Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, PR China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200011, PR China.
Shanghai Key Laboratory of Functional Materials Chemistry, East China University of Science and Technology, Shanghai, 200237, PR China.
Biomaterials. 2019 Feb;194:57-72. doi: 10.1016/j.biomaterials.2018.12.015. Epub 2018 Dec 15.
Biomaterials-mediated retinal progenitor cell (RPC)-based transplantation therapy has shown substantial potential for retinal degeneration (RD), but it is limited by the poor RPC survival, proliferation and differentiation. Herein, the gelatin-hyaluronic acid (Gel-HA)-based hydrogels formed via moderate Michael-type addition reaction with or without the introduction of mussel-inspired polydopamine (PDA), i.e. Gel-HA-PDA and its counterpart Gel-HA hydrogels are developed, and their effects on the biological behaviour of RPCs, including adhesion, survival, proliferation, differentiation, delivery and migration are investigated. The hybrid hydrogels can adopt the intricate structure of the retina with suitable mechanical strength, degradation rate and biological activity to support cellular adhesion, survival and delivery. Meanwhile, Gel-HA hydrogel can remarkably promote RPC proliferation with much larger cell clusters, while Gel-HA-PDA hydrogel significantly enhances RPC adhesion and migration, and directs RPCs to preferentially differentiate toward retinal neurons such as photoreceptors (the most crucial cell-type for RD treatment), which is mainly induced by the activation of integrin α5β1-phosphatidylinositol-3-kinase (PI3K) pathway. This study demonstrates that Gel-HA hydrogel possesses great potential for RPC proliferation, while mussel-inspired PDA-modified Gel-HA hydrogel with superior biocompatibility can significantly promote RPC neuronal differentiation, providing new insights for developing biomedical materials applied for RPC-based transplantation therapy.
基于生物材料的视网膜祖细胞（RPC）移植疗法在视网膜变性（RD）方面显示出巨大的潜力，但受到 RPC 存活、增殖和分化能力差的限制。本文通过适度的迈克尔加成反应制备了明胶-透明质酸（Gel-HA）基水凝胶，引入或不引入贻贝启发的聚多巴胺（PDA），即 Gel-HA-PDA 和其对应物 Gel-HA 水凝胶，并研究了它们对 RPC 生物学行为的影响，包括粘附、存活、增殖、分化、递送和迁移。混合水凝胶可以采用与视网膜相匹配的复杂结构，具有合适的机械强度、降解率和生物活性，以支持细胞黏附、存活和递送。同时，Gel-HA 水凝胶可以显著促进 RPC 的增殖，形成更大的细胞簇，而 Gel-HA-PDA 水凝胶则显著增强 RPC 的粘附和迁移，并引导 RPC 优先向视网膜神经元分化，如光感受器（治疗 RD 的最关键细胞类型），这主要是由整合素 α5β1-磷酸肌醇-3-激酶（PI3K）途径的激活所诱导的。本研究表明，Gel-HA 水凝胶具有促进 RPC 增殖的巨大潜力，而具有优越生物相容性的贻贝启发 PDA 修饰的 Gel-HA 水凝胶可以显著促进 RPC 神经元分化，为开发应用于 RPC 移植治疗的生物医学材料提供了新的思路。
