{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T17:45:26Z","timestamp":1792950326259,"version":"4.5.0"},"reference-count":44,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2024,12,2]],"date-time":"2024-12-02T00:00:00Z","timestamp":1733097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Ministry of Science and Technology of China","award":["2021ZD0202603"],"award-info":[{"award-number":["2021ZD0202603"]}]},{"name":"the Ministry of Science and Technology of China","award":["81970794"],"award-info":[{"award-number":["81970794"]}]},{"name":"the Ministry of Science and Technology of China","award":["2023B1212060018"],"award-info":[{"award-number":["2023B1212060018"]}]},{"name":"the Ministry of Science and Technology of China","award":["2023A03J0178"],"award-info":[{"award-number":["2023A03J0178"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2021ZD0202603"],"award-info":[{"award-number":["2021ZD0202603"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81970794"],"award-info":[{"award-number":["81970794"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2023B1212060018"],"award-info":[{"award-number":["2023B1212060018"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2023A03J0178"],"award-info":[{"award-number":["2023A03J0178"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012245","name":"Science and Technology Planning Project of Guangdong Province","doi-asserted-by":"publisher","award":["2021ZD0202603"],"award-info":[{"award-number":["2021ZD0202603"]}],"id":[{"id":"10.13039\/501100012245","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012245","name":"Science and Technology Planning Project of Guangdong Province","doi-asserted-by":"publisher","award":["81970794"],"award-info":[{"award-number":["81970794"]}],"id":[{"id":"10.13039\/501100012245","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012245","name":"Science and Technology Planning Project of Guangdong Province","doi-asserted-by":"publisher","award":["2023B1212060018"],"award-info":[{"award-number":["2023B1212060018"]}],"id":[{"id":"10.13039\/501100012245","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012245","name":"Science and Technology Planning Project of Guangdong Province","doi-asserted-by":"publisher","award":["2023A03J0178"],"award-info":[{"award-number":["2023A03J0178"]}],"id":[{"id":"10.13039\/501100012245","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Science and Technology Program of Guangzhou","award":["2021ZD0202603"],"award-info":[{"award-number":["2021ZD0202603"]}]},{"name":"Science and Technology Program of Guangzhou","award":["81970794"],"award-info":[{"award-number":["81970794"]}]},{"name":"Science and Technology Program of Guangzhou","award":["2023B1212060018"],"award-info":[{"award-number":["2023B1212060018"]}]},{"name":"Science and Technology Program of Guangzhou","award":["2023A03J0178"],"award-info":[{"award-number":["2023A03J0178"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Optic neuropathy such as glaucoma, stemming from retinal ganglion cell (RGC) degeneration, is a leading cause of visual impairment. Given the substantial loss of RGCs preceding clinical detection of visual impairment, cell replacement therapy emerges as a compelling treatment strategy. Human-induced pluripotent stem cells (hiPSCs) serve as invaluable tools for exploring the developmental processes and pathological mechanisms associated with human RGCs. Utilizing a 3D stepwise differentiation protocol for retinal organoids, we successfully differentiated RGC precursors from hiPSCs harboring a BRN3B-GFP RGC reporter, verified by GFP expression. Intravitreal transplantation of enriched RGC precursors into healthy or N-methyl-D-aspartate (NMDA)-injured mice demonstrated their survival, migration, and integration into the proper retinal layer, the ganglion cell layer, after 3 weeks. Notably, these transplanted cells differentiated into marker-positive RGCs and extended neurites. Moreover, enhanced cell survival was observed with immunosuppressive and anti-inflammatory treatments of the host prior to transplantation. These data underscore the potential of transplanted RGC precursors as a promising therapeutic avenue for treating degenerative retinal diseases resulting from RGC dysfunction.<\/jats:p>","DOI":"10.3390\/ijms252312947","type":"journal-article","created":{"date-parts":[[2024,12,2]],"date-time":"2024-12-02T06:58:58Z","timestamp":1733122738000},"page":"12947","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Integration and Differentiation of Transplanted Human iPSC-Derived Retinal Ganglion Cell Precursors in Murine Retinas"],"prefix":"10.3390","volume":"25","author":[{"given":"Qiannan","family":"Lei","sequence":"first","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8254-7303","authenticated-orcid":false,"given":"Fa","family":"Yuan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengqing","family":"Xiang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China"},{"name":"Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1016\/S0140-6736(10)61423-7","article-title":"Glaucoma","volume":"377","author":"Quigley","year":"2011","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1136\/bjo.2005.081224","article-title":"The number of people with glaucoma worldwide in 2010 and 2020","volume":"90","author":"Quigley","year":"2006","journal-title":"Br. J. Ophthalmol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1000.e7","DOI":"10.1016\/j.amjmed.2016.03.038","article-title":"Emerging Concepts in Glaucoma and Review of the Literature","volume":"129","author":"Greco","year":"2016","journal-title":"Am. J. Med."