@article{367a36cf672a4e6583853a54cfe6d4fd,
title = "Dry eye disease in mice activates adaptive corneal epithelial regeneration distinct from constitutive renewal in homeostasis",
abstract = "Many epithelial compartments undergo constitutive renewal in homeostasis but activate unique regenerative responses following injury. The clear corneal epithelium is crucial for vision and is renewed from limbal stem cells (LSCs). Using single-cell RNA sequencing, we profiled the mouse corneal epithelium in homeostasis, aging, diabetes, and dry eye disease (DED), where tear deficiency predisposes the cornea to recurrent injury. In homeostasis, we capture the transcriptional states that accomplish continuous tissue turnover. We leverage our dataset to identify candidate genes and gene networks that characterize key stages across homeostatic renewal, including markers for LSCs. In aging and diabetes, there were only mild changes with <15 dysregulated genes. The constitutive cell types that accomplish homeostatic renewal were conserved in DED but were associated with activation of cell states that comprise “adaptive regeneration.” We provide global markers that distinguish cell types in homeostatic renewal vs. adaptive regeneration and markers that specifically define DED-elicited proliferating and differentiating cell types. We validate that expression of SPARC, a marker of adaptive regeneration, is also induced in corneal epithelial wound healing and accelerates wound closure in a corneal epithelial cell scratch assay. Finally, we propose a classification system for LSC markers based on their expression fidelity in homeostasis and disease. This transcriptional dissection uncovers the dramatically altered transcriptional landscape of the corneal epithelium in DED, providing a framework and atlas for future study of these ocular surface stem cells in health and disease.",
keywords = "cornea, dry eye, epithelium, limbal, stem cell",
author = "Lin, {Joseph B.} and Xiaolei Shen and Pfeifer, {Charles W.} and Fion Shiau and Andrea Santeford and Ruzycki, {Philip A.} and Clark, {Brian S.} and Huang, {Andrew J.W.} and Apte, {Rajendra S.} and Qin Liu",
note = "Funding Information: This work was supported by the NIH grants R01 EY019287 (R.S.A.), R00 EY027844 (B.S.C.), R01 EY024704 (Q.L.), and P30 EY02687 (Vision Core Grant); Jeffery T. Fort Innovation Fund (R.S.A.); Centene Corporation contract (P19-00559) for the Washington University-Centene ARCH Personalized Medicine Initiative; Siteman Research Fund; and an unrestricted grant from the Research to Prevent Blindness to the John F. Hardesty, MD Department of Ophthalmology and Visual Sciences at the Washington University School of Medicine in St. Louis. J.B.L. was supported by the NIH grant F30 DK130282 and the Washington University in St. Louis Medical Scientist Training Program (NIH grant T32 GM07200). We also thank Washington University{\textquoteright}s Genome Technology Access Center for help with scRNAseq studies, the Morphology & Imaging Core for assistance with paraffin sectioning and staining (Washington University Department of Ophthalmology & Visual Sciences), and Dr. Todd Margolis and Nicolas Ledru for helpful discussions. Funding Information: ACKNOWLEDGMENTS. This work was supported by the NIH grants R01 EY019287 (R.S.A.), R00 EY027844 (B.S.C.), R01 EY024704 (Q.L.), and P30 EY02687 (Vision Core Grant); Jeffery T. Fort Innovation Fund (R.S.A.); Centene Corporation contract (P19-00559) for the Washington University-Centene ARCH Personalized Medicine Initiative; Siteman Research Fund; and an unrestricted grant from the Research to Prevent Blindness to the John F. Hardesty, MD Department of Ophthalmology and Visual Sciences at the Washington University School of Medicine in St. Louis. J.B.L. was supported by the NIH grant F30 DK130282 and the Washington University in St. Louis Medical Scientist Training Program (NIH grant T32 GM07200). We also thank Washington University{\textquoteright}s Genome Technology Access Center for help with scRNAseq studies, the Morphology & Imaging Core for assistance with paraffin sectioning and staining (Washington University Department of Ophthalmology & Visual Sciences), and Dr. Todd Margolis and Nicolas Ledru for helpful discussions. Publisher Copyright: Copyright {\textcopyright} 2023 the Author(s).",
year = "2023",
month = jan,
day = "10",
doi = "10.1073/pnas.2204134120",
language = "English",
volume = "120",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "2",
}