Activation of limbal epithelial proliferation is partly controlled by the ACE2-LCN2 pathway

Huimin Jiang; Min Liu; Wending Yang; Yi Kai Hong; Dan Xu; Elif Kayaalp Nalbant; Elwin D. Clutter; Parisa Foroozandeh; Nihal Kaplan; Jan Wysocki; Daniel Batlle; Stephen D. Miller; Kurt Lu; Han Peng

doi:10.1016/j.isci.2024.110534

Activation of limbal epithelial proliferation is partly controlled by the ACE2-LCN2 pathway

Huimin Jiang, Min Liu, Wending Yang, Yi Kai Hong, Dan Xu, Elif Kayaalp Nalbant, Elwin D. Clutter, Parisa Foroozandeh, Nihal Kaplan, Jan Wysocki, Daniel Batlle, Stephen D. Miller, Kurt Lu, Han Peng^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

In response to corneal injury, an activation of corneal epithelial stem cells and their direct progeny the early transit amplifying (eTA) cells to rapidly proliferate is critical for proper re-epithelialization. Thus, it is important to understand how such stem/eTA cell activation is regulated. Angiotensin-converting enzyme 2 (ACE2) is predominantly expressed in the stem/eTA-enriched limbal epithelium but its role in the limbal epithelium was unclear. Single cell RNA sequencing (scRNA-seq) suggested that Ace2 involved the proliferation of the stem/eTA cells. Ace2 was reduced following corneal injury. Such reduction enhanced limbal epithelial proliferation and downregulated LCN2, a negative regulator of proliferation in a variety of tissues, via upregulating TGFA and consequently activating epidermal growth factor receptor (EGFR). Inhibition of EGFR or overexpression of LCN2 reversed the increased proliferation in limbal epithelial cells lacking ACE2. Our findings demonstrate that after corneal injury, ACE2 is downregulated, which activates limbal epithelial cell proliferation via a TGFA/EGFR/LCN2 pathway.

Original language	English (US)
Article number	110534
Journal	iScience
Volume	27
Issue number	8
DOIs	https://doi.org/10.1016/j.isci.2024.110534
State	Published - Aug 16 2024

Funding

This study was supported by EY032922 and EY028560 (to H.P.). The NU-SBDRC Skin Tissue Engineering and Morphology Core facility assisted in morphologic analysis and GET In core helped in lentiviral vector packaging. The NU-SBDRC is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases grant AR075049 . Imaging was performed at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center . The Northwestern University NUSeq Core Facility assisted in single cell RNA sequencing, which is supported by NIH grant 1S10OD025120 for the 10x Chromium housed in the NUSeq Facility . D Batlle and J Wysocki are coinventors of patents entitled \u201CActive Low Molecular Weight Variants of ACE2,\u201D and \u201CSoluble ACE2 Variants and Uses therefor.\u201D D Batlle is founder of Angiotensin Therapeutics Inc. D Batlle has received consulting fees from Advicenne unrelated to this work and received unrelated research support from a grant from AstraZeneca; J Wysocki reports scientific advisor capacity for Angiotensin Therapeutics Inc. All other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Keywords

Functional aspects of cell biology
Molecular medicine
Stem cells research

ASJC Scopus subject areas

General

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10.1016/j.isci.2024.110534

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title = "Activation of limbal epithelial proliferation is partly controlled by the ACE2-LCN2 pathway",

abstract = "In response to corneal injury, an activation of corneal epithelial stem cells and their direct progeny the early transit amplifying (eTA) cells to rapidly proliferate is critical for proper re-epithelialization. Thus, it is important to understand how such stem/eTA cell activation is regulated. Angiotensin-converting enzyme 2 (ACE2) is predominantly expressed in the stem/eTA-enriched limbal epithelium but its role in the limbal epithelium was unclear. Single cell RNA sequencing (scRNA-seq) suggested that Ace2 involved the proliferation of the stem/eTA cells. Ace2 was reduced following corneal injury. Such reduction enhanced limbal epithelial proliferation and downregulated LCN2, a negative regulator of proliferation in a variety of tissues, via upregulating TGFA and consequently activating epidermal growth factor receptor (EGFR). Inhibition of EGFR or overexpression of LCN2 reversed the increased proliferation in limbal epithelial cells lacking ACE2. Our findings demonstrate that after corneal injury, ACE2 is downregulated, which activates limbal epithelial cell proliferation via a TGFA/EGFR/LCN2 pathway.",

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doi = "10.1016/j.isci.2024.110534",

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AU - Xu, Dan

AU - Nalbant, Elif Kayaalp

AU - Clutter, Elwin D.

AU - Foroozandeh, Parisa

AU - Kaplan, Nihal

AU - Wysocki, Jan

AU - Batlle, Daniel

AU - Miller, Stephen D.

AU - Lu, Kurt

AU - Peng, Han

PY - 2024/8/16

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N2 - In response to corneal injury, an activation of corneal epithelial stem cells and their direct progeny the early transit amplifying (eTA) cells to rapidly proliferate is critical for proper re-epithelialization. Thus, it is important to understand how such stem/eTA cell activation is regulated. Angiotensin-converting enzyme 2 (ACE2) is predominantly expressed in the stem/eTA-enriched limbal epithelium but its role in the limbal epithelium was unclear. Single cell RNA sequencing (scRNA-seq) suggested that Ace2 involved the proliferation of the stem/eTA cells. Ace2 was reduced following corneal injury. Such reduction enhanced limbal epithelial proliferation and downregulated LCN2, a negative regulator of proliferation in a variety of tissues, via upregulating TGFA and consequently activating epidermal growth factor receptor (EGFR). Inhibition of EGFR or overexpression of LCN2 reversed the increased proliferation in limbal epithelial cells lacking ACE2. Our findings demonstrate that after corneal injury, ACE2 is downregulated, which activates limbal epithelial cell proliferation via a TGFA/EGFR/LCN2 pathway.

AB - In response to corneal injury, an activation of corneal epithelial stem cells and their direct progeny the early transit amplifying (eTA) cells to rapidly proliferate is critical for proper re-epithelialization. Thus, it is important to understand how such stem/eTA cell activation is regulated. Angiotensin-converting enzyme 2 (ACE2) is predominantly expressed in the stem/eTA-enriched limbal epithelium but its role in the limbal epithelium was unclear. Single cell RNA sequencing (scRNA-seq) suggested that Ace2 involved the proliferation of the stem/eTA cells. Ace2 was reduced following corneal injury. Such reduction enhanced limbal epithelial proliferation and downregulated LCN2, a negative regulator of proliferation in a variety of tissues, via upregulating TGFA and consequently activating epidermal growth factor receptor (EGFR). Inhibition of EGFR or overexpression of LCN2 reversed the increased proliferation in limbal epithelial cells lacking ACE2. Our findings demonstrate that after corneal injury, ACE2 is downregulated, which activates limbal epithelial cell proliferation via a TGFA/EGFR/LCN2 pathway.

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Activation of limbal epithelial proliferation is partly controlled by the ACE2-LCN2 pathway

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