},{"key":"ref_4","first-page":"243","article-title":"Stem cell treatment of degenerative eye disease","volume":"14","author":"Mead","year":"2015","journal-title":"Stem Cell Reports"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1007\/s00417-007-0710-6","article-title":"Transplantation of cells from eye-like structures differentiated from embryonic stem cells in vitro and in vivo regeneration of retinal ganglion-like cells","volume":"246","author":"Aoki","year":"2008","journal-title":"Graefes Arch. Clin. Exp. Ophthalmol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1016\/j.exer.2007.01.007","article-title":"An in vitro mouse model for retinal ganglion cell replacement therapy using eye-like structures differentiated from ES cells","volume":"84","author":"Aoki","year":"2007","journal-title":"Exp. Eye Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1016\/j.stemcr.2014.03.011","article-title":"Transplantation of embryonic and induced pluripotent stem cell-derived 3D retinal sheets into retinal degenerative mice","volume":"2","author":"Assawachananont","year":"2014","journal-title":"Stem Cell Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"12769","DOI":"10.1073\/pnas.0601990103","article-title":"Efficient generation of retinal progenitor cells from human embryonic stem cells","volume":"103","author":"Lamba","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.bbrc.2009.01.038","article-title":"In vitro differentiation of retinal ganglion-like cells from embryonic stem cell derived neural progenitors","volume":"380","author":"Jagatha","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1089\/scd.2018.0076","article-title":"Transplantation of Retinal Progenitor Cells from Optic Cup-Like Structures Differentiated from Human Embryonic Stem Cells In Vitro and In Vivo Generation of Retinal Ganglion-Like Cells","volume":"28","author":"Wang","year":"2019","journal-title":"Stem Cells Dev."},{"key":"ref_11","first-page":"131","article-title":"Cell transplantation of retinal ganglion cells derived from hESCs","volume":"38","author":"Zhang","year":"2020","journal-title":"Restor. Neurol. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1002\/stem.320","article-title":"Induced Pluripotent Stem Cells Generate Both Retinal Ganglion Cells and Photoreceptors: Therapeutic Implications in Degenerative Changes in Glaucoma and Age-Related Macular Degeneration","volume":"28","author":"Parameswaran","year":"2010","journal-title":"Stem Cells"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"188","DOI":"10.5966\/sctm.2011-0005","article-title":"Human Muller Glia with Stem Cell Characteristics Differentiate into Retinal Ganglion Cell (RGC) Precursors In Vitro and Partially Restore RGC Function In Vivo Following Transplantation","volume":"1","author":"Singhal","year":"2012","journal-title":"Stem Cell Transl. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1634\/stemcells.2007-0898","article-title":"Chondroitin sulfate proteoglycans and microglia prevent migration and integration of grafted M\u00fcller stem cells into degenerating retina","volume":"26","author":"Singhal","year":"2008","journal-title":"Stem Cells"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e13550","DOI":"10.1111\/cpr.13550","article-title":"Rapid and efficient generation of a transplantable population of functional retinal ganglion cells from fibroblasts","volume":"57","author":"Xu","year":"2024","journal-title":"Cell Prolif."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5970","DOI":"10.1167\/iovs.09-4504","article-title":"Generation of retinal ganglion-like cells from reprogrammed mouse fibroblasts","volume":"51","author":"Chen","year":"2010","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"eaaz5858","DOI":"10.1126\/sciadv.aaz5858","article-title":"Generation of self-organized sensory ganglion organoids and retinal ganglion cells from fibroblasts","volume":"6","author":"Xiao","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"768391","DOI":"10.1155\/2014\/768391","article-title":"A Comparative View on Human Somatic Cell Sources for iPSC Generation","volume":"2014","author":"Raab","year":"2014","journal-title":"Stem Cells Int."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Cheng, L., Lei, Q., Yin, C., Wang, H.Y., Jin, K., and Xiang, M. (2017). Generation of Urine Cell-Derived Non-integrative Human iPSCs and iNSCs: A Step-by-Step Optimized Protocol. Front. Mol. Neurosci., 10.","DOI":"10.3389\/fnmol.2017.00348"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.stemcr.2023.11.004","article-title":"Human retinal organoids with an OPA1 mutation are defective in retinal ganglion cell differentiation and function","volume":"19","author":"Lei","year":"2024","journal-title":"Stem Cell Reports"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1038\/nature09941","article-title":"Self-organizing optic-cup morphogenesis in three-dimensional culture","volume":"472","author":"Eiraku","year":"2011","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1016\/j.stem.2012.05.009","article-title":"Self-formation of optic cups and storable stratified neural retina from human ESCs","volume":"10","author":"Nakano","year":"2012","journal-title":"Cell Stem Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1038\/nature05161","article-title":"Retinal repair by transplantation of photoreceptor precursors","volume":"444","author":"MacLaren","year":"2006","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1016\/j.neuron.2009.01.020","article-title":"Distinct roles of transcription factors brn3a and brn3b in controlling the development, morphology, and function of retinal ganglion cells","volume":"61","author":"Badea","year":"2009","journal-title":"Neuron"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3920","DOI":"10.1073\/pnas.93.9.3920","article-title":"POU domain factor Brn-3b is required for the development of a large set of retinal ganglion cells","volume":"93","author":"Gan","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1006\/dbio.1998.8868","article-title":"Requirement for Brn-3b in early differentiation of postmitotic retinal ganglion cell precursors","volume":"197","author":"Xiang","year":"1998","journal-title":"Dev. