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 ρ0 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.
Highlights
In the 1940s, Lederberg and Tatum discovered the conjugation phenomenon, which is a process of a unidirectional transfer of genetic information essential for survival on a minimal medium through the formation of a physical bridge between a donor bacterium and a recipient bacterium [1]
By using biochemical selection methods, we hereby showed that mesenchymal stem cells (MSCs) can transfer mitochondria to the cells lacking mitochondrial DNA (mtDNA), which is consistent with the previous report [2]
All recuperated cells were trans-mitochondrial hybrid 143B cells (TM143B) cybrid cells that contained the nuclear genome of 143B cells and mtDNAs from the MSCs
Summary
In the 1940s, Lederberg and Tatum discovered the conjugation phenomenon, which is a process of a unidirectional transfer of genetic information essential for survival on a minimal medium through the formation of a physical bridge between a donor bacterium and a recipient bacterium [1]. Similar to the earlier findings in prokaryotes, it was recently reported that human mesenchymal stem cells (MSCs) can transfer mitochondria (microorganelles containing their own genetic information) to the cells with nonfunctional mitochondria incapable of aerobic respiration due to defective or deleted mitochondrial DNA (mtDNA) [2]. Isolated mitochondria or platelets, which contain mitochondria, could not restore mitochondrial function of the cells with nonfunctional mitochondria [2]. It is uncertain whether the restoration of mitochondrial function is mediated by the transfer of mtDNA alone, which is similar to the conjugation phenomenon, or by the transfer of intact mitochondrial particles
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