Biology

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

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