title: Mesenchymal stem cells transfer mitochondria to the cells with virtually no mitochondrial function but not with pathogenic mtDNA mutations.
abstract: It has been reported that human mesenchymal stem cells (MSCs) can transfer mitochondria to the cells with severely compromised mitochondrial function. We tested whether the reported intercellular mitochondrial transfer could be replicated in different types of cells or under different experimental conditions, and tried to elucidate possible mechanism. Using biochemical selection methods, we found exponentially growing cells in restrictive media (uridine(-) and bromodeoxyuridine [BrdU](+)) during the coculture of MSCs (uridine-independent and BrdU-sensitive) and 143B-derived cells with severe mitochondrial dysfunction induced by either long-term ethidium bromide treatment or short-term rhodamine 6G (R6G) treatment (uridine-dependent but BrdU-resistant). The exponentially growing cells had nuclear DNA fingerprint patterns identical to 143B, and a sequence of mitochondrial DNA (mtDNA) identical to the MSCs. Since R6G causes rapid and irreversible damage to mitochondria without the removal of mtDNA, the mitochondrial function appears to be restored through a direct transfer of mitochondria rather than mtDNA alone. Conditioned media, which were prepared by treating mtDNA-less 143B ρ(0) cells under uridine-free condition, induced increased chemotaxis in MSC, which was also supported by transcriptome analysis. Cytochalasin B, an inhibitor of chemotaxis and cytoskeletal assembly, blocked mitochondrial transfer phenomenon in the above condition. However, we could not find any evidence of mitochondrial transfer to the cells harboring human pathogenic mtDNA mutations (A3243G mutation or 4,977 bp deletion). Thus, the mitochondrial transfer is limited to the condition of a near total absence of mitochondrial function. Elucidation of the mechanism of mitochondrial transfer will help us create a potential cell therapy-based mitochondrial restoration or mitochondrial gene therapy for human diseases caused by mitochondrial dysfunction.
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Young Min
authors.initials: YM
authors.lastname: Cho
authors.forename: Ju Han
authors.initials: JH
authors.lastname: Kim
authors.forename: Mingoo
authors.initials: M
authors.lastname: Kim
authors.forename: Su Jin
authors.initials: SJ
authors.lastname: Park
authors.forename: Sang Hyeok
authors.initials: SH
authors.lastname: Koh
authors.forename: Hyo Seop
authors.initials: HS
authors.lastname: Ahn
authors.forename: Gyeong Hoon
authors.initials: GH
authors.lastname: Kang
authors.forename: Jung-Bin
authors.initials: JB
authors.lastname: Lee
authors.forename: Kyong Soo
authors.initials: KS
authors.lastname: Park
authors.forename: Hong Kyu
authors.initials: HK
authors.lastname: Lee
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D018920:Coculture Techniques; D017077:Culture Media, Conditioned; D004272:DNA, Mitochondrial / Q000235:genetics*; D020869:Gene Expression Profiling; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D018895:Microsatellite Repeats / Q000235:genetics; D008928:Mitochondria / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D013997:Time Factors
chemical_list: D017077:Culture Media, Conditioned; D004272:DNA, Mitochondrial