Elevated Oxidative Stress Impairs Hematopoietic Progenitor Function in C57BL/6 Substrains

Abstract

Summary: C57BL/6N (N) and C57BL/6J (J) mice possess key genetic differences, including a deletion in the Nicotinamide nucleotide transhydrogenase (Nnt) gene that results in a non-functional protein in J mice. NNT regulates mitochondrial oxidative stress. Although elevated oxidative stress can compromise hematopoietic stem and progenitor cell (HSPC) function, it is unknown whether N- and J-HSPCs are functionally equivalent. Here, we report that J-HSPCs display compromised short-term hematopoietic repopulating activity relative to N-HSPCs that is defined by a delay in lymphoid reconstitution and impaired function of specific multi-potent progenitor populations post transplant. J-HSPCs also displayed elevated reactive oxygen species (ROS) relative to N-HSPCs post transplant and upregulate ROS levels more in response to hematopoietic stress. Nnt knockdown in N-HSPCs recapitulated J-HSPCs’ short-term repopulating defect, indicating that NNT loss contributes to this defect. In summary, C57BL/6N and C57BL/6J HSPCs are not functionally equivalent, which should be considered when determining the substrain most appropriate for investigations of HSPC biology. : By directly assessing the repopulating capability of mouse HSPCs in vivo, Morales-Hernández and colleagues describe critical functional differences between two widely used C57BL/6 substrains, including the ability of HSPCs to resolve oxidative stress during HSCT. This finding highlights the critical importance of genetic background when studying HSPCs, especially their metabolism, mitochondrial function, or response to hematopoietic stress. Keywords: hematopoietic stem cell transplantation, oxidative stress, nicotinamide nucleotide transhydrogenase, Nnt, C57BL/6