{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T22:26:52Z","timestamp":1792189612334,"version":"4.4.0"},"reference-count":51,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2021,11,10]],"date-time":"2021-11-10T00:00:00Z","timestamp":1636502400000},"content-version":"vor","delay-in-days":2458,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["EY021800"],"award-info":[{"award-number":["EY021800"]}]},{"name":"NIH","award":["EY003279"],"award-info":[{"award-number":["EY003279"]}]},{"name":"NIH","award":["EY008247"],"award-info":[{"award-number":["EY008247"]}]},{"name":"NIH","award":["EY010572"],"award-info":[{"award-number":["EY010572"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Normally, trabecular meshwork (TM) and Schlemm's canal inner wall endothelial cells within the aqueous humor outflow pathway maintain intraocular pressure within a narrow safe range. Elevation in intraocular pressure, because of the loss of homeostatic regulation by these outflow pathway cells, is the primary risk factor for vision loss due to glaucomatous optic neuropathy. A notable feature associated with glaucoma is outflow pathway cell loss. Using controlled cell loss in ex vivo perfused human outflow pathway organ culture, we developed compelling experimental evidence that this level of cell loss compromises intraocular pressure homeostatic function. This function was restored by repopulation of the model with fresh TM cells. We then differentiated induced pluripotent stem cells (iPSCs) and used them to repopulate this cell depletion model. These differentiated cells (TM-like iPSCs) became similar to TM cells in both morphology and expression patterns. When transplanted, they were able to fully restore intraocular pressure homeostatic function. This successful transplantation of TM-like iPSCs establishes the conceptual feasibility of using autologous stem cells to restore intraocular pressure regulatory function in open-angle glaucoma patients, providing a novel alternative treatment option. Stem Cells \u00a02015;33:751\u2013761<\/jats:p>","DOI":"10.1002\/stem.1885","type":"journal-article","created":{"date-parts":[[2014,11,6]],"date-time":"2014-11-06T05:49:36Z","timestamp":1415252976000},"page":"751-761","source":"Crossref","is-referenced-by-count":108,"title":["Induced Pluripotent Stem Cells Restore Function in a Human Cell Loss Model of Open-Angle Glaucoma"],"prefix":"10.1093","volume":"33","author":[{"given":"Diala W.","family":"Abu-Hassan","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Casey Eye Institute Oregon Health & Science University, Portland, Oregon, USA"},{"name":"Department of Biochemistry & Molecular Biology Oregon Health & Science University, Portland, Oregon, USA"},{"name":"Department of Biochemistry & Physiology University of Jordan, Amman, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinbo","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Casey Eye Institute Oregon Health & Science University, Portland, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eileen I.","family":"Ryan","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Casey Eye Institute Oregon Health & Science University, Portland, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ted S.","family":"Acott","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Casey Eye Institute Oregon Health & Science University, Portland, Oregon, USA"},{"name":"Department of Biochemistry & Molecular Biology Oregon Health & Science University, Portland, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary J.","family":"Kelley","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Casey Eye Institute Oregon Health & Science University, Portland, Oregon, USA"},{"name":"Department of Integrative Biosciences Oregon Health & Science University, Portland, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2015,2,17]]},"reference":[{"key":"2022010914421090000_stem1885-bib-0001","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":"2022010914421090000_stem1885-bib-0002","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":"2022010914421090000_stem1885-bib-0003","first-page":"34","volume-title":"Glaucoma: Science and Practice","author":"Morrison","year":"2003"},{"key":"2022010914421090000_stem1885-bib-0004","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1089\/jop.2013.0185","article-title":"Intraocular pressure homeostasis: Maintaining balance in a high-pressure environment","volume":"30","author":"Acott","year":"2014","journal-title":"J Ocul Pharmacol Ther"},{"key":"2022010914421090000_stem1885-bib-0005","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1016\/j.exer.2009.02.007","article-title":"The trabecular meshwork outflow pathways: Structural and functional aspects","volume":"88","author":"Tamm","year":"2009","journal-title":"Exp Eye