Metabolic Syndrome Impairs 3D Mitochondrial Structure, Dynamics, and Function in Swine Mesenchymal Stem Cells
Metabolic Syndrome Impairs 3D Mitochondrial Structure, Dynamics, and Function in Swine Mesenchymal Stem Cells
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DOI：
10.1007/s12015-020-09988-3
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发表时间：
2020-06-16
影响因子：
4.8
通讯作者：
Eirin, Alfonso
中科院分区：
文献类型：
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作者：
Farahani, Rahele A.;Farah, Mohamed C.;Eirin, Alfonso
自体间充质干细胞（MSCs）移植是治疗多种疾病的有效方法。线粒体调节MSC功能的几个重要方面，但可能受到合并症和心血管危险因素的损害。我们假设代谢综合征（MetS）损害了猪脂肪组织来源的间充质干细胞的3D线粒体结构、动力学和功能。家猪分别饲喂瘦肉饲粮和MetS饲粮（n = 6），为期16周。从皮下腹部脂肪中收集MSCs，并使用最先进的连续块面电子显微镜和3D重建分析其线粒体。线粒体动力学（融合/裂变）通过mRNA测序和Western blotting进行评估，生物能量学通过膜电位（TMRE）、细胞色素c氧化酶(COX)-IV活性和Seahorse分析仪进行评估。通过定量聚合酶链反应（qPCR）检测线粒体相关microRNAs （mitomiRs）的表达。MetS猪出现肥胖、高血压、胰岛素抵抗和高脂血症。各组间线粒体密度相似，但与Lean-MSCs相比，MetS-MSCs的3D线粒体和基质体积更低。与Lean-MSCs相比，MetS-MSCs的线粒体裂变率更高，但融合率更低，膜电位、COX-IV活性和ATP产量也是如此。相反，与Lean-MSCs相比，靶向支持线粒体结构、能量通路和动力学的线粒体基因的mitomiRs miR15a、miR-137和miR-181c的表达在MetS-MSCs中更高，表明可能调节其表达。MetS破坏MSC 3D线粒体结构、动力学和功能，并可能调节编码线粒体蛋白的基因。这些观察结果支持有丝分裂保护策略的发展，以保持MSCs的再生能力及其对MetS患者自体移植的适用性。
Transplantation of autologous mesenchymal stem cells (MSCs) is an effective therapy for several diseases. Mitochondria modulate several important aspects of MSC function, but might be damaged by comorbidities and cardiovascular risk factors. We hypothesized that metabolic syndrome (MetS) compromises 3D mitochondrial structure, dynamics, and function in swine adipose tissue-derived MSCs. Domestic pigs were fed a Lean or MetS diet (n = 6 each) for 16 weeks. MSCs were collected from subcutaneous abdominal fat and their mitochondria analyzed using state-of-the-art Serial Block Face Electron Microscopy and 3D reconstruction. Mitochondrial dynamics (fusion/fission) were assessed by mRNA sequencing and Western blotting, and bioenergetics by membrane potential (TMRE), cytochrome-c oxidase (COX)-IV activity, and Seahorse Analyzer. Expression of mitochondria-associated microRNAs (mitomiRs) was measured by quantitative polymerase chain reaction (qPCR). MetS pigs developed obesity, hypertension, insulin resistance, and hyperlipidemia. Mitochondrial density was similar between the groups, but 3D mitochondrial and matrix volumes were lower in MetS-MSCs versus Lean-MSCs. Mitochondrial fission was higher, but fusion lower in MetS-MSCs versus Lean-MSCs, as were membrane potential, COX-IV activity, and ATP production. Contrarily, expression of the mitomiRs miR15a, miR-137, and miR-181c, which target mitochondrial genes that support mitochondrial structure, energy pathways, and dynamics, was higher in MetS-MSCs compared to Lean-MSCs, suggesting a potential to modulate their expression. MetS damages MSC 3D mitochondrial structure, dynamics, and function, and may modulate genes encoding for mitochondrial proteins. These observations support development of mitoprotective strategies to preserve the regenerative potency of MSCs and their suitability for autologous transplantation in patients with MetS.