{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:08:56Z","timestamp":1792786136904,"version":"4.5.0"},"reference-count":28,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2023,8,26]],"date-time":"2023-08-26T00:00:00Z","timestamp":1693008000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"EJP-RD","award":["EJPRD20-135"],"award-info":[{"award-number":["EJPRD20-135"]}]},{"name":"AAK-INSIGHT"},{"name":"Agence Fran\u00e7aise contre les Myopathies","award":["AFM 24092"],"award-info":[{"award-number":["AFM 24092"]}]},{"DOI":"10.13039\/501100002341","name":"Academy of Finland","doi-asserted-by":"publisher","award":["338988"],"award-info":[{"award-number":["338988"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,12,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Congenital aniridia is caused by heterozygous mutations on the PAX6 gene leading to reduced amount of PAX6 protein (haploinsufficiency), abnormal eye development, and aniridia-associated keratopathy (AAK). This progressive corneal opacification resembles late-onset limbal stem cell (LSC) deficiency, leading to disrupted corneal epithelial renewal. The factors leading to AAK are not known and defects in native LSC differentiation and\/or features leading to ocular surface dysfunction like inflammation and loss of innervation could contribute to development of AAK. Here, we produced induced pluripotent stem cells (hiPSC) from 3 AAK patients and examined whether PAX6 haploinsufficiency affects LSC lineage commitment. During LSC differentiation, characterization of the AAK lines showed lowered PAX6 expression as compared to wild type (WT) controls and expression peak of PAX6 during early phase of differentiation was detected only in the WT hiPSC lines. Whether it reflects developmental regulation remains to be studied further. Nevertheless, the AAK-hiPSCs successfully differentiated toward LSC lineage, in line with the presence of LSCs in young patients before cell loss later in life. In addition, patient-specific LSCs showed similar wound healing capacity as WT cells. However, extensive batch-related variation in the LSC marker expression and wound healing efficacy was detected without clear correlation to AAK. As development and maintenance of corneal epithelium involves an interplay between LSCs and their environment, the AAK-hiPSCs generated here can be further used to study the crosstalk between LSCs and limbal niche including, eg, corneal immune cells, stroma cells, and neurons.<\/jats:p>","DOI":"10.1093\/stmcls\/sxad067","type":"journal-article","created":{"date-parts":[[2023,8,24]],"date-time":"2023-08-24T17:05:04Z","timestamp":1692896704000},"page":"1133-1141","source":"Crossref","is-referenced-by-count":7,"title":["Production and Limbal Lineage Commitment of Aniridia Patient-Derived Induced Pluripotent Stem Cells"],"prefix":"10.1093","volume":"41","author":[{"given":"Tanja","family":"Ilmarinen","sequence":"first","affiliation":[{"name":"BioMediTech, Faculty of Medicine and Health technology, Tampere University , Tampere , Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meri","family":"Vattulainen","sequence":"additional","affiliation":[{"name":"BioMediTech, Faculty of Medicine and Health technology, Tampere University , Tampere , Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeyalakshmi","family":"Kandhavelu","sequence":"additional","affiliation":[{"name":"BioMediTech, Faculty of Medicine and Health technology, Tampere University , Tampere , Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominique","family":"Bremond-Gignac","sequence":"additional","affiliation":[{"name":"Ophthalmology Department, Necker-Enfants Malades University Hospital , AP-HP, Paris , France"},{"name":"INSERM UMRS U1138, T17, Sorbonne Paris Cite\u0301 University, Centre des Cordeliers , Paris , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4019-5418","authenticated-orcid":false,"given":"Daniel","family":"Aberdam","sequence":"additional","affiliation":[{"name":"INSERM UMRS U1138, T17, Sorbonne Paris Cite\u0301 University, Centre des Cordeliers , Paris , France"},{"name":"Paris Cit\u00e9 University , Paris , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heli","family":"Skottman","sequence":"additional","affiliation":[{"name":"BioMediTech, Faculty of Medicine and Health technology, Tampere University , Tampere , Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,8,26]]},"reference":[{"key":"2023121511194866000_CIT0001","first-page":"1138","article-title":"Frequent chromosome aberrations revealed by molecular cytogenetic studies in patients with aniridia","volume-title":"Am J Hum Genet","author":"Crolla","year":"2002"},{"key":"2023121511194866000_CIT0002","first-page":"5978293","article-title":"Phenotypic variation in a four-generation family with aniridia carrying a novel PAX6 mutation","volume-title":"J Ophthalmol","author":"Wang","year":"2018"},{"key":"2023121511194866000_CIT0003","first-page":"e1198","article-title":"Nonsense suppression induced readthrough of a novel PAX6 mutation in patient-derived cells of congenital aniridia","volume-title":"Mol Genet Genomic Med","author":"Liu","year":"2020"},{"key":"2023121511194866000_CIT0004","first-page":"245","article-title":"Pathophysiology of aniridia-associated keratopathy: developmental aspects and unanswered questions","volume-title":"Ocul Surf","author":"Latta","year":"2021"},{"key":"2023121511194866000_CIT0005","first-page":"bjophthalmol","article-title":"Early ocular surface and tear film status in congenital aniridia indicates a supportive treatment window","volume-title":"Br J Ophthalmol","author":"Fries","year":"2022"},{"key":"2023121511194866000_CIT0006","first-page":"529","article-title":"Limbal epithelial crypts: a novel anatomical structure and a putative limbal stem cell niche","volume-title":"Br J Ophthalmol","author":"Dua","year":"2005"},{"key":"2023121511194866000_CIT0007","first-page":"1421","article-title":"Modeling of aniridia-related keratopathy by CRISPR\/Cas9 genome editing of human limbal epithelial cells and rescue by recombinant PAX6 protein","volume-title":"Stem Cells","author":"Roux","year":"2018"},{"key":"2023121511194866000_CIT0008","first-page":"163","article-title":"Stage-related central corneal epithelial transformation in congenital aniridia-associated keratopathy","volume-title":"Ocul Surf","author":"Lagali","year":"2018"},{"key":"2023121511194866000_CIT0009","first-page":"140","article-title":"The antipsychotropic drug duloxetine rescues PAX6 haploinsufficiency of mutant limbal stem cells through inhibition of the MEK\/ERK signaling pathway","volume-title":"Ocul Surf","author":"Dorot","year":"2022"},{"key":"2023121511194866000_CIT0010","first-page":"102184","article-title":"Generation of human iPSC line (UCLi013-A) from a patient with microphthalmia and aniridia, carrying a heterozygous missense mutation c.372C&gt;A p.(Asn124Lys) in PAX6","volume-title":"Stem Cell 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conditions","volume-title":"Cells","author":"Gr\u00f6nroos","year":"2021"},{"key":"2023121511194866000_CIT0018","first-page":"402","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2\u2212\u0394\u0394CT method","volume-title":"Methods","author":"Livak","year":"2001"},{"key":"2023121511194866000_CIT0019","first-page":"279","article-title":"A single cell atlas of human cornea that defines its development, limbal progenitor cells and their interactions with the immune cells","volume-title":"Ocul Surf","author":"Collin","year":"2021"},{"key":"2023121511194866000_CIT0020","first-page":"25","article-title":"Positive autoregulation of the transcription factor Pax6 in response to increased levels of either of its major isoforms, Pax6 or Pax6(5a), in cultured cells","volume-title":"BMC Dev Biol","author":"Pinson","year":"2006"},{"key":"2023121511194866000_CIT0021","first-page":"341","article-title":"Epigenetic variation between human induced 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