14
These hematopoietic progenitors also depend on signals from the microenviron-
ment for maintenance and differentiation but they are much less characterized than
HSC niches although significant progress has been made in identifying these cells.
Osteoblasts do not seem to regulate HSC function during homeostasis but they pro-
vide a niche for common lymphoid progenitors (CLP) via CXCL12 production
(Ding and Morrison 2013 ; Greenbaum et al. 2013 ). LepR+ cells are also necessary
for CLP maintenance via CXCL12 and IL7 production (Cordeiro Gomes et al.
2016 ). Bone marrow macrophages provide a niche for differentiating erythroid cells
(Chow et al. 2013 ; Ramos et al. 2013 ). Differentiating erythroid cells regulate HSPC
numbers via ACKR1 (Duchene et al. 2017 ). In the case of myeloid cells it is known
that stromal cells regulate monocyte egress (Shi et al. 2011 ) and proliferation after
TLR activation (Boettcher et al. 2012 , 2014 ); Crebbp haploinsufficiency in stromal
cells increased myelopoiesis (Zimmer et al. 2011 ) whereas IκBκ or DICER deletion
in the stroma lead to myeloproliferative disease (Raaijmakers et al. 2010 ; Rupec
et al. 2005 ). Also, osteocytes regulate myelopoiesis via GαS signaling (Fulzele et al.
2013 ). Identifying the specific niches for each hematopoietic progenitor is neces-
sary in order to understand how normal and pathological hematopoiesis occurs.
This has become more relevant with discoveries suggesting that HSC might not be
the main source of blood cells in the steady-state. Two independent analyses of
steady-state hematopoiesis suggest that more differentiated hematopoietic progeni-
tors are responsible for most blood cell production with rare input from HSC (Busch
et al. 2015 ; Sun et al. 2014 ) although these results have been challenged recently
(Sawai et al. 2016 ). In addition mice lacking functional HSC or mice in which most
HSC have been ablated are capable of maintaining almost normal hematopoiesis
(Jones et al. 2015 ; Schoedel et al. 2016 ).
2.6 Concluding Remarks
The bone marrow niche is incredibly complex with multiple cells cooperating to inte-
grate signals and provide input to regulate HSC, hematopoietic progenitors and blood
cell output. Understanding how these niches function in vivo is essential to under-
stand how hematopoiesis is regulated and might lead to the development of therapies
that target specific niche components to modulate blood cell production as needed.
References
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Phelps K, Morrison SJ (2015) Deep imaging of bone marrow shows non-dividing stem cells
are mainly perisinusoidal. Nature 526:126–130
Asada N, Katayama Y, Sato M, Minagawa K, Wakahashi K, Kawano H, Kawano Y, Sada A, Ikeda
K, Matsui T et al (2013) Matrix-embedded osteocytes regulate mobilization of hematopoietic
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D. Lucas