Identification of the Transcription Factor Sox9 as a Key Regulator of Limbal Stem Cell Fate and Corneal Epithelial Homeostasis

核心概念

Sox9 is a critical transcription factor that marks long-lived limbal stem cells and is required for the proper regulation of asymmetric cell fate decisions, which is essential to maintain corneal epithelial homeostasis.

摘要

The content explores the role of the transcription factor Sox9 in regulating the activity and fate of limbal stem cells (LSCs) and their progenitors in the corneal epithelium. Using single-cell transcriptomics and in vivo lineage tracing, the authors demonstrate that Sox9 is preferentially expressed in LSCs and is necessary for maintaining the balance between symmetric self-renewal and asymmetric differentiation of corneal progenitors.
Key highlights:

The authors utilized a cell cycle reporter mouse model to isolate and profile actively cycling basal cells across the corneal epithelium, revealing distinct progenitor cell identities.
Sox9 was identified as a key transcription factor that is highly expressed in LSCs compared to their transient amplifying progeny.
In vivo lineage tracing confirmed that Sox9 marks long-lived LSCs that maintain the corneal epithelium.
Conditional deletion of Sox9 from the corneal epithelium led to abnormal differentiation and squamous metaplasia, suggesting Sox9 is required to maintain corneal epithelial identity and homeostasis.
Mechanistically, the authors propose that Sox9 regulates the switch from symmetric to asymmetric cell fate decisions as LSC progeny exit the limbal niche, which is critical for proper tissue renewal and barrier function.
Suppressing differentiation of corneal progenitors phenocopied the loss of Sox9, leading to cellular crowding and plaque formation in the central cornea, further supporting the model.
Overall, the study identifies Sox9 as a key regulator of corneal epithelial stem cell fate and demonstrates its essential role in maintaining corneal homeostasis.

統計資料

The corneal epithelium exhibits a polarized lateral flow of progenitors from the peripheral stem cell niche to the center.
Sox9-high cells express all the typical limbal stem cell markers including Gpha2 and Krt15.
Compared to controls, Sox9-cKO corneas were thicker in the central cornea and limbal compartments.
In Sox9-cKO corneas that displayed severe thickening and plaque growth, Loricrin, a marker of epidermal differentiation, could be detected within the plaque growths.

引述

"Sox9 is a critical transcription factor that marks long-lived limbal stem cells and is required for the proper regulation of asymmetric cell fate decisions, which is essential to maintain corneal epithelial homeostasis."
"Conditional deletion of Sox9 from the corneal epithelium led to abnormal differentiation and squamous metaplasia, suggesting Sox9 is required to maintain corneal epithelial identity and homeostasis."
"Suppressing differentiation of corneal progenitors phenocopied the loss of Sox9, leading to cellular crowding and plaque formation in the central cornea, further supporting the model."

從以下內容提煉的關鍵洞見

Sox9 marks limbal stem cells and is required for asymmetric cell fate switch in the corneal epithelium

by Rice,G., Far... 於 www.biorxiv.org 04-11-2024

https://www.biorxiv.org/content/10.1101/2024.04.08.588195v2

深入探究

How might the stromal microenvironment contribute to the corneal-to-epidermal cell fate switch observed in the absence of Sox9?

The stromal microenvironment plays a crucial role in maintaining the homeostasis of the corneal epithelium. In the context of the corneal-to-epidermal cell fate switch observed in the absence of Sox9, the stromal microenvironment likely contributes to this phenomenon through various mechanisms:

Cell-Cell Communication: The stromal cells in the cornea communicate with the epithelial cells through paracrine signaling, providing cues that influence cell fate decisions. Disruption of Sox9 in the epithelial cells may alter the signaling pathways between the stroma and epithelium, leading to a shift in cell fate towards an epidermal-like phenotype.

Extracellular Matrix (ECM) Remodeling: The stromal microenvironment provides structural support to the corneal epithelium through the ECM. Changes in the composition or organization of the ECM in response to the loss of Sox9 could impact the behavior and fate of the epithelial cells, potentially promoting a switch to an epidermal cell fate.

