Li Shiding, Zhao Yu, Chen Junzhao, Wu Beibei, Wu Nianxuan, Sun Hao, Chen Liangbo, Feng Chuanliang, Fu Yao
Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
State Key Laboratory of Eye Health, Shanghai Jiao Tong University, Shanghai, 200011, China.
Adv Sci (Weinh). 2025 Aug;12(31):e04732. doi: 10.1002/advs.202504732. Epub 2025 May 30.
The differentiation and stemness maintenance of stem cells are the core topics in cell biology and regenerative medicine, involving cell fate determination, developmental regulation and tissue regeneration. Chirality is an essential factor influencing multiple biological processes, including protein interactions, stem cell development and disease pathogenesis. However, its roles in regulating stem cells fate, especially limbal epithelial stem cells (LESCs), remain elusive. Herein, it is first discovered that right-handed chiral hydrogel (DH) enhanced LESCs proliferation, migration, and differentiation into corneal epithelial cells, while left-handed chiral hydrogel (LH) can partially preserve LESCs stemness. Further in vivo experiments demonstrated that 3D DH effectively accelerated corneal wound healing process, inhibited both inflammation and vascularization in a partial limbal stem cell deficiency model. Mechanistically, DH activates Notch signaling by increasing its stereo-affinity to Notch1, facilitating Notch intracellular domain release and HES1 transcription, thereby directing LESCs fate. Collectively, this work highlights the novel role of chirality in LESCs fate determination and confirms DH as a drug-free, effective approach for corneal epithelial regeneration, offering a new direction for regenerative medicine and tissue engineering.
干细胞的分化与干性维持是细胞生物学和再生医学的核心主题，涉及细胞命运决定、发育调控和组织再生。手性是影响多种生物学过程的重要因素，包括蛋白质相互作用、干细胞发育和疾病发病机制。然而，其在调节干细胞命运，尤其是角膜缘上皮干细胞（LESCs）命运方面的作用仍不清楚。在此，首次发现右旋手性水凝胶（DH）可增强LESCs的增殖、迁移以及向角膜上皮细胞的分化，而左旋手性水凝胶（LH）可部分维持LESCs的干性。进一步的体内实验表明，三维DH可有效加速角膜伤口愈合过程，在部分角膜缘干细胞缺陷模型中抑制炎症和血管生成。机制上，DH通过增加其对Notch1的立体亲和力来激活Notch信号，促进Notch细胞内结构域释放和HES1转录，从而决定LESCs的命运。总的来说，这项工作突出了手性在LESCs命运决定中的新作用，并证实DH是一种无药物、有效的角膜上皮再生方法，为再生医学和组织工程提供了新方向。
