FoxC1 activates limbal epithelial stem cells following corneal epithelial debridement

Wending Yang; Sun Kyong Lee; Ordan J Lehmann; Zhijian Wu; Suja Hiriyanna; Anand Swaroop; Robert M Lavker; Han Peng; Tsutomu Kume

doi:10.1016/j.exer.2023.109599

FoxC1 activates limbal epithelial stem cells following corneal epithelial debridement

Exp Eye Res. 2023 Sep:234:109599. doi: 10.1016/j.exer.2023.109599. Epub 2023 Jul 22.

Authors

Wending Yang¹, Sun Kyong Lee², Ordan J Lehmann³, Zhijian Wu⁴, Suja Hiriyanna⁴, Anand Swaroop⁴, Robert M Lavker⁵, Han Peng⁶, Tsutomu Kume⁷

Affiliations

¹ Departments of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
² Departments of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
³ Department of Ophthalmology and Medical Genetics, University of Alberta, Edmonton, Alberta, T6G, 2H7, Canada.
⁴ Neurobiology Neurodegeneration& Repair Laboratory (N-NRL), National Eye Institute, NIH, Bethesda, MD, 20892, USA.
⁵ Departments of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA. Electronic address: r-lavker@northwestern.edu.
⁶ Departments of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA. Electronic address: han-peng@northwestern.edu.
⁷ Departments of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA. Electronic address: t-kume@northwestern.edu.

PMID: 37488009
PMCID: PMC10530263 (available on 2024-09-01)
DOI: 10.1016/j.exer.2023.109599

Abstract

Limbal epithelial stem cells are not only critical for corneal epithelial homeostasis but also have the capacity to change from a relatively quiescent mitotic phenotype to a rapidly proliferating cell in response to population depletion following corneal epithelial wounding. Pax6^+/- mice display many abnormalities including corneal vascularization and these aberrations are consistent with a limbal stem cell deficiency (LSCD) phenotype. FoxC1 has an inhibitory effect on corneal avascularity and a positive role in stem cell maintenance in many tissues. However, the role of FoxC1 in limbal epithelial stem cells remains unknown. To unravel FoxC1's role(s) in limbal epithelial stem cell homeostasis, we utilized an adeno-associated virus (AAV) vector to topically deliver human FOXC1 proteins into Pax6 ^+/- mouse limbal epithelium. Under unperturbed conditions, overexpression of FOXC1 in the limbal epithelium had little significant change in differentiation (PAI-2, Krt12) and proliferation (BrdU, Ki67). Conversely, such overexpression resulted in a marked increase in the expression of putative limbal epithelial stem cell markers, N-cadherin and Lrig1. After corneal injuries in Pax6 ^+/- mice, FOXC1 overexpression enhanced the behavior of limbal epithelial stem cells from quiescence to a highly proliferative status. Overall, the treatment of AAV8-FOXC1 may be beneficial to the function of limbal epithelial stem cells in the context of a deficiency of Pax6 function.

Keywords: Corneal wounding; FoxC1; Limbal stem cell deficiency; Pax6; Proliferation.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cornea
Corneal Diseases* / metabolism
Debridement
Epithelial Cells
Epithelium, Corneal* / metabolism
Humans
Limbus Corneae* / metabolism
Mice
Stem Cells

Substances

FOXC1 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding