{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"Research Square"}],"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T13:23:00Z","timestamp":1788182580786,"version":"build-2803163510"},"posted":{"date-parts":[[2026,6,24]]},"group-title":"In Review","reference-count":45,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T00:00:00Z","timestamp":1782259200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,6]]},"abstract":"<title>Abstract<\/title>\n                <p>\n                  The corneal and conjunctival epithelia have traditionally been regarded as distinct lineages separated by the limbus, a specialized niche proposed to enforce irreversible corneal identity through a hierarchically organized limbal stem cell compartment\n                  <sup>1\u20133<\/sup>\n                  . In this prevailing model, conjunctivalization of the cornea reflects failure of a lineage barrier. Here, we show that the adult human limbus does not function as a rigid boundary but rather as an instructive epithelial transition zone. Integrated single-cell transcriptomics, spatial mapping, and clonal functional analysis demonstrate that limbal basal progenitors are transcriptionally aligned with conjunctival basal cells and are intrinsically bipotent, capable of generating either conjunctival or corneal epithelium. Spatial profiling redefines the functional conjunctival-corneal boundary at the inner edge of the limbus and reveals a sharp transition between conjunctival-type and corneal-type basal programs. Mechanistically, we identify keratinocyte growth factor (KGF) derived from limbal fibroblasts as a niche signal that instructs corneal fate through enhanced PAX6 protein abundance and FGFR2-dependent activation of MYC, thereby coupling lineage specification with proliferative expansion. In contrast, epidermal growth factor (EGF) sustains conjunctival identity, establishing growth factor balance as a molecular switch governing epithelial fate at this interface. These findings redefine the human limbus as a dynamic fate-determining niche and demonstrate that epithelial identity in adult human tissue remains instructable.\n                <\/p>","DOI":"10.21203\/rs.3.rs-9948733\/v1","type":"posted-content","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T06:38:02Z","timestamp":1782283082000},"source":"Crossref","is-referenced-by-count":0,"title":["The human limbus functions as an instructive epithelial transition zone"],"prefix":"10.21203","author":[{"given":"Yuzuru","family":"Sasamoto","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, University of Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiko","family":"Fukuda","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Boston University Chobanian & Avedisian School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Lee","sequence":"additional","affiliation":[{"name":"Brigham and Women's Hospital"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8216-6164","authenticated-orcid":false,"given":"Shuoshuo","family":"Wang","sequence":"additional","affiliation":[{"name":"Beth Israel Deaconess Medical Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheethal","family":"Umesh","sequence":"additional","affiliation":[{"name":"Spatial Transcriptomics Unit, Beth Israel Deaconess Medical Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinri","family":"Sato","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2583-2338","authenticated-orcid":false,"given":"Kosei","family":"Suzuki","sequence":"additional","affiliation":[{"name":"University of Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoko","family":"Kiritoshi","sequence":"additional","affiliation":[{"name":"Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8849-808X","authenticated-orcid":false,"given":"Ioannis","family":"Vlachos","sequence":"additional","affiliation":[{"name":"Cancer Research Institute \/ Harvard Medical School Initiative for RNA Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nick Di","family":"Girolamo","sequence":"additional","affiliation":[{"name":"University of New South Wales"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1312-0488","authenticated-orcid":false,"given":"Markus","family":"Frank","sequence":"additional","affiliation":[{"name":"Transplant Research Program, Boston Children's Hospital, Harvard Medical School"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8196-0449","authenticated-orcid":false,"given":"Natasha","family":"Frank","sequence":"additional","affiliation":[{"name":"Brigham and Women's Hospital"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1038\/nature13426","article-title":"ABCB5 is a limbal stem cell gene required for corneal development and repair","volume":"511","author":"Ksander BR","year":"2014","unstructured":"Ksander BR et al (2014) ABCB5 is a limbal stem cell gene required for corneal development and repair. 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