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脊髓损伤（spinal cord injury，SCI）会造成严重的残疾和后遗症。随着细胞治疗的发展，基于干细胞的SCI治疗方案被认为是一种有前景的策略。骨髓间充质干细胞（bone marrow mesenchymal stem cells，BMSCs）因其相对容易获得、快速增殖能力以及多向分化潜能等特性，成为治疗SCI的潜在候选物。然而，BMSCs移植需要克服多项障碍，特别是移植干细胞的细胞存活不佳会影响疗效。 近日，来自温州医科大学附属第二医院的研究人员在Cell Death & Disease期刊发表文章，报道了受损的神经元细胞衍生的外泌体会促进脊髓损伤后移植的BMSCs的存活，为脊髓损伤的干细胞治疗提供了理论基础。为了模拟SCI中神经细胞或移植的BMSCs体内微环境，研究人员将PC12细胞的条件培养基以及PC12细胞外泌体在体外H2O2处理的氧化应激条件下与BMSCs一起培养。结果发现，PC12细胞条件培养基和PC12细胞外泌体显著加速H2O2诱导的BMSCs凋亡。此外，外泌体促进了BMSCs cleaved caspase-3、细胞色素C、乳酸脱氢酶（LDH）的释放，增加了凋亡细胞比例，并且Bcl-2 / Bax比值与细胞活力降低。通过Rab27a小干扰RNA抑制外泌体分泌可以阻止体外BMSCs凋亡。有趣的是，缺氧预处理则能够促进脊髓损伤后体内和体外氧化应激下BMSCs的存活。研究还表明，在氧化应激条件下，HIF-1α在缺氧预处理中对BMSCs的存活起着重要作用。siRNA-HIF-1α增加BMSCs的凋亡；相反，HIF-1α诱导激活剂FG-4592减弱BMSCs的凋亡。 综上所述，这项研究表明受损的PC12细胞来源的外泌体加速了脊髓损伤后BMSCs的凋亡，但对其进行缺氧预处理或激活HIF-1α的表达则对移植后的BMSCs的存活具有显著促进作用，这为基于BMSCs的SCI疗法开发提供了新的思考。 推荐阅读原文： 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. |
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