Vascularization: Increased vascularization in the stroma, as seen in Notch1-deleted corneas, can alter the microenvironment and provide additional cues that influence cell fate decisions. The vascularization may introduce factors that promote epidermal differentiation over corneal differentiation.

Inflammatory Response: Disruption of Sox9 in the corneal epithelium may trigger an inflammatory response in the stromal microenvironment. Inflammatory mediators can modulate cell behavior and differentiation, potentially contributing to the observed cell fate switch.

Overall, the stromal microenvironment likely plays a multifaceted role in driving the corneal-to-epidermal cell fate switch in the absence of Sox9 by influencing signaling pathways, ECM remodeling, vascularization, and inflammatory responses.

How might the stromal microenvironment contribute to the corneal-to-epidermal cell fate switch observed in the absence of Sox9?

The balance between symmetric and asymmetric cell divisions in the corneal epithelium is regulated by a complex interplay of transcription factors and signaling pathways. In addition to Sox9, several other factors interact with Sox9 to maintain this balance:

Notch Signaling: Notch signaling is a key pathway involved in regulating cell fate decisions in various tissues, including the corneal epithelium. Notch signaling interacts with Sox9 to control the differentiation of corneal progenitor cells and maintain the stem cell pool. Disruption of Notch signaling can lead to aberrant cell fate decisions and altered homeostasis.

P63: P63 is another transcription factor that plays a crucial role in maintaining the proliferative capacity of epithelial stem cells. It interacts with Sox9 to regulate the balance between self-renewal and differentiation in the corneal epithelium. Dysregulation of P63 can impact the fate of corneal stem cells and progenitors.

Wnt/β-catenin Pathway: The Wnt/β-catenin pathway is involved in stem cell maintenance and differentiation in various tissues. It crosstalks with Sox9 to regulate cell fate decisions in the corneal epithelium. Modulation of the Wnt/β-catenin pathway can influence the balance between symmetric and asymmetric divisions.

KLF4: Krüppel-like factor 4 (KLF4) is a transcription factor that has been implicated in regulating cell fate in the corneal epithelium. It interacts with Sox9 to modulate the differentiation of corneal progenitors and maintain tissue homeostasis. Changes in KLF4 expression can impact the fate of corneal stem cells.

By understanding the intricate network of transcription factors and signaling pathways that interact with Sox9, we can gain insights into the regulatory mechanisms governing the balance between symmetric and asymmetric cell divisions in the corneal epithelium.

Could modulating Sox9 expression or activity be a potential therapeutic strategy for corneal diseases characterized by abnormal epithelial homeostasis, such as limbal stem cell deficiency?

Modulating Sox9 expression or activity holds promise as a potential therapeutic strategy for corneal diseases characterized by abnormal epithelial homeostasis, including limbal stem cell deficiency. Here are some reasons why targeting Sox9 could be beneficial:

Regulation of Stem Cell Activity: Sox9 is a key regulator of stem cell maintenance and differentiation in various tissues, including the corneal epithelium. Modulating Sox9 expression or activity can influence the behavior of limbal stem cells and their progeny, potentially restoring normal epithelial homeostasis.

Promotion of Asymmetric Cell Divisions: By targeting Sox9, it may be possible to promote the switch from symmetric to asymmetric cell divisions in the corneal epithelium. This could help in maintaining a balance between stem cell renewal and differentiation, crucial for tissue regeneration and repair.

Prevention of Squamous Metaplasia: Abnormal differentiation and squamous metaplasia, as observed in the absence of Sox9, can be detrimental to corneal health. Modulating Sox9 expression could prevent or reverse these pathological changes, restoring the normal corneal epithelial phenotype.

Enhanced Tissue Repair: By modulating Sox9, it may be possible to enhance the regenerative capacity of the corneal epithelium, particularly in cases of injury or disease. Sox9-targeted therapies could promote proper wound healing and tissue regeneration.

Overall, targeting Sox9 as a therapeutic strategy for corneal diseases offers a promising avenue for restoring normal epithelial homeostasis, promoting tissue repair, and preventing pathological changes associated with limbal stem cell deficiency. Further research and clinical studies are needed to explore the full potential of Sox9 modulation in the treatment of corneal disorders.