13circulation (Itkin et al. 2016 ). Kusumbe et al., has also shown that arterioles support
HSPC. Constitutive activation of the Notch pathway in endothelial cells led to a
threefold increase in BM arterioles and associated perivascular cells and a ~ 50%
increase in HSC numbers indicating that arteriole density controls HSC frequency
(Kusumbe et al. 2016 ).
While the reports above support the idea that arterioles and periarteriolar cells
maintain and regulate a subset of HSC in the bone marrow other reports have found
no specific HSC association with arterioles. Acar et al., using α-catulin-GFP
reporter mice to label c-kit+GFP+ HSC found that 10% of these HSC were close
(less than 5 μm) to arterioles and they found no enrichment in quiescent HSC close
to arterioles (Acar et al. 2015 ).
Endosteal niches: As discussed above it is clear that most HSC reside in peri-
vascular niches. It is less clear whether the endosteal surface of the bone also pro-
vides a niche for HSC during homeostasis. A note of caution: some studies in the
literature have used the term “endosteal” to describe cells located in inner surface of
the bone while other studies have used this term to define cells with bone-forming
potential. The term “osteoblastic” have been used in a similar way. Through this
chapter we have used “endosteal” to describe a spatial location (proximity to the
inner surface of the bone) and “osteoblastic” to define differentiation potential into
bone cells. Studies in which different fractions of the bone marrow were purified
and then tested for HSC numbers have shown that HSC are enriched in the BM that
remains associated with the bone after fractionation supporting the idea of an end-
osteal niche (Nilsson et al. 2001 ). However, imaging studies have shown that less
than 5% of HSC are in direct contact with the cells that line the endosteal surface of
the bone (Acar et al. 2015 ). One possible explanation for this discrepancy is the fact
that most arterioles are located within ~40 μm of the bone surface (Itkin et al. 2016 ;
Kunisaki et al. 2013 ) and periarteriolar niches might thus account for HSC enrich-
ment in endosteal areas. However, the fact that macrophages are enriched in areas
close to the bone “osteomacs” (Christopher et al. 2011 ; Winkler et al. 2010 ) and that
bone-lining osteolineage cells are major sources of the HSC regulatory factors emb-
igin and angiogenin suggest that endosteal cells also support HSC (Goncalves et al.
2016 ; Silberstein et al. 2016 ). A second explanation for the lack of HSC in contact
with the bone surface is that endosteal cells might be capable of exerting their HSC-
regulatory function over longer distances than the ones used by endothelial and
perivascular cells. Additional studies are needed to define whether endosteal signals
regulate HSC during steady-state hematopoiesis.
2.5 Niches for Hematopoietic Progenitors Downstream
of the HSC
Hematopoiesis occurs in a hierarchical manner with more immature, multipotent,
stem and progenitor cells progressively committing into lineage-restricted progeni-
tors before giving rise to mature blood cells (reviewed in Babovic and Eaves ( 2014 )).
2 The Bone Marrow Microenvironment for Hematopoietic Stem Cells