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缺氧预处理通过诱导损伤神经元细胞衍生的外体培养系统中的 HIF-1α 促进骨髓间充质干细胞的存活。

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

机构信息

Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, P. R. China.

Zhejiang Provincial Key Laboratory of Orthpaedics, Wenzhou, Zhejiang, 325000, P. R. China.

出版信息

Cell Death Dis. 2019 Feb 12;10(2):134. doi: 10.1038/s41419-019-1410-y.

DOI:10.1038/s41419-019-1410-y
PMID:30755595
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6372680/
Abstract

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 HO-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 HO. 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.

摘要

骨髓源干细胞（BMSCs）移植被视为治疗脊髓损伤（SCI）的一种有前途的治疗方法。然而，SCI 后脊髓中的炎症微环境限制了移植 BMSCs 的存活和疗效。在这项研究中，我们研究了受损神经元细胞衍生的外泌体是否会影响 SCI 后移植 BMSCs 的存活。为了模拟神经元细胞或移植 BMSCs 在体内经历的 SCI 微环境，我们在体外将 PC12 细胞条件培养基和从 HO 处理的 PC12 细胞培养基中收集的 PC12 细胞外泌体与 BMSCs 在氧化应激下共培养。PC12 细胞条件培养基和 PC12 细胞外泌体显著加速了 HO 诱导的 BMSCs 凋亡。此外，裂解的 caspase-3、细胞色素 C（Cyt C）、乳酸脱氢酶（LDH）释放和凋亡百分比增加，Bcl-2/Bax 比值和细胞活力降低。通过 Rab27a 小干扰 RNA 抑制外泌体分泌可防止体外 BMSCs 凋亡。此外，缺氧预处理可促进 SCI 后体内和体外氧化应激下 BMSCs 的存活。我们的结果还表明，HIF-1α 在缺氧预处理下氧化应激条件下 BMSCs 的存活中起核心作用。siRNA-HIF-1α 增加了 BMSCs 的凋亡；相反，HIF-1α 诱导剂 FG-4592 减轻了 BMSCs 的凋亡。总之，我们发现受损的 PC12 细胞衍生的外泌体加速了 SCI 后和体外 BMSCs 的凋亡，缺氧预处理或激活 HIF-1α 的表达对移植后 BMSCs 的存活很重要，这为 BMSCs 在 SCI 治疗中的应用提供了基础。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a69/6372680/86e1e1b34dd2/41419_2019_1410_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a69/6372680/4208a0084aa2/41419_2019_1410_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a69/6372680/83d850aa6f3c/41419_2019_1410_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a69/6372680/b81b53ffe78a/41419_2019_1410_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a69/6372680/326998182c31/41419_2019_1410_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a69/6372680/a89b0994fc89/41419_2019_1410_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a69/6372680/d273033664fd/41419_2019_1410_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a69/6372680/2cddb74c6afa/41419_2019_1410_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a69/6372680/5895a03988e3/41419_2019_1410_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a69/6372680/86e1e1b34dd2/41419_2019_1410_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a69/6372680/4208a0084aa2/41419_2019_1410_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a69/6372680/83d850aa6f3c/41419_2019_1410_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a69/6372680/b81b53ffe78a/41419_2019_1410_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a69/6372680/326998182c31/41419_2019_1410_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a69/6372680/a89b0994fc89/41419_2019_1410_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a69/6372680/d273033664fd/41419_2019_1410_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a69/6372680/2cddb74c6afa/41419_2019_1410_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a69/6372680/5895a03988e3/41419_2019_1410_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a69/6372680/86e1e1b34dd2/41419_2019_1410_Fig9_HTML.jpg

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本文引用的文献

[1]
Regulation of RAB22A by mir-193b inhibits breast cancer growth and metastasis mediated by exosomes.

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The harsh microenvironment in infarcted heart accelerates transplanted bone marrow mesenchymal stem cells injury: the role of injured cardiomyocytes-derived exosomes.

Cell Death Dis. 2018-3-2

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Effects of Intrathecal Injection of the Conditioned Medium from Bone Marrow Stromal Cells on Spinal Cord Injury in Rats.

J Neurotrauma. 2017-11-20

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