脊髓損傷（spinal cord injury，SCI）會造成嚴重的殘疾和后遺癥。隨著細胞治療的發(fā)展，基于干細胞的SCI治療方案被認為是一種有前景的策略。骨髓間充質干細胞（bone marrow mesenchymal stem cells，BMSCs）因其相對容易獲得、快速增殖能力以及多向分化潛能等特性，成為治療SCI的潛在候選物。然而，BMSCs移植需要克服多項障礙，特別是移植干細胞的細胞存活不佳會影響療效。

近日，來自溫州醫(yī)科大學附屬第二醫(yī)院的研究人員在Cell Death & Disease期刊發(fā)表文章，報道了受損的神經(jīng)元細胞衍生的外泌體會促進脊髓損傷后移植的BMSCs的存活，為脊髓損傷的干細胞治療提供了理論基礎。為了模擬SCI中神經(jīng)細胞或移植的BMSCs體內微環(huán)境，研究人員將PC12細胞的條件培養(yǎng)基以及PC12細胞外泌體在體外H₂O₂處理的氧化應激條件下與BMSCs一起培養(yǎng)。結果發(fā)現(xiàn)，PC12細胞條件培養(yǎng)基和PC12細胞外泌體顯著加速H₂O₂誘導的BMSCs凋亡。此外，外泌體促進了BMSCs cleaved caspase-3、細胞色素C、乳酸脫氫酶（LDH）的釋放，增加了凋亡細胞比例，并且Bcl-2 / Bax比值與細胞活力降低。通過Rab27a小干擾RNA抑制外泌體分泌可以阻止體外BMSCs凋亡。有趣的是，缺氧預處理則能夠促進脊髓損傷后體內和體外氧化應激下BMSCs的存活。研究還表明，在氧化應激條件下，HIF-1α在缺氧預處理中對BMSCs的存活起著重要作用。siRNA-HIF-1α增加BMSCs的凋亡；相反，HIF-1α誘導激活劑FG-4592減弱BMSCs的凋亡。

綜上所述，這項研究表明受損的PC12細胞來源的外泌體加速了脊髓損傷后BMSCs的凋亡，但對其進行缺氧預處理或激活HIF-1α的表達則對移植后的BMSCs的存活具有顯著促進作用，這為基于BMSCs的SCI療法開發(fā)提供了新的思考。

推薦閱讀原文：

Hypoxia preconditioning promotes bone marrow mesenchymal stem cells survival by inducing HIF-1α in injured neuronal cells derived exosomes culture system.

Bone marrow derived stem cells (BMSCs) transplantation are viewed as a promising therapeutic candidate for spinal cord injury (SCI). However, the inflammatory microenvironment in the spinal cord following SCI limits the survival and efficacy of transplanted BMSCs. In this study, we investigate whether injured neuronal cells derived exosomes would influence the survival of transplanted BMSCs after SCI. In order to mimic the microenvironment in SCI that the neuronal cells or transplanted BMSCs suffer in vivo, PC12 cells conditioned medium and PC12 cell's exosomes collected from H₂O₂-treated PC12 cell's culture medium were cultured with BMSCs under oxidative stress in vitro. PC12 cells conditioned medium and PC12 cell's exosomes significantly accelerated the apoptosis of BMSCs induced by H₂O₂. Moreover, the cleaved caspase-3, cytochrome (Cyt) C, lactate dehydrogenase (LDH) releases, and apoptotic percentage were increased, and the ratio of Bcl-2/Bax and cell viability were decreased. Inhibition of exosome secretion via Rab27a small interfering RNA prevented BMSCs apoptosis in vitro. In addition, hypoxia-preconditioned promoted the survival of BMSCs under oxidative stress both in vivo after SCI and in vitro. Our results also indicate that HIF-1α plays a central role in the survival of BMSCs in hypoxia pretreatment under oxidative stress conditions. siRNA-HIF-1α increased apoptosis of BMSCs; in contrast, HIF-1α inducer FG-4592 attenuated apoptosis of BMSCs. Taken together, we found that the injured PC12 cells derived exosomes accelerate BMSCs apoptosis after SCI and in vitro, hypoxia pretreatment or activating expression of HIF-1α to be important in the survival of BMSCs after transplantation, which provides a foundation for application of BMSCs in therapeutic potential for SCI.