Tif1γ regulates the TGF-β1 receptor and promotes physiological aging of hematopoietic stem cells

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 29; pp. 10592 - 10597
• Main Authors: Quéré, Ronan, Saint-Paul, Laetitia, Carmignac, Virginie, Martin, Romain Z., Chrétien, Marie-Lorraine, Largeot, Anne, Hammann, Arlette, de Barros, Jean-Paul Pais, Bastie, Jean-Noël, Delva, Laurent
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 22.07.2014; National Acad Sciences
• Subjects: Aging - metabolism; Animals; Antigens, CD - metabolism; B lymphocytes; Biological Sciences; Cell lines; Cell Separation; Cellular Senescence - drug effects; Gene Expression Regulation - drug effects; Hematopoiesis; Hematopoiesis - drug effects; Hematopoietic stem cells; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - metabolism; Mice; Myeloid cells; Myeloid Cells - metabolism; Phenotype; Phenotypes; Polyubiquitin - metabolism; Progenitor cells; Protein-Serine-Threonine Kinases - metabolism; Receptors; Receptors, Cell Surface - metabolism; Receptors, Transforming Growth Factor beta - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction - drug effects; Signaling Lymphocytic Activation Molecule Family Member 1; Stem cells; T lymphocytes; Transcription Factors - deficiency; Transcription Factors - genetics; Transcription Factors - metabolism; Transforming Growth Factor beta1 - pharmacology; Ubiquitination - drug effects
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1405546111

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 1γ (Tif1γ) in HSCs developed an accelerated aging phenotype. To reinforce this result, we also show that Tif1γ is down-regulated in HSCs during aging in 20-mo-old wild-type mice. We established that Tif1γ controls TGF-β1 receptor (Tgfbr1) turnover. Compared with young HSCs, Tif1γ ⁻/⁻ and old HSCs are more sensitive to TGF-β 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 Tif1γ in regulating the balance between lymphoid- and myeloid-derived HSCs through TGF-β signaling, leading to HSC aging.