Sex differences alter primitive progenitors in the C57BL/6 Tet2 knockout mouse model

The precancerous expansion of hematopoietic cells, termed clonal hematopoiesis (CH), has been correlated to disease development and all-cause mortality. Despite multiple observations that hematopoietic stem cell and progenitors (HSPCs) are significantly affected by both sex and age, there remain few studies quantifying male and female HSPC populations in wild-type and transgenic Tet2 models over time. Here, we determine that male mice (with a hematopoietic deficiency of Tet2 and control) have more Lin^-Sca-1⁺c-kit⁺ (LSK) cells, that include multipotent progenitor cells (MPPs; LSK CD48^-CD150^-) and long-term hematopoietic stem cells (LT-HSC; LSK CD48^-CD150⁺) compared with females. LT-HSC, MPP, and progenitor populations were observed to possess equal male/female ratios in mice at 6 weeks of age; however, the LSK compartment was found most susceptible to sex-based effects in transgenic mice between 6 weeks and 4 months. In contrast, all differentiated progenitor populations analyzed in mice were observed to be unaffected by sex between 6 weeks to 4 months. This study provides a comprehensive analysis of bone-sourced HSPCs in Tet2-deficient mouse models and reveals important sex and age considerations that must be taken into account when using C57BL/6 mice for transgenic studies.