Res"},{"key":"2022010914421090000_stem1885-bib-0006","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1016\/j.exer.2008.11.033","article-title":"The changing paradigm of outflow resistance generation: Towards synergistic models of the JCT and inner wall endothelium","volume":"88","author":"Overby","year":"2009","journal-title":"Exp Eye Res"},{"key":"2022010914421090000_stem1885-bib-0007","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1097\/ICU.0b013e32834ff23e","article-title":"Current understanding of conventional outflow dysfunction in glaucoma","volume":"23","author":"Stamer","year":"2012","journal-title":"Curr Opin Ophthalmol"},{"key":"2022010914421090000_stem1885-bib-0008","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1016\/j.exer.2008.01.013","article-title":"Extracellular matrix in the trabecular meshwork (Review)","volume":"86","author":"Acott","year":"2008","journal-title":"Exp Eye Res"},{"key":"2022010914421090000_stem1885-bib-0009","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1016\/j.exer.2008.11.023","article-title":"Extracellular matrix turnover and outflow resistance","volume":"88","author":"Keller","year":"2009","journal-title":"Exp Eye Res"},{"key":"2022010914421090000_stem1885-bib-0010","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1016\/j.exer.2008.11.003","article-title":"The genetics of primary open-angle glaucoma: A review","volume":"88","author":"Allingham","year":"2009","journal-title":"Exp Eye Res"},{"key":"2022010914421090000_stem1885-bib-0011","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1038\/eye.2011.309","article-title":"Current concepts on primary open-angle glaucoma genetics: A contribution to disease pathophysiology and future treatment","volume":"26","author":"Gemenetzi","year":"2012","journal-title":"Eye (Lond)"},{"key":"2022010914421090000_stem1885-bib-0012","doi-asserted-by":"crossref","first-page":"3064","DOI":"10.1172\/JCI43085","article-title":"Glaucoma: Genes, phenotypes, and new directions for therapy","volume":"120","author":"Fan","year":"2010","journal-title":"J Clin Invest"},{"key":"2022010914421090000_stem1885-bib-0013","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1007\/s12041-009-0065-3","article-title":"Molecular complexity of primary open angle glaucoma: Current concepts","volume":"88","author":"Ray","year":"2009","journal-title":"J Genet"},{"key":"2022010914421090000_stem1885-bib-0014","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1016\/S0161-6420(84)34248-8","article-title":"Trabecular meshwork cellularity in primary open-angle glaucoma and nonglaucomatous normals","volume":"91","author":"Alvarado","year":"1984","journal-title":"Ophthalmology"},{"key":"2022010914421090000_stem1885-bib-0015","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1016\/j.exer.2008.10.024","article-title":"Stem cells in the trabecular meshwork: Present and future promises","volume":"88","author":"Kelley","year":"2009","journal-title":"Exp Eye Res"},{"key":"2022010914421090000_stem1885-bib-0016","first-page":"714","article-title":"Age-related changes in trabecular meshwork cellularity","volume":"21","author":"Alvarado","year":"1981","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"Pt 2","key":"2022010914421090000_stem1885-bib-0017","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1038\/eye.1987.38","article-title":"Age-related depletion of the cell population in the human trabecular meshwork","volume":"1","author":"Grierson","year":"1987","journal-title":"Eye"},{"key":"2022010914421090000_stem1885-bib-0018","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0002-9394(89)90805-2","article-title":"Trabecular repopulation by anterior trabecular meshwork cells after laser trabeculoplasty","volume":"107","author":"Acott","year":"1989","journal-title":"Am J Ophthalmol"},{"key":"2022010914421090000_stem1885-bib-0019","doi-asserted-by":"crossref","first-page":"1566","DOI":"10.1167\/iovs.11-9134","article-title":"Multipotent stem cells from trabecular meshwork become phagocytic TM cells","volume":"53","author":"Du","year":"2012","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"2022010914421090000_stem1885-bib-0020","doi-asserted-by":"crossref","first-page":"1450","DOI":"10.1167\/iovs.12-11056","article-title":"Stem cells from trabecular meshwork home to TM tissue in vivo","volume":"54","author":"Du","year":"2013","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"2022010914421090000_stem1885-bib-0021","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/1756-6606-7-22","article-title":"iPS cell technologies: Significance and applications to CNS regeneration and disease","volume":"7","author":"Okano","year":"2014","journal-title":"Mol