Ana Cordeiro Gomes^1†, Takahiro Hara²*^†, Vivian Y. Lim^1†, Dietmar Herndler-Brandstetter¹, Erin Nevius¹, Tatsuki Sugiyama³, Shizue Tani-ichi², Susan Schlenner⁴, Ellen Richie⁵, Hans-Reimer Rodewald⁶, Richard A. Flavell¹, Takashi Nagasawa³, Koichi Ikuta², and Joao Pedro Pereira¹*

^†Co-first author; *Correspondence author

(1 Yale University; 2 Laboratory of Biological Protection, Institute for Virus Research, Kyoto University; 3 Osaka University; 4 University of Leuven; 5 University of Texas, 6 German Cancer Research Center)

Immunity (2016)  45:1219-1231. doi: 10.1016/j.immuni.2016.11.004

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 encounter lineage-instructive differentiation signals in HSC niches. 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. 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 IL-7 deletion in mesenchymal progenitors reduced B-lineage committed CLPs, whereas IL-7 deletion in endothelial cells specifically reduced proB and preB cells. Moreover, conditional CXCL12 or SCF deletion in 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.

Figure
(A) Distribution of IL-7⁺ CAR cells. (B) Distance to IL-7⁺ CAR cells. (C~F) Phenotypes of IL-7Cre⁺ SCF cKO mice (C), LeprCre⁺ IL-7 cKO mice (D, E), and Tie2Cre⁺ IL-7 cKO mice (F).