{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T08:55:29Z","timestamp":1780476929875,"version":"3.54.1"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2018,3,7]],"date-time":"2018-03-07T00:00:00Z","timestamp":1520380800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100001839","name":"University Grants Committee Hong Kong","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001839","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81570849"],"award-info":[{"award-number":["81570849"]}],"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":["81470636"],"award-info":[{"award-number":["81470636"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013286","name":"Research Fund for the Doctoral Program of Higher Education of China","doi-asserted-by":"crossref","award":["20114402120007"],"award-info":[{"award-number":["20114402120007"]}],"id":[{"id":"10.13039\/501100013286","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003453","name":"Natural Science Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2015A030313446"],"award-info":[{"award-number":["2015A030313446"]}],"id":[{"id":"10.13039\/501100003453","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Optic neuropathies are the leading cause of irreversible blindness and visual impairment in the developed countries, affecting more than 80 million people worldwide. While most optic neuropathies have no effective treatment, there is intensive research on retinal ganglion cell (RGC) protection and axon regeneration. We previously demonstrated potential of human periodontal ligament-derived stem cells (PDLSCs) for retinal cell replacement. Here, we report the neuroprotective effect of human PDLSCs to ameliorate RGC degeneration and promote axonal regeneration after optic nerve crush (ONC) injury. Human PDLSCs were intravitreally injected into the vitreous chamber of adult Fischer rats after ONC in vivo as well as cocultured with retinal explants in vitro. Human PDLSCs survived in the vitreous chamber and were maintained on the RGC layer even at 3 weeks after ONC. Immunofluorescence analysis of \u03b2III-tubulin and Gap43 showed that the numbers of surviving RGCs and regenerating axons were significantly increased in the rats with human PDLSC transplantation. In vitro coculture experiments confirmed that PDLSCs enhanced RGC survival and neurite regeneration in retinal explants without inducing inflammatory responses. Direct cell\u2013cell interaction and elevated brain-derived neurotrophic factor secretion, but not promoting endogenous progenitor cell regeneration, were the RGC protective mechanisms of human PDLSCs. In summary, our results revealed the neuroprotective role of human PDLSCs by strongly promoting RGC survival and axonal regeneration both in vivo and in vitro, indicating a therapeutic potential for RGC protection against optic neuropathies.<\/jats:p>","DOI":"10.1002\/stem.2812","type":"journal-article","created":{"date-parts":[[2018,2,24]],"date-time":"2018-02-24T08:46:39Z","timestamp":1519461999000},"page":"844-855","source":"Crossref","is-referenced-by-count":66,"title":["Human Periodontal Ligament-Derived Stem Cells Promote Retinal Ganglion Cell Survival and Axon Regeneration After Optic Nerve Injury"],"prefix":"10.1093","volume":"36","author":[{"given":"Ling-Ping","family":"Cen","sequence":"first","affiliation":[{"name":"Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong Kong, Shantou, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7863-7229","authenticated-orcid":false,"given":"Tsz Kin","family":"Ng","sequence":"additional","affiliation":[{"name":"Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong Kong, Shantou, People's Republic of China"},{"name":"Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-Jian","family":"Liang","sequence":"additional","affiliation":[{"name":"Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong Kong, Shantou, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Zhuang","sequence":"additional","affiliation":[{"name":"Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong Kong, Shantou, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowu","family":"Yao","sequence":"additional","affiliation":[{"name":"Dentistry Department, Second Affiliated Hospital, Shantou University Medical College, Shantou, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary