Tif1γ controls the TGF-β receptor on hematopoietic stem cells: implication in physiological aging

Abstract

Hematopoietic stem cell (HSC) aging has been directly linked to the development of several hematological disorders including myeloproliferative diseases. We recently described that in elderly mice (20-month-old), physiological aging of the hematopoietic system is associated with a decreased expression of the Transcription Intermediary Factor 1γ (Tif1γ) gene in HSCs. In young mice (4-month-old), deleted for the Tif1γ gene in HSCs (Tif1γ -/- ), the hematopoiesis aging phenotype is intensified. We discovered that Tif1γ controls the TGF-b receptor 1 (Tgfbr1) and finely regulates the number of myeloid-restricted HSCs in bone marrow. Altogether, we established that young Tif1γ -/- mice develop a phenotype of premature hematopoietic aging, which may explain their tendency to myeloproliferative disease. We identified two populations of HSCs specifically discriminated by Tgfbr1 expression and afforded evidence of the capture of myeloid-restricted (Tgfbr1 hi ) and myeloid-lymphoid-balanced (Tgfbr1 lo ) HSC. In conclusion, our study proves that Tif1γ can regulate the balance between lymphoid and myeloid HSCs, through a modulation of the TGF-b signaling.