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Healthy, mtDNA-mutation free mesoangioblasts from mtDNA patients qualify for autologous therapy.
Stem Cell Research & Therapy ( IF 7.5 ) Pub Date : 2019-12-21 , DOI: 10.1186/s13287-019-1510-8
Florence van Tienen 1, 2, 3, 4 , Ruby Zelissen 2, 4 , Erika Timmer 2, 4 , Marike van Gisbergen 2, 5 , Patrick Lindsey 4 , Mattia Quattrocelli 6, 7 , Maurilio Sampaolesi 6, 8 , Elvira Mulder-den Hartog 9, 10 , Irenaeus de Coo 3, 4, 10 , Hubert Smeets 2, 3, 4
Affiliation  

BACKGROUND Myopathy and exercise intolerance are prominent clinical features in carriers of a point-mutation or large-scale deletion in the mitochondrial DNA (mtDNA). In the majority of patients, the mtDNA mutation is heteroplasmic with varying mutation loads between tissues of an individual. Exercise-induced muscle regeneration has been shown to be beneficial in some mtDNA mutation carriers, but is often not feasible for this patient group. In this study, we performed in vitro analysis of mesoangioblasts from mtDNA mutation carriers to assess their potential to be used as source for autologous myogenic cell therapy. METHODS We assessed the heteroplasmy level of patient-derived mesoangioblasts, isolated from skeletal muscle of multiple carriers of different mtDNA point-mutations (n = 25). Mesoangioblast cultures with < 10% mtDNA mutation were further analyzed with respect to immunophenotype, proliferation capacity, in vitro myogenic differentiation potential, mitochondrial function, and mtDNA quantity. RESULTS This study demonstrated that mesoangioblasts in half of the patients contained no or a very low mutation load (< 10%), despite a much higher mutation load in their skeletal muscle. Moreover, none of the large-scale mtDNA deletion carriers displayed the deletion in mesoangioblasts, despite high percentages in skeletal muscle. The mesoangioblasts with no or a very low mutation load (< 10%) displayed normal mitochondrial function, proliferative capacity, and myogenic differentiation capacity. CONCLUSIONS Our data demonstrates that in half of the mtDNA mutation carriers, their mesoangioblasts are (nearly) mutation free and can potentially be used as source for autologous cell therapy for generation of new muscle fibers without mtDNA mutation and normal mitochondrial function.

中文翻译:

来自mtDNA患者的健康,无mtDNA突变的中成血管细胞有资格进行自体治疗。

背景技术线粒体DNA(mtDNA)中的点突变或大规模缺失的携带者中,肌病和运动不耐症是突出的临床特征。在大多数患者中,mtDNA突变是异质性的,个体组织之间的突变负荷也不同。运动诱导的肌肉再生已被证明对某些mtDNA突变携带者有益,但对于该患者群体通常不可行。在这项研究中,我们对来自mtDNA突变携带者的中成血管细胞进行了体外分析,以评估其用作自体成肌细胞治疗来源的潜力。方法我们评估了来自患者的中成血管细胞的异质性水平,该细胞是从具有不同mtDNA点突变的多个载体的骨骼肌中分离出来的(n = 25)。中成血管细胞培养物,< 进一步分析了10%mtDNA突变的免疫表型,增殖能力,体外成肌分化潜能,线粒体功能和mtDNA数量。结果该研究表明,尽管骨骼肌中的突变负荷高得多,但一半的中成血管细胞不包含突变负荷或突变负荷非常低(<10%)。此外,尽管骨骼肌中的百分比很高,但是大规模的mtDNA缺失携带者都没有在中成血管细胞中显示出这种缺失。没有或没有非常低的突变负荷(<10%)的中成血管细胞显示出正常的线粒体功能,增殖能力和成肌分化能力。结论我们的数据表明,在一半的mtDNA突变携带者中,
更新日期:2019-12-21
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