Immunity
Volume 45, Issue 6, 20 December 2016, Pages 1219-1231
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Article
Hematopoietic Stem Cell Niches Produce Lineage-Instructive Signals to Control Multipotent Progenitor Differentiation

https://doi.org/10.1016/j.immuni.2016.11.004Get rights and content
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Highlights

  • Hematopoietic multipotent progenitors require CXCR4 for multilineage differentiation

  • IL-7 acts as a short-range signal for common lymphoid progenitor differentiation

  • IL-7+ cells are CXCL12-abundant reticular mesenchymal progenitor cells

  • CXCL12 and SCF expressed by IL-7+ cells control the number of HSCs and MPPs in BM

Summary

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.

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