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1016\/0896-6273(93)90079-7","article-title":"Brn-3b: A POU domain gene expressed in a subset of retinal ganglion cells","volume":"11","author":"Xiang","year":"1993","journal-title":"Neuron"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3392","DOI":"10.1523\/JNEUROSCI.0043-08.2008","article-title":"A comprehensive negative regulatory program controlled by Brn3b to ensure ganglion cell specification from multipotential retinal precursors","volume":"28","author":"Qiu","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"6286","DOI":"10.1038\/ncomms7286","article-title":"Generation of a ciliary margin-like stem cell niche from self-organizing human retinal tissue","volume":"6","author":"Kuwahara","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"855","DOI":"10.3727\/096368913X667024","article-title":"Survival and integration of developing and progenitor-derived retinal ganglion cells following transplantation","volume":"23","author":"Hertz","year":"2014","journal-title":"Cell Transplant."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4427","DOI":"10.1523\/JNEUROSCI.12-11-04427.1992","article-title":"Open-channel block of N-methyl-D-aspartate (NMDA) responses by memantine: Therapeutic advantage against NMDA receptor-mediated neurotoxicity","volume":"12","author":"Chen","year":"1992","journal-title":"J. Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1997","DOI":"10.1002\/stem.520","article-title":"Long-term survival of photoreceptors transplanted into the adult murine neural retina requires immune modulation","volume":"28","author":"West","year":"2010","journal-title":"Stem Cells"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"10472","DOI":"10.1038\/ncomms10472","article-title":"Transplanted neurons integrate into adult retinas and respond to light","volume":"7","author":"Venugopalan","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Divya, M.S., Rasheed, V.A., Schmidt, T., Lalitha, S., Hattar, S., and James, J. (2017). Intraocular Injection of ES Cell-Derived Neural Progenitors Improve Visual Function in Retinal Ganglion Cell-Depleted Mouse Models. Front. Cell Neurosci., 11.","DOI":"10.3389\/fncel.2017.00295"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Nickerson, P.E.B., Ortin-Martinez, A., and Wallace, V.A. (2018). Material Exchange in Photoreceptor Transplantation: Updating Our Understanding of Donor\/Host Communication and the Future of Cell Engraftment Science. Front. Neural Circuits, 12.","DOI":"10.3389\/fncir.2018.00017"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"13029","DOI":"10.1038\/ncomms13029","article-title":"Donor and host photoreceptors engage in material transfer following transplantation of post-mitotic photoreceptor precursors","volume":"7","author":"Pearson","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"13537","DOI":"10.1038\/ncomms13537","article-title":"Transplanted photoreceptor precursors transfer proteins to host photoreceptors by a mechanism of cytoplasmic fusion","volume":"7","author":"Singh","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/j.stemcr.2017.12.008","article-title":"Transplanted Donor- or Stem Cell-Derived Cone Photoreceptors Can Both Integrate and Undergo Material Transfer in an Environment-Dependent Manner","volume":"10","author":"Waldron","year":"2018","journal-title":"Stem Cell Reports"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Xiao, D., Jin, K., Qiu, S., Lei, Q., Huang, W., Chen, H., Su, J., Xu, Q., Xu, Z., and Gou, B. (2021). In vivo Regeneration of Ganglion Cells for Vision Restoration in Mammalian Retinas. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.755544"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"eabq7219","DOI":"10.1126\/sciadv.abq7219","article-title":"Reprogramming M\u00fcller glia to regenerate ganglion-like cells in adult mouse retina with developmental transcription factors","volume":"8","author":"Todd","year":"2022","journal-title":"Sci. Adv."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.stemcr.2020.05.009","article-title":"Retinal ganglion cells with a glaucoma OPTN(E50K) mutation exhibit neurodegenerative phenotypes when derived from three-dimensional retinal organoids","volume":"15","author":"VanderWall","year":"2020","journal-title":"Stem Cell Rep."},{"key":"ref_42","first-page":"245","article-title":"Establishment and application of a retinal ganglion cell-specific reporter stem cell line","volume":"37","author":"Zhang","year":"2022","journal-title":"Yan Ke Xue Bao"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1038\/nbt1310","article-title":"A ROCK inhibitor permits survival of dissociated human embryonic stem cells","volume":"25","author":"Watanabe","year":"2007","journal-title":"Nat. Biotechnol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1038\/s41419-023-05617-2","article-title":"A lncRNA-encoded mitochondrial micropeptide exacerbates microglia-mediated neuroinflammation in retinal ischemia\/reperfusion injury","volume":"14","author":"Zheng","year":"2023","journal-title":"Cell Death Dis."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/23\/12947\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:44:54Z","timestamp":1760114694000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/23\/12947"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,2]]},"references-count":44,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["ijms252312947"],"URL":"https:\/\/doi.org\/10.3390\/ijms252312947","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,2]]}}}