{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T06:05:32Z","timestamp":1768716332091,"version":"3.49.0"},"reference-count":63,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,5,31]],"date-time":"2023-05-31T00:00:00Z","timestamp":1685491200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010665","name":"H2020 Marie Sk\u0142odowska-Curie Actions","doi-asserted-by":"publisher","award":["801133"],"award-info":[{"award-number":["801133"]}],"id":[{"id":"10.13039\/100010665","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Bioeng. Biotechnol."],"abstract":"<jats:p>The potential for trilineage differentiation of cells in tissues represents a model for studying disease pathogenesis and regeneration pathways. Human lens trilineage differentiation has not yet been demonstrated, and so has calcification and osteogenic differentiation of human lens epithelial cells in the whole human lens. Such changes can pose a risk for complications during cataract surgery. Human lens capsules (<jats:italic>n<\/jats:italic> = 9) from cataract patients undergoing uneventful surgery were trilineage-differentiated toward osteogenesis, chondrogenesis, and adipogenesis. Furthermore, whole human healthy lenses (<jats:italic>n<\/jats:italic> = 3) collected from cadaveric eyes were differentiated into bone and characterized by immunohistochemistry. The cells in the human lens capsules were capable of undergoing trilineage differentiation, while the whole human healthy lenses could undergo osteogenesis differentiation, expressing osteocalcin, collagen I, and pigment epithelium-derived factor. We, hereby, show an <jats:italic>ex vivo<\/jats:italic> model for cataract formation through different stages of opacification, as well as provide <jats:italic>in vivo<\/jats:italic> evidence from patients undergoing calcified lens extraction with bone-like consistency.<\/jats:p>","DOI":"10.3389\/fbioe.2023.1164795","type":"journal-article","created":{"date-parts":[[2023,5,31]],"date-time":"2023-05-31T05:24:55Z","timestamp":1685510695000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["The human lens is capable of trilineage differentiation towards osteo-, chondro-, and adipogenesis\u2014a model for studying cataract pathogenesis"],"prefix":"10.3389","volume":"11","author":[{"given":"Gerard","family":"Boix-Lemonche","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard M.","family":"Nagymihaly","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xhevat","family":"Lumi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Goran","family":"Petrovski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,5,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"108201","DOI":"10.1016\/j.exer.2020.108201","article-title":"Stromal cells cultivated from the choroid of human eyes display a mesenchymal stromal cell (MSC) phenotype and inhibit the proliferation of choroidal vascular endothelial cells in vitro","volume":"200","author":"Alexander","year":"2020","journal-title":"Exp. Eye Res."},{"key":"B2","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1136\/bmj.333.7559.128","article-title":"Cataract and surgery for cataract","volume":"333","author":"Allen","year":"2006","journal-title":"BMJ"},{"key":"B3","doi-asserted-by":"publisher","first-page":"887","DOI":"10.2174\/156652409789105598","article-title":"Effects of \u03b1-crystallin on lens cell function and cataract pathology","volume":"9","author":"Andley","year":"2009","journal-title":"Curr. Mol. Med."},{"key":"B4","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1016\/S0140-6736(05)17911-2","article-title":"Age-related cataract","volume":"365","author":"Asbell","year":"2005","journal-title":"Lancet"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1724","DOI":"10.1016\/j.bbadis.2016.06.012","article-title":"Osteogenic differentiation of human lens epithelial cells might contribute to lens calcification","volume":"1862","author":"Balogh","year":"2016","journal-title":"Biochim. Biophys. Acta - Mol. Basis Dis."},{"key":"B6","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1042\/BJ20120813","article-title":"Lens and retina regeneration: New perspectives from model organisms","volume":"447","author":"Barbosa-Sabanero","year":"2012","journal-title":"Biochem. J."},{"key":"B7","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1159\/000456720","article-title":"Validation of the nuclear cataract grading system BCN 10","volume":"57","author":"Barraquer","year":"2017","journal-title":"Ophthalmic Res."},{"key":"B8","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1159\/000316481","article-title":"Oxidative damage and the prevention of age-related cataracts","volume":"44","author":"Beebe","year":"2010","journal-title":"Ophthalmic Res."},{"key":"B9","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/0040-8166(86)90009-1","article-title":"Macromolecular organization of bovine lens capsule","volume":"18","author":"Cammarata","year":"1986","journal-title":"Tissue Cell"},{"key":"B10","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1111\/j.1365-2818.2005.01491.x","article-title":"Calcification of senile cataractous lens determined by Fourier transform infrared (FTIR) and Raman microspectroscopies","volume":"219","author":"Chen","year":"2005","journal-title":"J. Microsc."