Institute for Vision Research, University of Iowa, Iowa City, IA, USA.
Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
Cell Transplant. 2022 Jan-Dec;31:9636897221104451. doi: 10.1177/09636897221104451.
Loss of photoreceptor cells is a primary feature of inherited retinal degenerative disorders including age-related macular degeneration and retinitis pigmentosa. To restore vision in affected patients, photoreceptor cell replacement will be required. The ideal donor cells for this application are induced pluripotent stem cells (iPSCs) because they can be derived from and transplanted into the same patient obviating the need for long-term immunosuppression. A major limitation for retinal cell replacement therapy is donor cell loss associated with simple methods of cell delivery such as subretinal injections of bolus cell suspensions. Transplantation with supportive biomaterials can help maintain cellular integrity, increase cell survival, and encourage proper cellular alignment and improve integration with the host retina. Using a pig model of retinal degeneration, we recently demonstrated that polycaprolactone (PCL) scaffolds fabricated with two photon lithography have excellent local and systemic tolerability. In this study, we describe rapid photopolymerization-mediated production of PCL-based bioabsorbable scaffolds, a technique for loading iPSC-derived retinal progenitor cells onto the scaffold, methods of surgical transplantation in an immunocompromised rat model and tolerability of the subretinal grafts at 1, 3, and 6 months of follow-up ( = 150). We observed no local or systemic toxicity, nor did we observe any tumor formation despite extensive clinical evaluation, clinical chemistry, hematology, gross tissue examination and detailed histopathology. Demonstrating the local and systemic compatibility of biodegradable scaffolds carrying human iPSC-derived retinal progenitor cells is an important step toward clinical safety trials of this approach in humans.
光感受器细胞的丧失是遗传性视网膜退行性疾病的主要特征，包括年龄相关性黄斑变性和色素性视网膜炎。为了恢复受影响患者的视力，需要进行光感受器细胞替代。对于这种应用，理想的供体细胞是诱导多能干细胞（iPSC），因为它们可以从同一患者中获得并移植，从而避免了长期免疫抑制的需要。视网膜细胞替代治疗的一个主要限制是与简单的细胞递送方法（例如视网膜下注射大体积细胞悬浮液）相关的供体细胞损失。与支持性生物材料的移植可以帮助维持细胞完整性，增加细胞存活，并鼓励适当的细胞排列和改善与宿主视网膜的整合。使用视网膜变性的猪模型，我们最近证明了使用双光子光刻制造的聚己内酯（PCL）支架具有极好的局部和全身耐受性。在这项研究中，我们描述了快速光聚合介导的基于 PCL 的生物可吸收支架的生产，这是一种将 iPSC 衍生的视网膜祖细胞加载到支架上的技术，在免疫功能低下的大鼠模型中进行手术移植的方法以及在 1、3 和 6 个月的随访（= 150）中对视网膜下移植物的耐受性。尽管进行了广泛的临床评估、临床化学、血液学、大体组织检查和详细的组织病理学检查，但我们没有观察到局部或全身毒性，也没有观察到任何肿瘤形成。证明携带人 iPSC 衍生的视网膜祖细胞的可生物降解支架的局部和全身相容性是在人体中进行该方法的临床安全性试验的重要步骤。
