Mitochondrial transfer to host cells from ex vivo expanded donor hematopoietic stem cells

Abstract: Mitochondrial dysfunction is observed in various conditions, from metabolic syndromes to mitochondrial diseases. Moreover, Mitochondrial DNA (mtDNA) transfer is an emerging mechanism that enables restoration of mitochondrial function in damaged cells. Hence, developing the technology that facilitates transfer of mtDNA can be a promising strategy for the treatment of these conditions. Here, we utilized an ex vivo culture of mouse hematopoietic stem cells (HSCs) and succeeded in expanding HSCs efficiently. Upon transplantation, sufficient donor HSC engraftment was attained in host. To assess the mitochondrial transfer via donor HSCs, we used mitochondrial-nuclear exchange (MNX) mice with nuclei from C57BL/6J and mitochondria from the C3H/HeN strain. Cells from MNX mice have C57BL/6J immunophenotype and C3H/HeN mtDNA, which is known to confer a higher stress resistance to mitochondria. Ex vivo expanded MNX HSCs were transplanted into irradiated C57BL/6J mice and the analyses were done at six weeks post transplantation. We observed high engraftment of donor cells in peripheral blood as well as in bone marrow. We also found that HSCs from the MNX mice could transfer mtDNA to host cells. This work highlights the utility of ex vivo expanded HSC to achieve the mitochondrial transfer from donor to host in the transplant setting.