Boston Children's Hospital, Boston, MA, USA.
Stem Cells. 2013 Jul;31(7):1287-97. doi: 10.1002/stem.1354.
In congenital mitochondrial DNA (mtDNA) disorders, a mixture of normal and mutated mtDNA (termed heteroplasmy) exists at varying levels in different tissues, which determines the severity and phenotypic expression of disease. Pearson marrow pancreas syndrome (PS) is a congenital bone marrow failure disorder caused by heteroplasmic deletions in mtDNA. The cause of the hematopoietic failure in PS is unknown, and adequate cellular and animal models are lacking. Induced pluripotent stem (iPS) cells are particularly amenable for studying mtDNA disorders, as cytoplasmic genetic material is retained during direct reprogramming. Here, we derive and characterize iPS cells from a patient with PS. Taking advantage of the tendency for heteroplasmy to change with cell passage, we isolated isogenic PS-iPS cells without detectable levels of deleted mtDNA. We found that PS-iPS cells carrying a high burden of deleted mtDNA displayed differences in growth, mitochondrial function, and hematopoietic phenotype when differentiated in vitro, compared to isogenic iPS cells without deleted mtDNA. Our results demonstrate that reprogramming somatic cells from patients with mtDNA disorders can yield pluripotent stem cells with varying burdens of heteroplasmy that might be useful in the study and treatment of mitochondrial diseases.
在先天性线粒体 DNA（mtDNA）疾病中，正常和突变的 mtDNA（称为异质性）以不同水平存在于不同的组织中，这决定了疾病的严重程度和表型表达。Pearson 骨髓胰腺综合征（PS）是一种由 mtDNA 异质性缺失引起的先天性骨髓衰竭疾病。PS 中造血衰竭的原因尚不清楚，并且缺乏足够的细胞和动物模型。诱导多能干细胞（iPS）特别适合研究 mtDNA 疾病，因为细胞质遗传物质在直接重编程过程中得以保留。在这里，我们从 PS 患者中获得并表征了 iPS 细胞。利用异质性随细胞传代而变化的趋势，我们分离出了具有可检测水平缺失 mtDNA 的同基因 PS-iPS 细胞。我们发现，与没有缺失 mtDNA 的同基因 iPS 细胞相比，携带大量缺失 mtDNA 的 PS-iPS 细胞在体外分化时，在生长、线粒体功能和造血表型方面存在差异。我们的结果表明，对 mtDNA 疾病患者的体细胞进行重编程可以产生具有不同异质性负担的多能干细胞，这可能有助于线粒体疾病的研究和治疗。
