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abundance of other stromal components of the niche illustrating their central role in
the niche (Kusumbe et al. 2016 ; Ramasamy et al. 2014 ). In close contact with sinu-
soids and arterioles, and connected to them and to each other via different adhesion
molecules (including GAP junctions (Gonzalez-Nieto et al. 2012 ; Schajnovitz et al.
2011 )), is a tridimensional network of LepR+ stromal cells that are also major
sources of the CXCL12 and SCF that maintain HSC (Asada et al. 2017a; Ding and
Morrison 2013 ; Ding et al. 2012 ; Greenbaum et al. 2013 ). These cells have been
Fig. 2.1 Structure of the HSC niche. For simplicity hematopoietic cells are depicted with nuclei
whereas stromal cells are shown without nucleus. Block arrows indicate direct regulation. Most
hematopoietic stem cells (HSC) are located near perivascular areas (arterioles or sinusoids) where
endothelial cells (EC) provide critical signals for HSC maintenance and function. LepR+ reticular
cells form a tridimensional network intimately associated with the vasculature. They produce sig-
nals like CXCL12 and SCF that regulate HSC directly. Megakaryocytes (Mk) are associated with
the sinusoids and restrict HSC proliferation via CXCL4, TGFβ and TPO signaling. Bone marrow
macrophages (MΦ) are interspersed through the bone marrow but enriched in the endosteal surface
close to osteoblasts. They promote HSC retention in the bone marrow by regulating CXCL
production by perivascular stromal cells through an unknown mechanism. Macrophages are in turn
regulated by aged neutrophils that return from the periphery. When macrophages phagocytose
these aged neutrophils they became activated triggering CXCL12 downregulation in perivascular
niche cells and thus HSC release. In the arterioles Ng2+ periarteriolar cells promote quiescence in
a subset of HSC suggesting the existence of a periarteriolar niche. Sympathetic nerves enter the
bone marrow associated with arteries and regulate HSC trafficking by controlling CXCL12 pro-
duction by perivascular stromal cells. Associated with sympathetic fibers are non-myelinating
Schwann cells that restrict HSC proliferation via TGFβ signaling. Osteolineage cells (OLC) in the
endosteal surface of the bone regulate HSC maintenance via embigin and angiogenin signaling
D. Lucas