Keratin-14-Positive Precursor Cells Spawn a Population of Migratory Corneal Epithelia that Maintain Tissue Mass throughout Life

• Published in: Stem cell reports Vol. 9; no. 4; pp. 1081 - 1096
• Main Authors: Richardson, Alexander, Lobo, Erwin P., Delic, Naomi C., Myerscough, Mary R., Lyons, J. Guy, Wakefield, Denis, Di Girolamo, Nick
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10-10-2017; Elsevier
• Subjects: Aging - genetics; Animals; Apoptosis - genetics; Cell Differentiation; Cell Lineage; Cell Movement; Confetti mouse; cornea; development; epithelium; Epithelium, Corneal - anatomy & histology; Epithelium, Corneal - cytology; Epithelium, Corneal - embryology; Keratin-14 - genetics; Keratin-14 - metabolism; limbus; lineage tracing; Mice; Mice, Transgenic; Microscopy, Fluorescence; Molecular Imaging; Organ Size; Organogenesis - genetics; stem cell; Stem Cells - cytology; Stem Cells - metabolism; development; stem cell; cornea; limbus; epithelium; lineage tracing; Confetti mouse
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2017.08.015

The dynamics of epithelial stem cells (SCs) that contribute to the formation and maintenance of the cornea are poorly understood. Here, we used K14CreERT2-Confetti (Confetti) mice, sophisticated imaging, and computational modeling to trace the origins and fate of these cells during embryogenesis and adult life. We show that keratin-14 (K14+)-expressing progenitors are defined and widely distributed across the E16.5 cornea, after which they undergo cycles of proliferation and dispersal prior to eyelid opening. K14+ clonal patches disappear from the central cornea and are replaced by limbal-derived K14+ streaks, a finding that aligned with bromodeoxyuridine label-retaining studies. We also elucidated the mechanism by which SC clones are lost during life and propose this is due to population asymmetry and neutral drift. Finally, we established that the occurrence of an equatorial migratory mid-line is a consequence of apoptosis in a narrow nasal-temporal region, the site where eyelids meet during blinking.
•Embryonic K14+-progenitor-derived clonal expansion is biphasic•Limbal, not central, epithelial stem cells replenish the corneal epithelium•Age-related LESC dynamics are consistent with population asymmetric neutral drift•Normal clonal migration patterns are altered by central corneal apoptosis
Richardson et al. demonstrate the biphasic nature of corneal epithelial development during late embryogenesis. Progenitor cells of the central cornea are lost during post-natal life, replaced by those in the peripheral limbus, whose age-related dynamics align with population asymmetry. Apoptosis within the central corneal epithelium alters normal clonal migration patterns.