Hin-Fai","family":"Yam","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoyu","family":"Chen","sequence":"additional","affiliation":[{"name":"Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong Kong, Shantou, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herman S.","family":"Cheung","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, College of Engineering, University of Miami, Coral Gables, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingzhi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong Kong, Shantou, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi Pui","family":"Pang","sequence":"additional","affiliation":[{"name":"Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong Kong, Shantou, People's Republic of China"},{"name":"Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2018,3,7]]},"reference":[{"key":"2022022512393456100_stem2812-bib-0001","doi-asserted-by":"crossref","first-page":"4368","DOI":"10.1523\/JNEUROSCI.14-07-04368.1994","article-title":"Axotomy results in delayed death and apoptosis of retinal ganglion cells in adult rats","volume":"14","author":"Berkelaar","year":"1994","journal-title":"J Neurosci"},{"key":"2022022512393456100_stem2812-bib-0002","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/35000219","article-title":"Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1","volume":"403","author":"Chen","year":"2000","journal-title":"Nature"},{"key":"2022022512393456100_stem2812-bib-0003","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1038\/nature00867","article-title":"Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth","volume":"417","author":"Wang","year":"2002","journal-title":"Nature"},{"key":"2022022512393456100_stem2812-bib-0004","first-page":"760","article-title":"CNTF, not other trophic factors, promotes axonal regeneration of axotomized retinal ganglion cells in adult hamsters","volume":"40","author":"Cui","year":"1999","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"2022022512393456100_stem2812-bib-0005","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/j.neuroscience.2016.12.027","article-title":"AAV-mediated transfer of RhoA shRNA and CNTF promotes retinal ganglion cell survival and axon regeneration","volume":"343","author":"Cen","year":"2017","journal-title":"Neuroscience"},{"key":"2022022512393456100_stem2812-bib-0006","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1167\/iovs.15-17841","article-title":"Apoptotic retinal ganglion cell death after optic nerve transection or crush in mice: Delayed RGC loss with BDNF or a caspase 3 inhibitor","volume":"57","author":"S\u00e1nchez-Migall\u00f3n","year":"2016","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"2022022512393456100_stem2812-bib-0007","doi-asserted-by":"crossref","first-page":"4045","DOI":"10.1073\/pnas.1211284110","article-title":"Functional genomic screening identifies dual leucine zipper kinase as a key mediator of retinal ganglion cell death","volume":"110","author":"Welsbie","year":"2013","journal-title":"Proc Natl Acad Sci USA"},{"key":"2022022512393456100_stem2812-bib-0008","doi-asserted-by":"crossref","first-page":"8726","DOI":"10.1523\/JNEUROSCI.2774-04.2004","article-title":"Switching mature retinal ganglion cells to a robust growth state in vivo: Gene expression and synergy with RhoA inactivation","volume":"24","author":"Fischer","year":"2004","journal-title":"J Neurosci"},{"key":"2022022512393456100_stem2812-bib-0009","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1038\/nature10594","article-title":"Sustained axon regeneration induced by co-deletion of PTEN and SOCS3","volume":"480","author":"Sun","year":"2011","journal-title":"Nature"},{"key":"2022022512393456100_stem2812-bib-0010","doi-asserted-by":"crossref","first-page":"3323","DOI":"10.1111\/j.1460-9568.2006.05230.x","article-title":"Cooperative effects of bcl-2 and AAV-mediated expression of CNTF on retinal ganglion cell survival and axonal regeneration in adult transgenic mice","volume":"24","author":"Leaver","year":"2006","journal-title":"Eur J Neurosci"},{"key":"2022022512393456100_stem2812-bib-0011","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1097\/APO.0b013e31827e3e5d","article-title":"Prospects of stem cells for retinal diseases","volume":"2","author":"Ng","year":"2013","journal-title":"Asia Pac J Ophthalmol"},{"key":"2022022512393456100_stem2812-bib-0012","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":"2022022512393456100_stem2812-bib-0013","doi-asserted-by":"crossref","first-page":"4244","DOI":"10.1167\/iovs.08-3239","article-title":"Transplanted