neurosci 52:156–165. https://doi.org/10.1007/s12031-013-0190-6
Hanrahan J, Snyder M (2003) Cytoskeletal activation of a checkpoint kinase. Mol Cell 12:663–673. https://doi.org/10.1016/j.molcel.2003.08.006
Hu J, Qian H, Xue Y, Fu XD (2018) PTB/nPTB: master regulators of neuronal fate in mammals. Biophys Rep 4:204–214. https://doi.org/10.1007/s41048-018-0066-y
Hu Y, Luo M, Ni N, Den Y, Xia J, Chen J, Ji J, Zhou X, Fan X, Gu P (2014) Reciprocal actions of microRNA-9 and TLX in the proliferation and differentiation of retinal progenitor cells. Stem Cells Dev 23:2771–2781. https://doi.org/10.1089/scd.2014.0021
Jiao S, Liu Y, Yao Y, Teng J (2018) miR-124 promotes proliferation and neural differentiation of neural stem cells through targeting DACT1 and activating Wnt/beta-catenin pathways. Mol Cell Biochem 449:305–314. https://doi.org/10.1007/s11010-018-3367-z
Jiao SJ, Liu YL, Yao YB, Teng JF (2017) miR-124 promotes proliferation and differentiation of neuronal stem cells through inactivating Notch pathway. Cell Biosci 7:68. https://doi.org/10.1186/s13578-017-0194-y
Kato Y, Kusakabe R, Inoue K, Tochinai S (2013) MiR-124 is involved in post-transcriptional regulation of polypyrimidine tract binding protein 1 (PTBP1) during neural development in the medaka, Oryzias latipes. Zoolog Sci 30:891–900. https://doi.org/10.2108/zsj.30.891
Kinoshita M, Konoe Y (2006) Emerging roles for the septin family of GTP-binding proteins in mitosis and cellular morphogenesis. Seikagaku 78:755–759
Leshinsky-Silver E, Ginzberg M, Dabby R, Sadeh M, Lev D, Lerman-Sagie T (2013) Neonatal vocal cord paralysis-an early presentation of hereditary neuralgic amyotrophy due to a mutation in the SEPT9 gene. Eur J Paediatr Neuro 17:64–67. https://doi.org/10.1016/j.ejpn.2012.08.006
Liu B, Li J, Cairns MJ (2014) Identifying miRNAs, targets and functions. Brief Bioinform 15:1–19. https://doi.org/10.1093/bib/bbs075
Liu K, Liu Y, Mo W, Qiu R, Wang X, Wu JY, He R (2011) MiR-124 regulates early neurogenesis in the optic vesicle and forebrain, targeting NeuroD1. Nucleic Acids Res 39:2869–2879. https://doi.org/10.1093/nar/gkq904
MacLaren RE, Pearson RA, MacNeil A, Douglas RH, Salt TE, Akimoto M, Swaroop A, Sowden JC, Ali RR (2006) Retinal repair by transplantation of photoreceptor precursors. Nature 444:203–207. https://doi.org/10.1038/nature05161
Meng Y, Shang F, Zhu Y (2019) miR-124 participates in the proliferation and differentiation of brain glioma stem cells through regulating Nogo/NgR expression. Exp Ther Med 18:2783–2788. https://doi.org/10.3892/etm.2019.7914
Mokabber H, Najafzadeh N, Mohammadzadeh Vardin M (2019) miR-124 promotes neural differentiation in mouse bulge stem cells by repressing Ptbp1 and Sox9. J Cell Physiol 234:8941–8950. https://doi.org/10.1002/jcp.27563
Nazari H, Zhang L, Zhu DH, Chader GJ, Falabella P, Stefanini F, Rowland T, Clegg DO, Kashani AH, Hinton DR, Humayun MS (2015) Stem cell based therapies for age-related macular degeneration: the promises and the challenges. Prog Retin Eye Res 48:1–39. https://doi.org/10.1016/j.preteyeres.2015.06.004
Ni N, Zhang DD, Xie Q, Chen JZ, Wang Z, Deng Y, Wen XY, Zhu MY, Ji J, Fan XQ et al (2014) Effects of let-7b and TLX on the proliferation and differentiation of retinal progenitor cells in vitro. Sci Rep-Uk 4:6671. https://doi.org/10.1038/srep06671
Okerlund ND, Kivimae S, Tong CK, Peng IF, Ullian EM, Cheyette BN (2010) Dact1 is a postsynaptic protein required for dendrite, spine, and excitatory synapse development in the mouse forebrain. J Neurosci 30:4362–4368. https://doi.org/10.1523/JNEUROSCI.0354-10.2010
Poche RA, Furuta Y, Chaboissier MC, Schedl A, Behringer RR (2008) Sox9 is expressed in mouse multipotent retinal progenitor cells and functions in Muller glial cell development. J Comp Neurol 510:237–250. https://doi.org/10.1002/cne.21746
Rapaport DH, Wong LL, Wood ED, Yasumura D, LaVail MM (2004) Timing and topography of cell genesis in the rat retina. J Comp Neurol 474:304–324. https://doi.org/10.1002/cne.20134
Rejdak R, Szkaradek M, Czepita M, Taslaq W, Lewicka-Chomont A, Grieb P (2012) Retinal degenerative diseases–mechanisms and perspectives of treatment. Klin Oczna 114:301–307
Russell SE, Hall PA (2011) Septin genomics: a road less travelled. Biol Chem 392:763–767. https://doi.org/10.1515/BC.2011.079
Scott CE, Wynn SL, Sesay A, Cruz C, Cheung M, Gomez Gaviro MV, Booth S, Gao B, Cheah KS, Lovell-Badge R, Briscoe J (2010) SOX9 induces and maintains neural stem cells. Nat Neurosci 13:1181–1189. https://doi.org/10.1038/nn.2646
