11the osteoblastic lineage have increased HSC numbers (Calvi et al. 2003 ; Zhang
et al. 2003 ) strongly suggested that osteoblast were niche components. However,
mice deficient in biglycan have a twofold reduction in bone marrow osteoblasts but
no changes in HSC numbers or function (Kiel et al. 2007 ). Similarly, strontium
treatment expands osteoblasts but has no effect on HSC numbers (Lymperi et al.
2008 ). These results suggest that the HSC expansion observed by Calvi et al., and
Zhang et al., were mediated by expansion of osteoprogenitors (including LepR+
cells and angiogenin-producing osteolineage cells) and not mature osteoblasts
which seem dispensable for HSC maintenance in the steady-state.
Osteocytes are bone cells that are completely embedded in the bone. Conditional
deletion of Gsα in osteocytes using DMP1-cre mice led to expansion of BM myeloid
cells but not HSC suggesting that osteocytes can control hematopoiesis (Fulzele
et al. 2013 ). A different study showed that osteocyte depletion did not affect bone
marrow hematopoietic stem and progenitor numbers in the steady-state but blocked
G-CSF-induced mobilization (Asada et al. 2013 ). These studies suggest that osteo-
cytes can regulate physiological and emergency hematopoiesis but do not regulate
HSC during homeostasis.
Osteoclasts are multinucleated cells that arise via differentiation of myeloid pro-
genitors. They reside in the surface of the bone where they digest the mineralized
matrix to promote bone resorption. The first study to propose a role for osteoclasts
in regulating HSC showed that treatment of mice with the cytokine RANKL
increased osteoclasts numbers and mobilized HSC to the circulation. RANKL-
induced mobilization was inhibited in PTPε-knockout females-which have a mild
impairment in osteoclast function-suggesting that the observed phenotype was
mediated by osteoclasts (Kollet et al. 2006 ). However, a different study found that
acute osteoclast depletion via treatment with the bisphosphonate zoledronate did
not mobilize HSC (Winkler et al. 2010 ). Lymperi et al., found that chronic osteo-
clast ablation with the bisphosphonate alendronate reduced HSC numbers (Lymperi
et al. 2011 ). In contrast Miyamoto et al., examined three mouse models of osteo-
clasts deficiency (op/op, c-Fos-deficient and RANKL-deficient) and found increases
in HSC numbers (Miyamoto et al. 2011 ). Paradoxically, the same authors also found
that HSC mobilization was reduced in mice with a genetic mutation that increased
osteoclasts numbers but increased in wild-type mice in which osteoclasts have been
inhibited via alendronate treatment (Miyamoto et al. 2011 ). Thus the function of
osteoclasts in the steady-state niche is far from clear and additional studies are
needed to clarify the role of these cells in regulating HSC and their niches.
2.4 Heterogeneity of the HSC Niche
The niche cells described above are in different spatial locations in the BM and have
distinct effects on regulation of HSC like maintenance (e.g. endothelial cells, LepR+
cells (Ding and Morrison 2013 ; Ding et al. 2012 ; Greenbaum et al. 2013 )); inhibi-
tion of proliferation (e.g. megakaryocytes or non-myelinating Schwann cells (Bruns
2 The Bone Marrow Microenvironment for Hematopoietic Stem Cells