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1586","DOI":"10.1016\/j.jcrs.2003.11.036","article-title":"Calcified cataractous lens","volume":"30","author":"Chiang","year":"2004","journal-title":"J. Cataract. Refract. Surg."},{"key":"B12","doi-asserted-by":"publisher","first-page":"831","DOI":"10.1001\/archopht.1993.01090060119035","article-title":"The lens Opacities classification system III","volume":"111","author":"Chylack","year":"1993","journal-title":"Arch. Ophthalmol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"860","DOI":"10.3390\/pharmaceutics13060860","article-title":"Factors affecting posterior capsule opacification in the development of intraocular lens materials","volume":"13","author":"Cooksley","year":"2021","journal-title":"Pharmaceutics"},{"key":"B15","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1667\/RR1398.1","article-title":"Dietary supplements reduce the cataractogenic potential of proton and HZE-particle radiation in mice","volume":"173","author":"Davis","year":"2010","journal-title":"Radiat. Res."},{"key":"B16","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1001\/archophthalmol.2009.65","article-title":"Stem cells as tools in regenerative therapy for retinal degeneration","volume":"127","author":"Enzmann","year":"2009","journal-title":"Arch. Ophthalmol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"965","DOI":"10.1016\/0014-4835(86)90074-6","article-title":"Human and experimental lens repair and calcification","volume":"43","author":"Fagerholm","year":"1986","journal-title":"Exp. Eye Res."},{"key":"B18","first-page":"207","article-title":"The postnatal growth of the capsule of the human crystalline lens","volume":"112","author":"Fisher","year":"1972","journal-title":"J. Anat."},{"key":"B19","doi-asserted-by":"publisher","first-page":"790","DOI":"10.1111\/j.1755-3768.1975.tb01195.x","article-title":"Cataracta ossea and other intraocular ossifications: A case report and a thirty\u2010year Danish material","volume":"53","author":"Fledelius","year":"1975","journal-title":"Acta Ophthalmol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1492","DOI":"10.1016\/j.ophtha.2018.04.013","article-title":"Global prevalence of presbyopia and vision impairment from uncorrected presbyopia","volume":"125","author":"Fricke","year":"2018","journal-title":"Ophthalmology"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1097\/00004397-200104000-00003","article-title":"Aging of the human crystalline lens and presbyopia","volume":"41","author":"Glasser","year":"2001","journal-title":"Int. Ophthalmol. Clin."},{"key":"B22","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1080\/09273948.2016.1203161","article-title":"Osseous metaplasia (cataracta ossea) of lens remnants in chronic uveitis\u2014a clinicopathologic report","volume":"26","author":"Hadayer","year":"2018","journal-title":"Ocul. Immunol. Inflamm."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1208","DOI":"10.1002\/ajmg.1320470816","article-title":"Genetic etiology of nuclear cataract: Evidence for a major gene","volume":"47","author":"Heiba","year":"1993","journal-title":"Am. J. Med. Genet."},{"key":"B24","first-page":"119","article-title":"Overview of the lens","volume-title":"Progress in molecular biology and translational science","author":"Hejtmancik","year":"2015"},{"key":"B25","doi-asserted-by":"publisher","first-page":"652","DOI":"10.1016\/S0886-3350(99)00009-7","article-title":"Degeneration and transdifferentiation of human lens epithelial cells in nuclear and anterior polar cataracts","volume":"25","author":"Joo","year":"1999","journal-title":"J. Cataract. Refract. Surg."},{"key":"B26","doi-asserted-by":"publisher","first-page":"90","DOI":"10.3341\/kjo.2007.21.2.90","article-title":"Analysis of aqueous humor calcium and phosphate from cataract eyes with and without diabetes mellitus","volume":"21","author":"Kim","year":"2007","journal-title":"Korean J. Ophthalmol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1016\/j.aanat.2009.08.003","article-title":"Cataracta ossea \u2013 ultrastructural and specimen analysis","volume":"191","author":"Koinzer","year":"2009","journal-title":"Ann. Anat. - Anat. Anz."},{"key":"B28","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1038\/scientificamerican0788-92","article-title":"How the human eye focuses","volume":"259","author":"Koretz","year":"1988","journal-title":"Sci. Am."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fonc.2022.818182","article-title":"Pigment epithelium derived factor is involved in the late phase of osteosarcoma metastasis by increasing extravasation and cell-cell adhesion","volume":"12","author":"Kuriyama","year":"2022","journal-title":"Front. Oncol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1007\/BF02405093","article-title":"Calcergy and calciphylaxis: Timed appearance of \u03b3-carboxyglutamic acid and osteocalcin in mineral deposits","volume":"35","author":"Lian","year":"1983","journal-title":"Calcif. Tissue Int."