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Review
. 2018 Jan 22;145(2):dev139691.
doi: 10.1242/dev.139691.

The hematopoietic stem cell niche: from embryo to adult

Xin Gao  1   2 , Chunliang Xu  1   2 , Noboru Asada  1   2 , Paul S Frenette  3   2
Affiliations
Review

The hematopoietic stem cell niche: from embryo to adult

Xin Gao et al. Development. .

Abstract

Hematopoietic stem cells (HSCs) develop in discrete anatomical niches, migrating during embryogenesis from the aorta-gonad-mesonephros (AGM) region to the fetal liver, and finally to the bone marrow, where most HSCs reside throughout adult life. These niches provide supportive microenvironments that specify, expand and maintain HSCs. Understanding the constituents and molecular regulation of HSC niches is of considerable importance as it could shed new light on the mechanistic principles of HSC emergence and maintenance, and provide novel strategies for regenerative medicine. However, controversy exists concerning the cellular complexity of the bone marrow niche, and our understanding of the different HSC niches during development remains limited. In this Review, we summarize and discuss what is known about the heterogeneity of the HSC niches at distinct stages of their ontogeny, from the embryo to the adult bone marrow, drawing predominantly on data from mouse studies.

Keywords: Bone marrow; Hematopoietic stem cell; Hemogenic endothelium; Microenvironment; Niche.

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Conflict of interest statement

Competing interestsThe authors declare no competing or financial interests.

Figures

Fig. 1.
Fig. 1.
HSC niche during mouse embryonic development. (A,B) Schematics of mouse embryos at E10.5 (A) and E12.5 (B). Rostral is top, dorsal to the right. (A) At E10.5, HSCs are generated from hemogenic endothelium within the dorsal aorta (A), which is located in the AGM (shown in magnified view), between the mesenchymal (M) tissue that gives rise to the gonads (G) and mesonephros (Me). The magnified image (right) shows a cross-section of the dorsal aorta, in which stromal cells and catecholamines, released from sympathetic nervous system, contribute to the embryonic HSC niche and regulate HSC specification within the AGM. (B) At E12.5, HSCs migrate through the circulation to the fetal liver (FL) via the portal sinus. In the fetal liver, HSCs undergo a dramatic expansion before colonizing the bone marrow. The magnified image shows a cross-section showing NG2+ nestin+ pericytes, which associate with portal vessels, contributing to a niche that promotes HSC expansion.
Fig. 2.
Fig. 2.
HSC niche players in the adult bone marrow. Schematic of the adult bone marrow, showing various cell types that contribute to the HSC bone marrow niche. Sinusoid endothelial cells regulate HSC maintenance by producing SCF and Jag1. Peri-arteriolar NG2- and Nes-GFP-expressing stromal cells (dark red) secrete CXCL12, which is essential for HSC maintenance. CXCL12-abundant reticular (CAR) cells that co-express LepR and Nes-GFP (green), mainly locate around sinusoids. CXCL12 secreted from these cells controls the mobilizing pool of HSCs. CXCL12 secreted from arteriole-associated stromal cells controls HSC quiescence. SCF secreted from peri-sinusoidal stromal cells (CAR, LepR+, Nes-GFP+ cell) contributes to maintaining HSCs. Non- myelinating Schwann cells activate latent TGFβ into its active form, which is important for HSC maintenance. Mature hematopoietic cells also participate in the orchestration of HSC function; CD169+ bone marrow macrophages promote HSC retention by increasing CXCL12 production by Nes-GFP+ stromal cells and megakaryocytes maintain HSC quiescence via CXCL4, TGFβ and thrombopoietin (TPO).
Fig. 3.
Fig. 3.
The aging HSC niche. Schematic of the aging HSC niche and its associated alterations. The number of phenotypic HSCs (e.g. identified by fluorescence-activated cell sorting analysis) in the bone marrow increases with aging. Aged HSCs exhibit increased proliferation, reduced homing and regenerative capacity, and myeloid-biased differentiation. The potential effects of HSC aging on the bone marrow include various abnormalities, such as altered vasculature, increased adipogenesis, reduced osteogenesis, altered secretion of extrinsic factors from niche cells (increased secretion of CCL5 and decreased OPN levels), and reduced adhesion between HSCs and stroma cells.
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