Retinal degeneration (RD) is one of the most common causes of visual impairment and blindness and is characterized by progressive degeneration of photoreceptors. Transplantation of neural stem/progenitor cells (NPCs) is a promising treatment for RD, although the mechanisms underlying the efficacy remain unclear. Accumulated evidence supports the notion that paracrine effects of transplanted stem cells is likely the major approach to rescuing early degeneration, rather than cell replacement. NPC-derived exosomes (NPC-exos), a type of extracellular vesicles (EVs) released from NPCs, are thought to carry functional molecules to recipient cells and play therapeutic roles. In present study, we found that grafted human NPCs (hNPCs) secreted EVs and exosomes in the subretinal space (SRS) of RCS rats, an RD model. And direct administration of mouse neural progenitor cell-derived exosomes (mNPC-exos) delayed photoreceptor degeneration, preserved visual function, prevented thinning of the outer nuclear layer (ONL), and decreased apoptosis of photoreceptors in RCS rats. Mechanistically, mNPC-exos were specifically internalized by retinal microglia and suppressed their activation in vitro and in vivo. RNA sequencing and miRNA profiling revealed a set of 17 miRNAs contained in mNPC-exos that markedly inhibited inflammatory signal pathways by targeting TNF-α, IL-1β, and COX-2 in activated microglia. The exosomes derived from hNPC (hNPC-exos) contained similar miRNAs to mNPC-exos that inhibited microglial activation. We demonstrated that NPC-exos markedly suppressed microglial activation to protect photoreceptors from apoptosis, suggesting that NPC-exos and their contents may be the mechanism of stem cell therapy for treating RD.

中文翻译：

---

来自神经祖细胞的外来体通过使小胶质细胞失活而在视网膜变性期间保留感光细胞。

视网膜变性（RD）是视力障碍和失明的最常见原因之一，其特征是感光细胞逐渐退化。神经干/祖细胞（NPC）的移植是一种有前途的RD治疗，尽管疗效的基本机制尚不清楚。越来越多的证据支持这样的观点，即移植的干细胞的旁分泌作用可能是挽救早期变性而非细胞替代的主要方法。NPC衍生的外来体（NPC-exos）是一种从NPC释放的细胞外囊泡（EV），被认为可以将功能性分子带入受体细胞并发挥治疗作用。在本研究中，我们发现嫁接的人NPC（hNPC）在RCS大鼠（一种RD模型）的视网膜下间隙（SRS）中分泌EV和外泌体。直接施用小鼠神经祖细胞衍生的外来体（mNPC-exos）可以延迟RCS大鼠的光感受器变性，保留视觉功能，防止外核层（ONL）变薄并减少光感受器的凋亡。从机制上讲，mNPC-exos被视网膜小胶质细胞特异性内化，并在体外和体内抑制了它们的活化。RNA测序和miRNA分析显示，mNPC-exos中包含一组17种miRNA，可通过靶向活化小胶质细胞中的TNF-α，IL-1β和COX-2来显着抑制炎症信号途径。源自hNPC的外泌体（hNPC-exos）含有与抑制小胶质细胞活化的mNPC-exos类似的miRNA。我们证明了NPC-exos可以显着抑制小胶质细胞的活化，从而保护感光细胞免于凋亡，