Tif1 gamma regulates the TGF-beta 1 receptor and promotes physiological aging of hematopoietic stem cells

The hematopoietic system declines with age. Myeloid-biased differentiation and increased incidence of myeloid malignancies feature aging of hematopoietic stem cells (HSCs), but the mechanisms involved remain uncertain. Here, we report that 4-mo-old mice deleted for transcription intermediary factor 1 gamma (Tif1 gamma) in HSCs developed an accelerated aging phenotype. To reinforce this result, we also show that Tif1 gamma is down-regulated in HSCs during aging in 20-mo-old wild-type mice. We established that Tif1 gamma controls TGF-beta 1 receptor (Tgfbr1) turnover. Compared with young HSCs, Tif1 gamma(-/-) and old HSCs are more sensitive to TGF-beta signaling. Importantly, we identified two populations of HSCs specifically discriminated by Tgfbr1 expression level and provided evidence of the capture of myeloid-biased (Tgfbr1(hi)) and myeloid-lymphoid-balanced (Tgfbr1(lo)) HSCs. In conclusion, our data provide a new paradigm for Tif1 gamma in regulating the balance between lymphoid-and myeloid-derived HSCs through TGF-beta signaling, leading to HSC aging.