oligodendrocyte precursor cells reduce neurodegeneration in a model of glaucoma","volume":"50","author":"Bull","year":"2009","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"2022022512393456100_stem2812-bib-0014","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.brainres.2013.07.037","article-title":"The anti-apoptotic and neuro-protective effects of human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) on acute optic nerve injury is transient","volume":"1532","author":"Chen","year":"2013","journal-title":"Brain Res"},{"key":"2022022512393456100_stem2812-bib-0015","doi-asserted-by":"crossref","first-page":"2051","DOI":"10.1167\/iovs.09-4509","article-title":"Neuroprotective effects of intravitreal mesenchymal stem cell transplantation in experimental glaucoma","volume":"51","author":"Johnson","year":"2010","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"2022022512393456100_stem2812-bib-0016","doi-asserted-by":"crossref","first-page":"111","DOI":"10.4252\/wjsc.v6.i2.111","article-title":"Progress of mesenchymal stem cell therapy for neural and retinal diseases","volume":"6","author":"Ng","year":"2014","journal-title":"World J Stem Cells"},{"key":"2022022512393456100_stem2812-bib-0017","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1186\/1423-0127-18-49","article-title":"Immunomodulatory properties of human adult and fetal multipotent mesenchymal stem cells","volume":"18","author":"Chen","year":"2011","journal-title":"J Biomed Sci"},{"key":"2022022512393456100_stem2812-bib-0018","doi-asserted-by":"crossref","first-page":"7544","DOI":"10.1167\/iovs.13-13045","article-title":"Intravitreally transplanted dental pulp stem cells promote neuroprotection and axon regeneration of retinal ganglion cells after optic nerve injury","volume":"54","author":"Mead","year":"2013","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"2022022512393456100_stem2812-bib-0019","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.3892\/ijmm.2016.2532","article-title":"Human umbilical cord blood mononuclear cells and chorionic plate-derived mesenchymal stem cells promote axon survival in a rat model of optic nerve crush injury","volume":"37","author":"Chung","year":"2016","journal-title":"Int J Mol Med"},{"key":"2022022512393456100_stem2812-bib-0020","first-page":"35","article-title":"Neuroprotective effects of BDNF and GDNF in intravitreally transplanted mesenchymal stem cells after optic nerve crush in mice","volume":"10","author":"Hu","year":"2017","journal-title":"Int J Ophthalmol"},{"key":"2022022512393456100_stem2812-bib-0021","first-page":"2529","article-title":"Therapeutic effect of adipose-derived stem cell transplantation on optic nerve injury in rats","volume":"17","author":"Li","year":"2018","journal-title":"Mol Med Rep"},{"key":"2022022512393456100_stem2812-bib-0022","doi-asserted-by":"crossref","first-page":"7828","DOI":"10.1038\/srep07828","article-title":"Cigarette smoking hinders human periodontal ligament-derived stem cell proliferation, migration and differentiation potentials","volume":"5","author":"Ng","year":"2015","journal-title":"Sci Rep"},{"key":"2022022512393456100_stem2812-bib-0023","doi-asserted-by":"crossref","first-page":"3965","DOI":"10.1167\/iovs.13-11910","article-title":"Directing adult human periodontal ligament-derived stem cells to retinal fate","volume":"54","author":"Huang","year":"2013","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"2022022512393456100_stem2812-bib-0024","doi-asserted-by":"crossref","first-page":"16429","DOI":"10.1038\/srep16429","article-title":"Transdifferentiation of periodontal ligament-derived stem cells into retinal ganglion-like cells and its microRNA signature","volume":"5","author":"Ng","year":"2015","journal-title":"Sci Rep"},{"key":"2022022512393456100_stem2812-bib-0025","doi-asserted-by":"crossref","first-page":"4615","DOI":"10.1523\/JNEUROSCI.20-12-04615.2000","article-title":"Lens injury stimulates axon regeneration in the mature rat optic nerve","volume":"20","author":"Leon","year":"2000","journal-title":"J Neurosci"},{"key":"2022022512393456100_stem2812-bib-0026","doi-asserted-by":"crossref","first-page":"2284","DOI":"10.1523\/JNEUROSCI.23-06-02284.2003","article-title":"Macrophage-derived factors stimulate optic nerve regeneration","volume":"23","author":"Yin","year":"2003","journal-title":"J