Brain"},{"key":"2022010914421090000_stem1885-bib-0022","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1016\/j.cell.2006.07.024","article-title":"Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors","volume":"126","author":"Takahashi","year":"2006","journal-title":"Cell"},{"key":"2022010914421090000_stem1885-bib-0023","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1016\/j.stem.2012.05.005","article-title":"Induced pluripotent stem cells: Past, present, and future","volume":"10","author":"Yamanaka","year":"2012","journal-title":"Cell Stem Cell"},{"key":"2022010914421090000_stem1885-bib-0024","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.stem.2007.05.012","article-title":"Strategies and new developments in the generation of patient-specific pluripotent stem cells","volume":"1","author":"Yamanaka","year":"2007","journal-title":"Cell Stem Cell"},{"key":"2022010914421090000_stem1885-bib-0025","first-page":"464","article-title":"Human trabecular cells. II. Growth pattern and ultrastructural characteristics","volume":"23","author":"Alvarado","year":"1982","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"2022010914421090000_stem1885-bib-0026","first-page":"172","article-title":"Expression of matrix metalloproteinases and inhibitor by human trabecular meshwork","volume":"32","author":"Alexander","year":"1991","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"2022010914421090000_stem1885-bib-0027","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/0042-6989(81)90151-6","article-title":"Studies on human trabecular cells propagated in vitro","volume":"21","author":"Polansky","year":"1981","journal-title":"Vision Res"},{"key":"2022010914421090000_stem1885-bib-0028","first-page":"1043","article-title":"Human trabecular cells. I. Establishment in tissue culture and growth characteristics","volume":"18","author":"Polansky","year":"1979","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"2022010914421090000_stem1885-bib-0029","first-page":"945","article-title":"Human trabecular meshwork organ culture","volume":"28","author":"Johnson","year":"1987","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"2022010914421090000_stem1885-bib-0030","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/0014-4835(89)90080-8","article-title":"The effect of organ culture on human trabecular meshwork","volume":"49","author":"Johnson","year":"1989","journal-title":"Exp Eye Res"},{"key":"2022010914421090000_stem1885-bib-0031","first-page":"1505","article-title":"Effects of mechanical stretching on trabecular matrix metalloproteinases","volume":"42","author":"Bradley","year":"2001","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"2022010914421090000_stem1885-bib-0032","first-page":"2649","article-title":"Effects of matrix metalloproteinase activity on outflow in perfused human organ culture","volume":"39","author":"Bradley","year":"1998","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"2022010914421090000_stem1885-bib-0033","first-page":"90","article-title":"Human trabecular meshwork organ culture: Morphology and glycosaminoglycan synthesis","volume":"29","author":"Acott","year":"1988","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"2022010914421090000_stem1885-bib-0034","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.exer.2007.10.018","article-title":"The mechanism of increasing outflow facility by rho-kinase inhibition with Y-27632 in bovine eyes","volume":"86","author":"Lu","year":"2008","journal-title":"Exp Eye Res"},{"key":"2022010914421090000_stem1885-bib-0035","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/j.cell.2007.11.019","article-title":"Induction of pluripotent stem cells from adult human fibroblasts by defined factors","volume":"131","author":"Takahashi","year":"2007","journal-title":"Cell"},{"key":"2022010914421090000_stem1885-bib-0036","doi-asserted-by":"crossref","first-page":"2588","DOI":"10.1167\/iovs.02-1099","article-title":"Gene expression profile of the human trabecular meshwork: NEIBank sequence tag analysis","volume":"44","author":"Tomarev","year":"2003","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"2022010914421090000_stem1885-bib-0037","first-page":"1803","article-title":"Expression of aquaporin-1 in human trabecular meshwork cells: Role in resting cell volume","volume":"42","author":"Stamer","year":"2001","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"2022010914421090000_stem1885-bib-0038","first-page":"3867","article-title":"Localization of aquaporin CHIP in the human eye: Implications in the pathogenesis of glaucoma and other disorders of ocular fluid balance","volume":"35","author":"Stamer","year":"1994","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"2022010914421090000_stem1885-bib-0039","first-page":"774","article-title":"Genome-wide expression profile of human trabecular meshwork cultured cells, nonglaucomatous and primary open angle glaucoma