Retinal degeneration is a leading cause of blindness in the world; its etiology is complex and involves genetic defects and stress-associated aging. In addition to gene therapies for known genetically defective retinal degeneration, cellular therapies have been widely explored for restoring vision in both preclinical animal models and clinical trials. Stem cells of distinct tissue sources and their derived lineages have been tested for treating retinal degeneration; most of them were reported to be effective to some extent in restoring/improving deteriorated vision. Whether this visual improvement is due to a functional integration of grafted cells to substitute for lost retinal neurons in recipients or due to their neuroprotective and neurotrophic effects to retain recipient functional neurons, or both, is still under debate. We compared the results of subretinal transplantation of various somatic cell types, such as stem cells and differentiated cells, into RhoP23H/+ mice, a retinal degeneration model for human retinitis pigmentosa (RP) by evaluating their optokinetic response (OKR) and retinal histology. We identified some paracrine factors in the media that cultured cells secreted by western blotting (WB) and functionally evaluated the vascular endothelial growth factor Vegfa for its potential neurotrophic and neuroprotective effects on the neuroretina of model animals by intravitreal injection of VEGF antibody. We found that live cells, regardless of whether they were stem cells or differentiated cell types, had a positive effect on improving degenerating retinas after subretinal transplantation; the efficacy depended on their survival duration in the host tissue. A few paracrine factors were identified in cell culture media; Vegfa was the most relevant neurotrophic and neuroprotective factor identified by our experiments to extend neuron survival duration in vivo. Cellular therapy-produced benefits for remediating retinal degeneration are mostly, if not completely, due to a paracrine effect of implanted cells on the remaining host retinal neurons.

中文翻译：

---

眼内植入细胞对小鼠退化视网膜的旁分泌作用。


视网膜变性是世界上导致失明的主要原因；其病因很复杂，涉及遗传缺陷和压力相关的衰老。除了针对已知的遗传缺陷性视网膜变性的基因疗法之外，细胞疗法也已在临床前动物模型和临床试验中广泛探索用于恢复视力。不同组织来源的干细胞及其衍生谱系已被测试用于治疗视网膜变性；据报道，其中大多数在某种程度上对恢复/改善恶化的视力有效。这种视觉改善是否是由于移植细胞的功能整合来替代受体中丢失的视网膜神经元，还是由于它们对保留受体功能神经元的神经保护和神经营养作用，或两者兼而有之，目前仍在争论中。我们通过评估RhoP23H/+小鼠的视动反应（OKR）和视网膜组织学，比较了各种体细胞类型（例如干细胞和分化细胞）视网膜下移植到RhoP23H/+小鼠（人类视网膜色素变性（RP）的视网膜变性模型）的结果。我们通过蛋白质印迹（WB）鉴定了培养细胞分泌的培养基中的一些旁分泌因子，并通过玻璃体内注射VEGF抗体对血管内皮生长因子Vegfa对模型动物神经视网膜的潜在神经营养和神经保护作用进行了功能评估。我们发现活细胞，无论是干细胞还是分化细胞类型，对改善视网膜下移植后退化的视网膜都有积极作用；功效取决于它们在宿主组织中的存活时间。 在细胞培养基中鉴定出一些旁分泌因子； Vegfa 是我们的实验确定的最相关的神经营养和神经保护因子，可延长体内神经元的存活时间。细胞疗法对视网膜变性的修复所产生的益处，如果不是完全的话，大部分是由于植入细胞对剩余宿主视网膜神经元的旁分泌作用。