},{"key":"B31","doi-asserted-by":"publisher","first-page":"3142","DOI":"10.3390\/nu12103142","article-title":"Vitamin C and the lens: New insights into delaying the onset of cataract","volume":"12","author":"Lim","year":"2020","journal-title":"Nutrients"},{"key":"B32","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1038\/nature17181","article-title":"Lens regeneration using endogenous stem cells with gain of visual function","volume":"531","author":"Lin","year":"2016","journal-title":"Nature"},{"key":"B33","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1016\/j.saa.2010.07.012","article-title":"Spectral analysis and comparison of mineral deposits forming in opacified intraocular lens and senile cataractous lens","volume":"77","author":"Lin","year":"2010","journal-title":"Spectrochim. Acta Part A Mol. Biomol. Spectrosc."},{"key":"B34","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1007\/s12020-014-0401-0","article-title":"A four-season molecule: Osteocalcin. Updates in its physiological roles","volume":"48","author":"Lombardi","year":"2015","journal-title":"Endocrine"},{"key":"B35","doi-asserted-by":"publisher","first-page":"3503","DOI":"10.3390\/jcm9113503","article-title":"A simple pre-operative nuclear classification score (SPONCS) for grading cataract hardness in clinical studies","volume":"9","author":"Mandelblum","year":"2020","journal-title":"J. Clin. Med."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1278","DOI":"10.1098\/rstb.2010.0300","article-title":"The ageing lens and cataract: A model of normal and pathological ageing","volume":"366","author":"Michael","year":"2011","journal-title":"Philos. Trans. R. Soc. B Biol. Sci."},{"key":"B37","doi-asserted-by":"publisher","first-page":"10376","DOI":"10.3390\/ijerph191610376","article-title":"Levels of trace elements in the lens, aqueous humour, and plasma of cataractous patients\u2014a narrative review","volume":"19","author":"Micun","year":"2022","journal-title":"Int. J. Environ. Res. Public Health"},{"key":"B38","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1016\/j.aanat.2009.08.003","article-title":"Ossification of the choroid: Three clinical cases and literature review of the pathogenesis of intraocular ossification","volume":"54","author":"Munteanu","year":"2013","journal-title":"Rom. J. Morphol. Embryol."},{"key":"B39","first-page":"1168","article-title":"Expression of pigment epithelium-derived factor in normal adult rat eye and experimental choroidal neovascularization","volume":"43","author":"Ogata","year":"2002","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"B40","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1111\/j.1432-0436.1984.tb00266.x","article-title":"Localisation of laminin and fibronectin during rat lens morphogenesis","volume":"28","author":"Parmigiani","year":"1984","journal-title":"Differentiation"},{"key":"B41","doi-asserted-by":"publisher","first-page":"102537","DOI":"10.1016\/j.jbc.2022.102537","article-title":"Insights into the biochemical and biophysical mechanisms mediating the longevity of the transparent optics of the eye lens","volume":"298","author":"Quinlan","year":"2022","journal-title":"J. Biol. Chem."},{"key":"B42","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1006\/exer.1997.0434","article-title":"Immunolocalization of prolyl 4-hydroxylase subunits, \u03b1-smooth muscle actin, and extracellular matrix components in human lens capsules with lens implants","volume":"66","author":"Saika","year":"1998","journal-title":"Exp. Eye Res."},{"key":"B43","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/j.exer.2004.03.003","article-title":"Accumulation of thrombospondin-1 in post-operative capsular fibrosis and its down-regulation in lens cells during lens fiber formation","volume":"79","author":"Saika","year":"2004","journal-title":"Exp. Eye Res."},{"key":"B44","doi-asserted-by":"publisher","first-page":"2094","DOI":"10.1167\/iovs.02-1059","article-title":"Response of lens epithelial cells to injury: Role of lumican in epithelial-mesenchymal transition","volume":"44","author":"Saika","year":"2003","journal-title":"Investig. Opthalmology Vis. Sci."},{"key":"B45","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1159\/000267064","article-title":"Classification system for cataracts","volume":"22","author":"Sasaki","year":"1990","journal-title":"Ophthalmic Res."},{"key":"B46","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1055\/s-2008-1046446","volume":"195","author":"Schnaudigel","year":"1989","journal-title":"Intraokul. Knochenbildung."