tissue","volume":"12","author":"Liton","year":"2006","journal-title":"Mol Vis"},{"key":"2022010914421090000_stem1885-bib-0040","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1167\/iovs.04-0330","article-title":"Specific targeting of gene expression to a subset of human trabecular meshwork cells using the chitinase 3-like 1 promoter","volume":"46","author":"Liton","year":"2005","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"2022010914421090000_stem1885-bib-0041","first-page":"3678","article-title":"Characterization of gene expression in human trabecular meshwork using single-pass sequencing of 1060 clones","volume":"41","author":"Gonzalez","year":"2000","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"2022010914421090000_stem1885-bib-0042","first-page":"2577","volume-title":"Principles and Practice of Ophthalmology","author":"Johnson","year":"2000","edition":"2nd ed."},{"key":"2022010914421090000_stem1885-bib-0043","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.3109\/02713688909000037","article-title":"Trabecular meshwork recovery after phagocytic challenge","volume":"8","author":"Johnson","year":"1989","journal-title":"Curr Eye Res"},{"key":"2022010914421090000_stem1885-bib-0044","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/j.exer.2005.10.011","article-title":"\u2018What controls aqueous humour outflow resistance?'","volume":"82","author":"Johnson","year":"2006","journal-title":"Exp Eye Res"},{"key":"2022010914421090000_stem1885-bib-0045","doi-asserted-by":"crossref","first-page":"S30","DOI":"10.1016\/j.ophtha.2009.06.024","article-title":"A comprehensive perspective on patient adherence to topical glaucoma therapy","volume":"116","author":"Tsai","year":"2009","journal-title":"Ophthalmology"},{"key":"2022010914421090000_stem1885-bib-0046","doi-asserted-by":"crossref","first-page":"454","DOI":"10.3129\/i08-076","article-title":"Multicenter study of compliance and drop administration in glaucoma","volume":"43","author":"Kholdebarin","year":"2008","journal-title":"Can J Ophthalmol"},{"key":"2022010914421090000_stem1885-bib-0047","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1097\/IJG.0b013e3181f7b10e","article-title":"Prevalence and correlates of self-reported nonadherence with eye drop treatment: The Belgian Compliance Study in Ophthalmology (BCSO)","volume":"20","author":"Vandenbroeck","year":"2011","journal-title":"J Glaucoma"},{"key":"2022010914421090000_stem1885-bib-0048","doi-asserted-by":"crossref","first-page":"S93","DOI":"10.4103\/0301-4738.73693","article-title":"Compliance and adherence in glaucoma management","volume":"59 suppl","author":"Robin","year":"2011","journal-title":"Indian J Ophthalmol"},{"key":"2022010914421090000_stem1885-bib-0049","first-page":"227","article-title":"Molecular genetics of the glaucomas: Mapping of the first five \u201cGLC\u201d loci","volume":"60","author":"Raymond","year":"1997","journal-title":"Am J Hum Genet"},{"key":"2022010914421090000_stem1885-bib-0050","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1126\/science.270.5239.1189","article-title":"Fas ligand-induced apoptosis as a mechanism of immune privilege","volume":"270","author":"Griffith","year":"1995","journal-title":"Science"},{"key":"2022010914421090000_stem1885-bib-0051","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/0039-6257(90)90048-Z","article-title":"Anterior chamber associated immune deviation: The privilege of immunity in the eye","volume":"35","author":"Streilein","year":"1990","journal-title":"Surv Ophthalmol"}],"container-title":["Stem Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fstem.1885","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fstem.1885","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/stem.1885","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/stem.1885","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/stmcls\/article-pdf\/33\/3\/751\/42015524\/stmcls_33_3_751.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/stmcls\/article-pdf\/33\/3\/751\/42015524\/stmcls_33_3_751.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,18]],"date-time":"2022-01-18T21:54:32Z","timestamp":1642542872000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/stmcls\/article\/33\/3\/751-761\/6407147"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,2,17]]},"references-count":51,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2015,2,17]]},"published-print":{"date-parts":[[2015,3,1]]}},"URL":"https:\/\/doi.org\/10.1002\/stem.1885","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.725228600.793527643","asserted-by":"object"}]},"ISSN":["1066-5099","1549-4918"],"issn-type":[{"value":"1066-5099","type":"print"},{"value":"1549-4918","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2015,3,1]]},"published":{"date-parts":[[2015,2,17]]}}}