Department of Pediatrics, McMaster University, Hamilton, ON, Canada.
Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, Children's Health Research Institute, London, ON, Canada.
FASEB J. 2020 Jul;34(7):9297-9306. doi: 10.1096/fj.202000463R. Epub 2020 May 22.
Studies have shown that mitochondrial DNA (mtDNA) can be exchanged between tissues; however, the mechanism(s) behind this phenomenon remain unclear. Exosomes and other extracellular vesicles (EVs) including microvesicles (MV) have been shown to contain mtDNA. EVs can be derived from a number of tissues; however, the source and relative proportion of EVs containing mtDNA remains unknown. We sampled whole blood and the EV fractions (exosome-enriched, MV-enriched, and apoptotic body-enriched) as well as several tissues (epithelial-cheek and urine sediment), connective (fibroblasts), and skeletal muscle in two subjects who received allogenic bone marrow transplants. Next generation sequencing of the mtDNA confirmed that all EV fractions contained mtDNA and most was derived from the donor, confirming that most of the EV fractions in the serum are bone marrow/blood cell-derived. Even after exposure to the donor mtDNA in EV fractions (and potentially free in the plasma) for years, there was little to no transfer of the donor mtDNA to the host mtDNA fraction in epithelial, connective, or skeletal muscle tissues. These data call into question the potential therapeutic use of bone marrow transplant or EV-based delivery systems for mtDNA-based disorders and establish bone marrow as the primary source of most of the mtDNA enriched EVs in serum.
研究表明，线粒体 DNA（mtDNA）可以在组织间进行交换；然而，这种现象背后的机制尚不清楚。外泌体和其他细胞外囊泡（EVs），包括微泡（MV），已被证明含有 mtDNA。EVs 可以来源于多种组织；然而，含有 mtDNA 的 EVs 的来源和相对比例尚不清楚。我们在两名接受同种异体骨髓移植的受试者中采集了全血和 EV 部分（富含外泌体、富含 MV 和富含凋亡小体）以及几种组织（上皮-颊和尿沉淀物）、结缔组织（成纤维细胞）和骨骼肌。mtDNA 的下一代测序证实，所有 EV 部分均含有 mtDNA，且大部分来自供体，证实血清中的大多数 EV 部分来源于骨髓/血细胞。即使在接受 EV 部分中的供体 mtDNA（并可能在血浆中自由存在）暴露多年后，供体 mtDNA 向宿主 mtDNA 部分在上皮、结缔或骨骼肌组织中的转移也很少或没有。这些数据对骨髓移植或基于 EV 的递药系统治疗基于 mtDNA 的疾病的潜在用途提出了质疑，并确立了骨髓是富含 mtDNA 的 EVs 在血清中的主要来源。
