脊髓損傷（spinal cord injury,，SCI）可引起嚴(yán)重的不可逆運(yùn)動(dòng)功能障礙甚至死亡，而神經(jīng)干細(xì)胞（neural stem cell,，NSC）移植可促進(jìn)脊髓損傷后的功能恢復(fù),，并通過釋放旁分泌因子促進(jìn)組織再生，目前NSC衍生的細(xì)胞外囊泡在脊髓損傷治療中的應(yīng)用還未有報(bào)道,。近日,，來自南京醫(yī)科大學(xué)第一附屬醫(yī)院的研究人員發(fā)現(xiàn)神經(jīng)干細(xì)胞分泌的小細(xì)胞外囊泡通過激活自噬發(fā)揮脊髓損傷后的細(xì)胞修復(fù)活性，相關(guān)研究結(jié)果發(fā)表在Cell Death and Disease雜志上,。

脊髓損傷的嚴(yán)重程度取決于最初的創(chuàng)傷程度,，脊髓損傷破壞神經(jīng)元或切斷軸突，并且由于炎癥引起延遲性繼發(fā)性損傷,，可能導(dǎo)致水腫,、神經(jīng)細(xì)胞凋亡、空洞化和反應(yīng)性神經(jīng)膠質(zhì)增生,。研究表明,，NSC移植具有獨(dú)特的神經(jīng)保護(hù)功能，可促進(jìn)急性脊髓損傷后的功能恢復(fù),，但將干細(xì)胞直接移植到靶組織中仍然具有挑戰(zhàn)性,。例如，移植的干細(xì)胞由于缺血而導(dǎo)致存活率較低,，還可能存在細(xì)胞去分化,、免疫排斥等問題，限制了直接NSC移植治療SCI的臨床應(yīng)用,。在這項(xiàng)新的研究里,，研究人員首次表明，NSC源小細(xì)胞外囊泡（NSC-derived small extracellular vesicles,，NSC-sEVs）能夠通過激活自噬減少神經(jīng)細(xì)胞凋亡,、抑制神經(jīng)炎癥和促進(jìn)脊髓損傷模型大鼠的功能恢復(fù),。研究結(jié)果顯示，NSC-sEVs可以顯著降低SCI的程度,、改善功能恢復(fù),、并減少大鼠的神經(jīng)細(xì)胞凋亡、小膠質(zhì)細(xì)胞激活和神經(jīng)炎癥,。此外,，NSC-sEVs可通過誘導(dǎo)自噬來調(diào)節(jié)細(xì)胞凋亡和炎癥過程。具體地,，NSC-sEVs增加了自噬標(biāo)記蛋白LC3B和beclin-1的表達(dá),，并促進(jìn)自噬體形成。NSC-sEV處理后,，SCI區(qū)域顯著減少,，促凋亡蛋白Bax、caspase-3和促炎細(xì)胞因子TNF-α,、IL-1β和IL-6的表達(dá)水平均顯著降低,，而抗凋亡蛋白Bcl-2的表達(dá)水平上調(diào)。然而,，在自噬抑制劑3MA作用下,，NSC-sEVs對(duì)細(xì)胞凋亡和神經(jīng)炎癥的這些抑制作用被顯著逆轉(zhuǎn)。這項(xiàng)研究結(jié)果表明,，NSC-sEVs有可能通過促進(jìn)自噬介導(dǎo)了早期SCI的功能恢復(fù),，是有潛力的SCI治療手段。

推薦閱讀原文：

Neural stem cell-derived small extracellular vesicles attenuate apoptosis and neuroinflammation after traumatic spinal cord injury by activating autophagy.

Spinal cord injury (SCI) can cause severe irreversible motor dysfunction and even death. Neural stem cell (NSC) transplantation can promote functional recovery after acute SCI in experimental animals, but numerous issues, including low-transplanted cell survival rate, cell de-differentiation, and tumor formation need to be resolved before routine clinical application is feasible. Recent studies have shown that transplanted stem cells facilitate regeneration through release of paracrine factors. Small extracellular vesicles (sEVs), the smallest known membrane-bound nanovesicles, are involved in complex intercellular communication systems and are an important vehicle for paracrine delivery of therapeutic agents. However, the application of NSC-derived small extracellular vesicles (NSC-sEVs) to SCI treatment has not been reported. We demonstrate that NSC-sEVs can significantly reduce the extent of SCI, improve functional recovery, and reduce neuronal apoptosis, microglia activation, and neuroinflammation in rats. Furthermore, our study suggests that NSC-sEVs can regulate apoptosis and inflammatory processes by inducing autophagy. In brief, NSC-sEVs increased the expression of the autophagy marker proteins LC3B and beclin-1, and promoted autophagosome formation. Following NSC-sEV infusion, the SCI area was significantly reduced, and the expression levels of the proapoptotic protein Bax, the apoptosis effector cleaved caspase-3, and the pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 were significantly reduced, whereas the expression level of the anti-apoptotic protein Bcl-2 was upregulated. In the presence of the autophagy inhibitor 3MA, however, these inhibitory effects of NSC-sEVs on apoptosis and neuroinflammation were significantly reversed. Our results show for the first time that NSC-sEV treatment has the potential to reduce neuronal apoptosis, inhibit neuroinflammation, and promote functional recovery in SCI model rats at an early stage by promoting autophagy.