Biomaterial enhancement of stem cell transplant efficacy for macular degeneration

生物材料增强干细胞移植治疗黄斑变性的疗效 目前尚无有效的治疗晚期黄斑变性的方法。危重患者的视力恢复 需要更换视网膜色素上皮(RPE)和感光器，因为感光器 需要功能正常的RPE才能生存。然而，还没有一种方法来取代这两种细胞类型 介绍。此外，以前更换光感受器的尝试在啮齿动物身上取得的成功有限。 模型，可能是因为低存活率和移植细胞的有限分布。 这个项目整合了对这两个挑战的解决方案：我们提议移植人类胚胎 干细胞(ES)来源的原始视网膜干细胞(HpRSCs)，一种比 先前为恢复视力而移植的细胞类型。我们已经证明，hpRSC既产生RPE，又产生RPE 在体外和体内的光感受器；在体内取代这两种细胞类型将产生更持久的视觉 改进，因为移植来源的RPE将支持移植来源的光感受器。为了 开发最有效的治疗方法，我们将在可注射水凝胶中输送hpRSCs，该水凝胶 生物化学和力学与眼部细胞外基质的生物化学和力学密切相关，后者最近 被证明可以将移植的细胞均匀地分布在视网膜上。 该项目旨在将胚胎干细胞来源的RPC转化为临床使用。这一进步的关键是 是PI之间的合作，将黄斑变性模型的领导者和 干细胞分化为视网膜神经元(张)与生物材料研究小组(阿尔穆泰里)。这个 张氏集团的专业技术将确保该项目推动HAMC眼科技术的发展 移植意义重大：以前的工作没有采用相关的动物模型，所以对 关于移植细胞分化和功能恢复的材料尚未得到评估。此外， 它依赖于最容易衍生的细胞，而这个项目将使用ES细胞衍生的RPC， 这是临床上唯一可行的选择。 在这项计划完成后，我们预期： 1.评估HAMC注射对视网膜下注射的视网膜干细胞存活和分布的影响 2.明确HAMC对视网膜干细胞分化为RPE和RPE能力的影响 体内外的光感受器 3.确定最大限度提高视网膜下注射药物视力的给药方法 皇家外科学院(RCS)大鼠的视网膜干细胞

Biomaterial enhancement of stem cell transplant efficacy for macular degeneration No effective therapies yet exist for advanced macular degeneration. Restoring vision in severe cases requires replacing both retinal pigmented epithelium (RPE) and photoreceptors because photoreceptors require functional RPE to survive. However, no approach to replace both cell types has yet been introduced. Further, previous attempts to replace photoreceptors have met limited success in rodent models, likely because of low survival rates and restricted distribution of transplanted cells. This project integrates solutions to both of these challenges: we propose to transplant human embryonic stem (ES) cell-derived primitive retinal stem cells (hpRSCs), a cell population that is more pluripotent than cell types previously transplanted to restore vision. We have shown that hpRSCs yield both RPE and photoreceptors in vitro and in vivo; replacing both cell types in vivo would yield longer-lasting visual improvements, as transplant-derived RPE would support transplant-derived photoreceptors. In order to develop a maximally effective therapy, we will deliver hpRSCs in an injectable hydrogel whose biochemistry and mechanics closely match those of the ocular extracellular matrix, which has recently been shown to uniformly distribute transplanted cells across the retina. This project stands to position ES cell-derived RPCs for translation into the clinic. The key to this advance is the collaboration between the PIs, bringing together a leader in macular degeneration models and the differentiation of stem cells into retinal neurons (Zhang) with a biomaterials research group (Almutairi). The Zhang group's expertise will ensure that this project advances development of HAMC for ocular transplantation significantly: previous work has not employed relevant animal models, so the impact of the material on transplanted cells' differentiation and functional recovery has not yet been assessed. Further, it has relied on cells that are easiest to derive, whereas this project will employ ES cell-derived RPCs, which are the only clinically viable option. By completion of this project, we expect to: 1. Assess the effect of HAMC delivery on survival and distribution of subretinally injected retinal stem cells 2. Define the effect of HAMC on the ability of retinal stem cells to differentiate into RPE and photoreceptors in vitro and in vivo 3. Identify the delivery method that maximizes visual improvement ensuing from subretinal injection of retinal stem cells in Royal College of Surgeons (RCS) rats