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

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.