Sreekanth S, Rasheed VA, Soundararajan L, Antony J, Saikia M, Sivakumar KC, Das AV (2017) miR cluster 143/145 directly targets Nrl and regulates rod photoreceptor development. Mol Neurobiol 54:8033–8049. https://doi.org/10.1007/s12035-016-0237-0
Stern JH, Tian Y, Funderburgh J, Pellegrini G, Zhang K, Goldberg JL, Ali RR, Young M, Xie Y, Temple S (2018) Regenerating eye tissues to preserve and restore vision. Cell Stem Cell 23:453. https://doi.org/10.1016/j.stem.2018.08.014
Sun N, Zhang D, Ni N, Tang Z, Gao H, Ju Y, Dai X, Wang J, Gu P, Ji J (2020) miR-17 regulates the proliferation and differentiation of retinal progenitor cells by targeting CHMP1A. Biochem Biophys Res Commun 523:493–499. https://doi.org/10.1016/j.bbrc.2019.11.108
Suzuki A, Yoshioka H, Summakia D, Desai NG, Jun G, Jia P, Loose DS, Ogata K, Gajera MV, Zhao Z, Iwata J (2019) MicroRNA-124-3p suppresses mouse lip mesenchymal cell proliferation through the regulation of genes associated with cleft lip in the mouse. BMC Genomics 20:852. https://doi.org/10.1186/s12864-019-6238-4
Suzuki F, Okuno M, Tanaka T, Sanuki R (2020) Overexpression of neural miRNAs miR-9/9* and miR-124 suppresses differentiation to Muller glia and promotes differentiation to neurons in mouse retina in vivo. Genes Cells 25:741–752. https://doi.org/10.1111/gtc.12809
Svahn AJ, Giacomotto J, Graeber MB, Rinkwitz S, Becker TS (2016) miR-124 Contributes to the functional maturity of microglia. Dev Neurobiol 76:507–518. https://doi.org/10.1002/dneu.22328
Tropepe V, Coles BLK, Chiasson BJ, Horsford DJ, Elia AJ, McInnes RR, van der Kooy D (2000) Retinal stem cells in the adult mammalian eye. Science 287:2032–2036. https://doi.org/10.1126/science.287.5460.2032
Uyama H, Mandai M, Takahashi M (2021) Stem-cell-based therapies for retinal degenerative diseases: current challenges in the establishment of new treatment strategies. Dev Growth Differ 63:59–71. https://doi.org/10.1111/dgd.12704
Visvanathan J, Lee S, Lee B, Lee JW, Lee SK (2007) The microRNA miR-124 antagonizes the anti-neural REST/SCP1 pathway during embryonic CNS development. Genes Dev 21:744–749. https://doi.org/10.1101/gad.1519107
Wang K, Pan S, Zhao P, Liu L, Chen Z, Bao H, Wang H, Zhang Y, Zhuge Q, Yang J (2022) PTBP1 knockdown promotes neural differentiation of glioblastoma cells through UNC5B receptor. Theranostics 12:3847–3861. https://doi.org/10.7150/thno.71100
Wang YY, Zhang DD, Tang ZM, Zhang Y, Gao HQ, Ni N, Shen BQ, Sun H, Gu P (2018) REST, regulated by RA through miR-29a and the proteasome pathway, plays a crucial role in RPC proliferation and differentiation. Cell Death Dis 9:444. https://doi.org/10.1038/s41419-018-0473-5
Wei C, Ren L, Li K, Lu Z (2018) The regulation of survival and differentiation of neural stem cells by miR-124 via modulating PAX3. Neurosci Lett 683:19–26. https://doi.org/10.1016/j.neulet.2018.05.051
Xia J, Liu H, Fan XQ, Hu YM, Zhang YD, Wang ZL, Zhou XJ, Luo M, Gu P (2012) An in vitro comparison of two different subpopulations of retinal progenitor cells for self-renewal and multipotentiality. Brain Res 1433:38–46. https://doi.org/10.1016/j.brainres.2011.11.054
Xia X, Teotia P, Ahmad I (2019) miR-29c regulates neurogliogenesis in the mammalian retina through REST. Dev Biol 450:90–100. https://doi.org/10.1016/j.ydbio.2019.03.013
Xie Y, Zhou J, Chen B (2022) Critical examination of Ptbp1-mediated glia-to-neuron conversion in the mouse retina. Cell Rep 39:110960. https://doi.org/10.1016/j.celrep.2022.110960
Yang P, Seiler MJ, Aramant RB, Whittemore SR (2002) Differential lineage restriction of rat retinal progenitor cells in vitro and in vivo. J Neurosci Res 69:466–476. https://doi.org/10.1002/jnr.10320
Young RW (1985) Cell differentiation in the retina of the mouse. Anat Rec 212:199–205. https://doi.org/10.1002/ar.1092120215
Zent E, Wittinghofer A (2014) Human septin isoforms and the GDP-GTP cycle. Biol Chem 395:169–180. https://doi.org/10.1515/hsz-2013-0268
Funding
This work was supported by the National Natural Science Foundation of China (no. 81870652, no. 82070953, no. 8200088, no. 82101179, no. 82000885, no. 32000972); Shanghai Sailing Program of China (no. 21YF1422900); and Shanghai Natural Science Foundation (no. 21ZR1439700).
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Shen, B., Gao, H., Zhang, D. et al. miR-124-3p regulates the proliferation and differentiation of retinal progenitor cells through SEPT10. Cell Tissue Res 392, 689–704 (2023). https://doi.org/10.1007/s00441-023-03750-0
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DOI: https://doi.org/10.1007/s00441-023-03750-0