Cordeiro Gomes Ana, Hara Takahiro, Lim Vivian Y, Herndler-Brandstetter Dietmar, Nevius Erin, Sugiyama Tatsuki, Tani-Ichi Shizue, Schlenner Susan, Richie Ellen, Rodewald Hans-Reimer, Flavell Richard A, Nagasawa Takashi, Ikuta Koichi, Pereira João Pedro
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto, 4099-002 Porto, Portugal.
Laboratory of Biological Protection, Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan.
Immunity. 2016 Dec 20;45(6):1219-1231. doi: 10.1016/j.immuni.2016.11.004. Epub 2016 Nov 29.
Hematopoietic stem cells (HSCs) self-renew in bone marrow niches formed by mesenchymal progenitors and endothelial cells expressing the chemokine CXCL12, but whether a separate niche instructs multipotent progenitor (MPP) differentiation remains unclear. We show that MPPs resided in HSC niches, where they encountered lineage-instructive differentiation signals. Conditional deletion of the chemokine receptor CXCR4 in MPPs reduced differentiation into common lymphoid progenitors (CLPs), which decreased lymphopoiesis. CXCR4 was required for CLP positioning near Interleukin-7 (IL-7) cells and for optimal IL-7 receptor signaling. IL-7 cells expressed CXCL12 and the cytokine SCF, were mesenchymal progenitors capable of differentiation into osteoblasts and adipocytes, and comprised a minor subset of sinusoidal endothelial cells. Conditional Il7 deletion in mesenchymal progenitors reduced B-lineage committed CLPs, while conditional Cxcl12 or Scf deletion from IL-7 cells reduced HSC and MPP numbers. Thus, HSC maintenance and multilineage differentiation are distinct cell lineage decisions that are both controlled by HSC niches.
造血干细胞（HSCs）在由表达趋化因子CXCL12的间充质祖细胞和内皮细胞形成的骨髓龛中自我更新，但是否存在一个独立的龛指导多能祖细胞（MPP）分化仍不清楚。我们发现MPP存在于HSC龛中，在那里它们会遇到指导谱系分化的信号。在MPP中条件性删除趋化因子受体CXCR4会减少向常见淋巴祖细胞（CLP）的分化，进而降低淋巴细胞生成。CXCR4对于CLP定位在白细胞介素-7（IL-7）细胞附近以及最佳IL-7受体信号传导是必需的。IL-7细胞表达CXCL12和细胞因子干细胞因子（SCF），是能够分化为成骨细胞和脂肪细胞的间充质祖细胞，并且构成了一小部分窦状内皮细胞。间充质祖细胞中条件性删除Il7会减少B谱系定向的CLP，而从IL-7细胞中条件性删除Cxcl12或Scf会减少HSC和MPP的数量。因此，HSC的维持和多谱系分化是由HSC龛控制的不同细胞谱系决定。
