Tet2-mediated clonal hematopoiesis in nonconditioned mice accelerates age-associated cardiac dysfunction

Area of Science:

• Hematology
• Cardiovascular Biology
• Aging Research

Background:

• Clonal hematopoiesis of indeterminate potential (CHIP) is common in the elderly and linked to mortality and cardiovascular disease.
• Existing mouse models do not fully capture CHIP dynamics in cardiovascular health under homeostatic conditions.

Purpose of the Study:

• To develop and characterize a novel mouse model for studying CHIP and its cardiovascular consequences in a non-conditioned setting.
• To investigate the impact of Tet2-mutant hematopoiesis on cardiac function and inflammation.

Main Methods:

• Adoptive transfer of ten-eleven translocation 2-mutant (Tet2-mutant) bone marrow cells into nonirradiated mice.
• Analysis of Tet2-deficient cell expansion in hematopoietic stem and progenitor cells and various blood lineages.
• Transcriptome profiling of cardiac myeloid cells.
• Assessment of cardiac structure and function.

Main Results:

• Tet2-mutant cells progressively expanded in hematopoietic compartments and blood lineages, mirroring human age-related CHIP.
• Tet2-mutant cells infiltrated cardiac myeloid populations, with donor-derived macrophages showing an enhanced inflammatory signature.
• Mice developed spontaneous age-related cardiac dysfunction, including increased hypertrophy and fibrosis.

Conclusions:

• Tet2-mediated hematopoiesis contributes to cardiac dysfunction in a model that accurately reflects human CHIP in unperturbed bone marrow.
• The findings support the hypothesis that CHIP itself may diminish health span by impacting cardiovascular health.