Ex Vivo Mitochondrial Transfer as a Way to Improve Stem Cell Therapy Outcomes

A sizable portion of the variable efficacy of first generation stem cell therapies as presently practiced may be due to a poor quality of cells following expansion in culture. Regardless of quality, near all such cells die shortly after transplantation. Few clinics and few approaches to cell therapy lead to lasting survival and engraftment of transplanted cells, and beneficial effects are largely mediated by the short period of signaling produced by these cells. A range of approaches have been taken in attempts to make transplanted cells more robust: methodological improvements in the process of obtaining and culturing cells for transplant; transplanting a scaffold material along with cells; providing cells with supporting signals or nutrients; engineering cells to produce proteins that will help in survival; culling senescent cells from the culture prior to transplantation. Adding to these, researchers here report on the use of mitochondrial transfer, taking advantage of a process that does occur naturally, in which cells take up mitochondria from the surrounding medium.

Bone marrow-derived mesenchymal stem cell (BMSC) transplantation is considered a promising therapeutic approach for bone defect repair. However, during the transplantation procedure, the functions and viability of BMSCs may be impaired due to extended durations of in vitro culture, aging, and disease conditions of patients. Inspired by spontaneous intercellular mitochondria transfer that naturally occurs within injured tissues to rescue cellular or tissue function, we investigated whether artificial mitochondria transfer into pre-transplant BMSCs in vitro could improve cellular function and enhance their therapeutic effects on bone defect repair in situ.

Mitochondria were isolated from donor BMSCs and transferred into recipient BMSCs of the same batch and passage. Subsequently, changes in proliferative capacity and cell senescence were evaluated. After that, in vivo experiments were performed by transplanting mitochondria-recipient BMSCs into a rat cranial critical-size bone defect model. Micro CT scanning and histological analysis were conducted at 4 and 8 weeks after transplantation to evaluate osteogenesis in situ. Finally, in order to establish the correlation between cellular behavioral changes and aerobic metabolism, OXPHOS (oxidative phosphorylation) and ATP production were assessed and inhibition of aerobic respiration by oligomycin was performed.

Mitochondria-recipient BMSCs exhibited significantly enhanced proliferation and migration, and increased osteogenesis upon osteogenic induction. The in vivo results showed more new bone formation after transplantation of mitochondria-recipient BMSCs in situ. Increased OXPHOS activity and ATP production were observed, which upon inhibition by oligomycin attenuated the enhancement of proliferation, migration, and osteogenic differentiation induced by mitochondria transfer. Thus mitochondria transfer is a feasible technique to enhance BMSC function in vitro and promote bone defect repair in situ through the upregulation of aerobic metabolism.

Link: https://doi.org/10.1186/s13287-020-01704-9

Comments

Mitochondrial Transfer looks like a promising treatment even for the existing cells. I hope we will see more research sooner. It seems like a low-hanging fruit for medial applications: grow generic cells with mitochondria (and other organelles). Blend/break the cells, freeze the organelles to be ready for injection.
Use off the shelf injections to treat the vulnerable tissues.

Posted by: cuberat at July 9th, 2020 2:07 PM

I'm wondering how much an in vivo experiment would cost using mitochondria inside Oisin's fusogenix lipid nanoparticles (to aid cell take up)?

You could inject into the muscles of an aged animal model to measure effects on sarcopenia.

I doubt Oisin have the money or management time to carry out such an experiment (particularly with investors money) but it would be interesting to see the result. It might be one of those research areas like senescent cells that just sit around for an extended period of time before some group finally scrapes together the funding for an experiment.

Posted by: jimofoz at July 11th, 2020 4:45 AM

@jimofoz
I don't see much benefit of using OISINs technology here since it seems the existing cells can shed extracellular vesicles containing mitochondria. What it takes is culture enough cells with the desired strain of mitos, induce "shedding", collect and inject.
OISIN on the other hand seems to be geared towards smaller particles, like small molecules that are encapsulated in lipid vehicles but can have very targeted delivery with cells with specific expression. The experiment would need to produce enough mitochondria, collect, purify them and encapsulate without killing them. Seems a much harder approach then using the natural process. There are a lot of unknowns there but they are mainly about the yield ...

Posted by: cuberat at July 11th, 2020 5:20 PM

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