Neurosci"},{"key":"2022022512393456100_stem2812-bib-0027","doi-asserted-by":"crossref","first-page":"4257","DOI":"10.1167\/iovs.06-0791","article-title":"Chemotactic effect of ciliary neurotrophic factor on macrophages in retinal ganglion cell survival and axonal regeneration","volume":"48","author":"Cen","year":"2007","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"2022022512393456100_stem2812-bib-0028","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1038\/nn1701","article-title":"Oncomodulin is a macrophage-derived signal for axon regeneration in retinal ganglion cells","volume":"9","author":"Yin","year":"2006","journal-title":"Nat Neurosci"},{"key":"2022022512393456100_stem2812-bib-0029","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.brainres.2004.09.038","article-title":"Intravitreal transplants of Schwann cells and fibroblasts promote the survival of axotomized retinal ganglion cells in rats","volume":"1029","author":"Li","year":"2004","journal-title":"Brain Res"},{"key":"2022022512393456100_stem2812-bib-0030","doi-asserted-by":"crossref","first-page":"1855","DOI":"10.1073\/pnas.87.5.1855","article-title":"Schwann cells promote the survival of rat retinal ganglion cells after optic nerve section","volume":"87","author":"Maffei","year":"1990","journal-title":"Proc Natl Acad Sci USA"},{"key":"2022022512393456100_stem2812-bib-0031","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1002\/nbm.1778","article-title":"In vivo MRI of olfactory ensheathing cell grafts and regenerating axons in transplant mediated repair of the adult rat optic nerve","volume":"25","author":"Sandvig","year":"2012","journal-title":"NMR Biomed"},{"key":"2022022512393456100_stem2812-bib-0032","doi-asserted-by":"crossref","first-page":"391","DOI":"10.3727\/096368910X524764","article-title":"Bone marrow mononuclear cells increase retinal ganglion cell survival and axon regeneration in the adult rat","volume":"20","author":"Zaverucha-do-Valle","year":"2011","journal-title":"Cell Transplant"},{"key":"2022022512393456100_stem2812-bib-0033","first-page":"167","article-title":"Differentiation potential of stem cells from human dental origin - promise for tissue engineering","volume":"60","author":"Kadar","year":"2009","journal-title":"J Physiol Pharmacol"},{"key":"2022022512393456100_stem2812-bib-0034","first-page":"399","article-title":"Human umbilical cord blood-derived mesenchymal stem cells do not differentiate into neural cell types or integrate into the retina after intravitreal grafting in neonatal rats. Stem Cells","volume":"18","author":"Hill","year":"2009","journal-title":"Dev"},{"key":"2022022512393456100_stem2812-bib-0035","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1093\/brain\/awt292","article-title":"Identification of retinal ganglion cell neuroprotection conferred by platelet-derived growth factor through analysis of the mesenchymal stem cell secretome","volume":"137","author":"Johnson","year":"2014","journal-title":"Brain"},{"key":"2022022512393456100_stem2812-bib-0036","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1177\/039463201402700309","article-title":"Human mesenchymal stem cells produce bioactive neurotrophic factors: Source, individual variability and differentiation issues","volume":"27","author":"Paradisi","year":"2014","journal-title":"Int J Immunopathol Pharmacol"}],"container-title":["Stem Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fstem.2812","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/stem.2812","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/stem.2812","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/stmcls\/article-pdf\/36\/6\/844\/42608254\/stmcls_36_6_844.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/stmcls\/article-pdf\/36\/6\/844\/42608254\/stmcls_36_6_844.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,25]],"date-time":"2022-02-25T12:42:04Z","timestamp":1645792924000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/stmcls\/article\/36\/6\/844\/6453156"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,3,7]]},"references-count":36,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2018,3,7]]},"published-print":{"date-parts":[[2018,6,1]]}},"URL":"https:\/\/doi.org\/10.1002\/stem.2812","relation":{},"ISSN":["1066-5099","1549-4918"],"issn-type":[{"value":"1066-5099","type":"print"},{"value":"1549-4918","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2018,6,1]]},"published":{"date-parts":[[2018,3,7]]}}}