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

Area of Science:

• Hematology
• Immunology
• Genetics

Background:

• Clonal hematopoiesis (CH) is linked to disease and mortality.
• Hematopoietic stem and progenitor cells (HSPCs) are known to be influenced by sex and age.
• Limited data exists on sex-based differences in HSPC populations within Tet2 models.

Purpose of the Study:

• To quantify and compare male and female HSPC populations in wild-type and Tet2-transgenic mouse models.
• To investigate the impact of sex and age on specific HSPC subsets, including LSK, MPP, and LT-HSC.
• To establish sex and age considerations for C57BL/6 mouse models in transgenic studies.

Main Methods:

• Analysis of bone marrow-sourced HSPCs from male and female wild-type and Tet2-deficient C57BL/6 mice.
• Flow cytometry to quantify Lin-Sca-1+c-kit+ (LSK) cells, multipotent progenitors (MPPs), and long-term hematopoietic stem cells (LT-HSCs).
• Comparison of cell populations across different age groups (6 weeks to 4 months).

Main Results:

• Male mice showed significantly higher numbers of LSK cells, including MPPs and LT-HSCs, compared to females.
• Initial equal male/female ratios in LT-HSC and MPP populations at 6 weeks were observed.
• The LSK compartment demonstrated the greatest susceptibility to sex-based effects in Tet2-deficient mice between 6 weeks and 4 months.
• Differentiated progenitor populations remained unaffected by sex during this period.

Conclusions:

• Significant sex-based differences exist in HSPC populations, particularly LSK cells, in Tet2-deficient mice.
• Age and sex are critical factors influencing HSPC dynamics in mouse models.
• Findings highlight the importance of accounting for sex and age in C57BL/6 mouse studies involving Tet2 deficiency.