},{"key":"B47","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1038\/sj.eye.6701423","article-title":"Downregulation of gene expression in the ageing lens: A possible contributory factor in senile cataract","volume":"19","author":"Segev","year":"2005","journal-title":"Eye"},{"key":"B48","doi-asserted-by":"publisher","first-page":"e3709","DOI":"10.1371\/journal.pone.0003709","article-title":"Human sclera maintains common characteristics with cartilage throughout evolution","volume":"3","author":"Seko","year":"2008","journal-title":"PLoS One"},{"key":"B49","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1080\/019131201753136287","article-title":"Opacification of artificial intraocular lens: An electron microscopic study","volume":"25","author":"Shek","year":"2001","journal-title":"Ultrastruct. Pathol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/0039-6257(88)90069-0","article-title":"Choroidal osteoma","volume":"33","author":"Shields","year":"1988","journal-title":"Surv. Ophthalmol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"260","DOI":"10.3390\/cells7120260","article-title":"Stem cells derived from lipoma and adipose tissue\u2014similar mesenchymal phenotype but different differentiation capacity governed by distinct molecular signature","volume":"7","author":"Stojanovi\u0107","year":"2018","journal-title":"Cells"},{"key":"B52","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1076\/opep.9.2.83.1523","article-title":"A simplified cataract grading system","volume":"9","author":"Thylefors","year":"2002","journal-title":"Ophthalmic Epidemiol."},{"key":"B53","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1016\/j.bbagen.2015.08.016","article-title":"The etiology of human age-related cataract. Proteins don\u2019t last forever","volume":"1860","author":"Truscott","year":"2016","journal-title":"Biochim. Biophys. Acta - Gen. Subj."},{"key":"B54","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1161\/01.ATV.0000059406.92165.31","article-title":"Osteo\/chondrocytic transcription factors and their target genes exhibit distinct patterns of expression in human arterial calcification","volume":"23","author":"Tyson","year":"2003","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"B55","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1111\/cxo.12922","article-title":"Pigment epithelial\u2010derived factor in the lens anterior capsule of patients with senile cataract with pseudoexfoliation","volume":"103","author":"Utlu","year":"2020","journal-title":"Clin. Exp. Optom."},{"key":"B56","first-page":"183","article-title":"Intraocular osseous metaplasia. A clinico-pathological study","volume":"50","author":"Vemuganti","year":"2002","journal-title":"Indian J. Ophthalmol."},{"key":"B57","doi-asserted-by":"publisher","first-page":"536","DOI":"10.1046\/j.1432-1327.2001.01885.x","article-title":"UV-A-related alterations of young and adult lens water-insoluble \u03b1-crystallin, plasma membranous and cytoskeletal proteins","volume":"268","author":"Weinreb","year":"2001","journal-title":"Eur. J. Biochem."},{"key":"B58","article-title":"Blindness and vision impairment: WHO factsheet","volume-title":"World heal. Organ","year":"2022"},{"key":"B59","first-page":"138","article-title":"Chondrogenesis in scleral stem\/progenitor cells and its association with form-deprived myopia in mice","volume":"21","author":"Wu","year":"2015","journal-title":"Mol. Vis."},{"key":"B60","doi-asserted-by":"publisher","first-page":"28564","DOI":"10.1038\/srep28564","article-title":"Prevalence and epidemiological characteristics of congenital cataract: A systematic review and meta-analysis","volume":"6","author":"Wu","year":"2016","journal-title":"Sci. Rep."},{"key":"B61","first-page":"105","article-title":"Down regulation of the PEDF gene in human lens epithelium cells changed the expression of proteins vimentin and alphaB-crystallin","volume":"16","author":"Yang","year":"2010","journal-title":"Mol. Vis."},{"key":"B62","doi-asserted-by":"publisher","first-page":"971","DOI":"10.1016\/j.apjtm.2015.10.009","article-title":"Mechanism of PEDF promoting the proliferation of lens epithelial cells in human eyes","volume":"8","author":"Yang","year":"2015","journal-title":"Asian pac. J. Trop. Med."},{"key":"B63","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1111\/j.1442-9071.2004.00869.x","article-title":"Calcification of intraocular hydrogel lens: Evidence of dystrophic calcification","volume":"32","author":"Yong","year":"2004","journal-title":"Clin. Exp. Ophthalmol."},{"key":"B64","doi-asserted-by":"publisher","first-page":"734","DOI":"10.1111\/1440-1681.12366","article-title":"Correlation between osteocalcin-positive endothelial progenitor cells and spotty calcification in patients with coronary artery disease","volume":"42","author":"Zhang","year":"2015","journal-title":"Clin. Exp. Pharmacol. Physiol."}],"container-title":["Frontiers in Bioengineering and Biotechnology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fbioe.2023.1164795\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,31]],"date-time":"2023-05-31T05:25:02Z","timestamp":1685510702000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fbioe.2023.1164795\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,31]]},"references-count":63,"alternative-id":["10.3389\/fbioe.2023.1164795"],"URL":"https:\/\/doi.org\/10.3389\/fbioe.2023.1164795","relation":{},"ISSN":["2296-4185"],"issn-type":[{"value":"2296-4185","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,31]]},"article-number":"1164795"}}