Barnes Laurent, Konstantinou Evangelia, Saurat Jean-Hilaire, Moulin Alexandre, Kaya Gürkan
Department of Dermatology, University Hospital of Geneva, CH-1205 Geneva, Switzerland.
Department of Medicine, University of Geneva, CH-1206 Geneva, Switzerland.
Int J Mol Sci. 2025 Jul 2;26(13):6383. doi: 10.3390/ijms26136383.
We previously showed that selective suppression of CD44 in the corneal epithelium leads to structural abnormalities in the mouse cornea. Our comparative studies of young and aged ocular biopsies revealed that CD44 expression is downregulated in aged corneas, while leucine-rich repeats and immunoglobulin-like domain 1 (Lrig1+) stem cells remain preserved in the peripheral limbus. These findings suggest an age-related shift in the corneal stem cell compartmentalization, characterized by impaired CD44 expression in the central cornea and preservation of Lrig1+ stem cells in the limbus, which become the main stem cells in the senescent cornea. To investigate this further, we performed topical tamoxifen-inducible, diphtheria toxin-mediated ablation of Lrig1+ stem cells in mouse corneas. We then assessed both activated and non-activated beta-catenin expression in wild-type (WT) and CD44 knockout (CD44KO) mice, given that CD44 modulates the Wingless-related integration site (Wnt) pathway. Our results indicate that two distinct stem cell populations operate in the mouse cornea: Lrig1-derived stem cells and Wnt-activity/CD44-dependent stem cells. The Lrig1-derived cells act as a reservoir of quiescent stem cells that regenerate the cornea upon injury, whereas under homeostatic conditions, the Wnt-activity/CD44-dependent stem cells are primarily responsible for corneal renewal. In the aged cornea, the loss of CD44 expression leads to reduced Wnt signaling, making the tissue increasingly dependent on Lrig1+ stem cells for regeneration. In mice, Lrig1+ stem cells are capable of sustaining permanent corneal renewal, even in the absence of CD44.
我们之前发现，选择性抑制角膜上皮中的CD44会导致小鼠角膜出现结构异常。我们对年轻和老年眼部活检组织的比较研究表明，老年角膜中CD44表达下调，而富含亮氨酸重复序列和免疫球蛋白样结构域1（Lrig1+）的干细胞在外周角膜缘得以保留。这些发现表明角膜干细胞区室化存在与年龄相关的转变，其特征为中央角膜中CD44表达受损，而角膜缘中Lrig1+干细胞得以保留，后者成为衰老角膜中的主要干细胞。为进一步研究这一现象，我们对小鼠角膜进行了局部他莫昔芬诱导、白喉毒素介导的Lrig1+干细胞消融。鉴于CD44调节无翅相关整合位点（Wnt）信号通路，我们随后评估了野生型（WT）和CD44基因敲除（CD44KO）小鼠中活化和未活化的β-连环蛋白表达。我们的结果表明，小鼠角膜中有两种不同的干细胞群体发挥作用：Lrig1衍生的干细胞和Wnt活性/CD44依赖的干细胞。Lrig1衍生的细胞作为静止干细胞的储存库，在角膜受伤时进行再生，而在稳态条件下，Wnt活性/CD44依赖的干细胞主要负责角膜更新。在老年角膜中，CD44表达缺失导致Wnt信号传导减少，使组织在再生过程中越来越依赖Lrig1+干细胞。在小鼠中，即使没有CD44，Lrig1+干细胞也能够维持角膜的永久更新。
