Catelain Cyril, Michelet Fabio, Hattabi Aurore, Poirault-Chassac Sonia, Kortulewski Thierry, Tronik-Le Roux Diana, Vainchenker William, Lauret Evelyne
Inserm U974, CNRS (UMR 7215), UM 76, Institut de Myologie, Paris F-75013, France; Inserm, U1009, 114 rue E. Vaillant, Villejuif, F-94805, France; Institut Gustave Roussy, Villejuif, F-94805, France; Université Paris-Sud 11, Orsay, F-91405, France.
Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France; Inserm, U1016, Paris, France.
Stem Cell Res. 2014 Nov;13(3 Pt A):431-41. doi: 10.1016/j.scr.2014.10.002. Epub 2014 Oct 13.
Understanding the role of Notch and its ligands within the different bone marrow niches could shed light on the mechanisms regulating haematopoietic progenitor cells (HPCs) maintenance and self-renewal. Here, we report that murine bone marrow HPCs activation by the vascular Notch Delta-4 ligand maintains a significant proportion of cells specifically in the G0 state. Furthermore, Delta-4/Notch pathway limits significantly the loss of the in vivo short-term reconstitutive potential upon transplantation of Delta-4 activated HPCs into lethally irradiated recipient mice. Both effects are directly correlated with the decrease of cell cycle genes transcription such as CYCLIN-D1, -D2, and -D3, and the upregulation of stemness related genes transcription such as BMI1, GATA2, HOXB4 and C-MYC. In addition, the transcriptional screening also highlights new downstream post-transcriptional factors, named PUMILIO1 and -2, as part of the stem signature associated with the Delta-4/Notch signalling pathway.
了解Notch及其配体在不同骨髓微环境中的作用，有助于阐明调节造血祖细胞（HPC）维持和自我更新的机制。在此，我们报告称，血管Notch Delta-4配体激活小鼠骨髓HPC可使相当比例的细胞特异性维持在G0状态。此外，Delta-4/Notch信号通路显著限制了将Delta-4激活的HPC移植到受致死性照射的受体小鼠体内后体内短期重建潜力的丧失。这两种效应都与细胞周期基因如CYCLIN-D1、-D2和-D3转录的减少以及干性相关基因如BMI1、GATA2、HOXB4和C-MYC转录的上调直接相关。此外，转录筛选还突出了新的下游转录后因子，即PUMILIO1和-2，作为与Delta-4/Notch信号通路相关的干性特征的一部分。
