Cell子刊：潜藏的线粒体DNA突变，可能会破坏iPSC治疗价值

4月14日，《Cell Stem Cell》一项研究指出，随着年龄的增长，人类线粒体DNA中会积累突变。这一发现，对于使用诱导多能干细胞治疗疾病有重要意义。如果iPS细胞来源于一位上了年纪的病人的细胞，那么可能就含有错误的线粒体DNA，这可能削弱“诱导多能性”细胞的治疗价值。

4月14日，《Cell Stem Cell》发表的一项研究指出，随着年龄的增长，人类线粒体DNA中会积累突变。这一发现，对于使用诱导多能干细胞（iPSC）的潜在疗法有重要意义，iPSC是从患者的皮肤细胞生成，并可用于修复受损组织或器官。如果“诱导多能性”细胞来源于一位上了年纪的病人的细胞，那么可能就含有错误的线粒体DNA，这可能削弱“诱导多能性”细胞的治疗价值。

Shoukhrat Mitalipov是国际上著名的干细胞技术应用于线粒体疾病治疗领域的专家，曾在2007年成功建立出灵长类动物猴子的克隆干细胞系，曾经入选《Nature》2013年度十大人物，也被称为克隆“酋长”和“线粒体狂人”。黄涛生博士早年毕业于福建医学院，1986年在第三军医大学获得硕士学位，博士毕业于美国西奈山医学院，现任美国辛辛那提大学、辛辛那提儿童医院终身教授，多项突破性成果被刊登在权威学术期刊上。

Mitalipov教授说，线粒体基因组相对较小，只包含37个基因，因此使用新一代测序筛选，应该可行的。这应该是相对便宜和办得到的。

• # Age-Related Accumulation of Somatic Mitochondrial DNA Mutations in Adult-Derived Human iPSCs

Induced pluripotent stem cells (iPSCs) offer an unlimited source for autologous cell replacement therapies to treat age-associated degenerative diseases. Aging is generally characterized by increased DNA damage and genomic instability (Garinis et al., 2008, Lombard et al., 2005); thus, iPSCs derived from elderly subjects may harbor point mutations and larger genomic rearrangements. Indeed, iPSCs display increased chromosome aberrations (Mayshar et al., 2010), subchromosomal copy number variations (CNVs) (Abyzov et al., 2012, Laurent et al., 2011), and exome mutations (Johannesson et al., 2014), compared to natural embryonic stem cell (ESC) counterparts (Ma et al., 2014). The rate of mtDNA mutations is believed to be at least 10- to 20-fold higher than that observed in the nuclear genome (Wallace, 1994), and often both mutated and wild-type mtDNA (heteroplasmy) can coexist in the same cell (Rossignol et al., 2003). Large deletions are most frequently observed mtDNA abnormalities in aged post-mitotic tissues such as brain, heart, and muscle (Bender et al., 2006, Bua et al., 2006, Corral-Debrinski et al., 1992, Cortopassi et al., 1992, Mohamed et al., 2006) and have been implicated in aging and diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and diabetes (Larsson, 2010, Lin and Beal, 2006, Petersen et al., 2003, Wallace, 2005). In addition, mtDNA point mutations were reported in some tumors and replicating tissues (Chatterjee et al., 2006, Ju et al., 2014, Michikawa et al., 1999, Taylor et al., 2003). However, the extent of mtDNA defects in proliferating peripheral tissues commonly used for iPSC induction, such as skin and blood, is thought to be low and limited to common non-coding variants (Schon et al., 2012, Yao et al., 2015). Accumulation of mtDNA variants in these tissues with age was insignificant (Greaves et al., 2010, Hashizume et al., 2015). Several point mutations were identified in iPSCs generated from the newborn foreskin fibroblasts, although most of these variants were non-coding, common for the general population, and did not affect their metabolic activity (Prigione et al., 2011). Somatic mtDNA mutations may be under-reported secondary to the level of sample interrogation. Here, we describe the accumulation of somatic mtDNA mutations revealed in multiple skin and blood iPSCs derived from 14 adult subjects as a function of age through whole mtDNA next-generation sequencing (NGS) (Table S1).