21Mendelson and Frenette 2014 ). Recent advances in microscopy and transgenic ani-
mal models have revolutionized the understanding of these niches (Morrison and
Scadden 2014 ). Quiescent HSCs associated with periarteriolar niches are found
within the endosteal BM (Kunisaki et al. 2013 ), where arterioles run in proximity to
the endosteal surface, accompanied by sympathetic nerve fibers ensheathed by non-
myelinating Schwann cells. In turn, sinusoids, fenestrated and lined by reticular-
shaped sinusoidal cells, are associated with less-quiescent HSCs re-localizing to
perisinusoidal niches (Kunisaki et al. 2013 ; Kfoury et al. 2014 ). The surface of the
endosteum in the endosteal niche is lined by osteoblasts and osteoclasts. Osteoblasts
are progenitor bone-forming cells derived from pluripotent MSCs (Adams et al.
2006 ). Interactions between angiopoietin-1 (ANG1) in osteoblasts with its receptor
Tyrosine kinase with immunoglobulin-like and EGF-like domains 2 (TIE2) on
HSCs result in activation of β1-integrin and N-cadherin and enhanced adhesion
between niche cells and HSCs, which contributes to the maintenance of stem cell
quiescence (Arai et al. 2004 ). Notably, AML cells induce a preosteoblast-rich niche
in the BM that in turn facilitates AML expansion (Battula et al. 2017 ). The C-X-C
motif chemokine 12 (CXCL12), which is produced by osteoblasts, is the major
chemoattractant of HSCs (Christopher et al. 2009 ).
Bone-resorbing osteoclasts participate in the initial formation and maintenance
of cavities that constitute the endosteal niche (Adams et al. 2006 ; Mendelson and
Frenette 2014 ). Osteoclastic bone resorption produces abundant active transforming
growth factor beta (TGF-β) from bone, which is the largest latent reservoir of TGF-β
(Morrison and Scadden 2014 ). The sympathetic nervous system is responsible for
regulating HSCs residing in the periarteriolar position via norepinephrine signaling
(Katayama et al. 2006 ). A mechanistic analysis showed that nonmyelinating
Schwann cells activate latent TGF-β, and the neoplastic niche is altered by leukemic
cells through sympathetic neuropathy (Hanoun et al. 2014 ). For example, MLL-AF9
acute myeloid leukemia (AML) cells transform the HSC niche, reducing the num-
bers of arteriole-associated niche cells and the density of their sympathetic nerve
network (Hanoun et al. 2014 ; Price and Sipkins 2014 ). Sympathetic neuropathy by
myeloproliferative neoplasia (MPN) alter the HSC niche and progression of the
disease; MPN cells produce interleukin-1β (IL-1β) that destroys Schwann cells sup-
porting sympathetic nerve fibers, followed by the apoptotic loss of Nestin-positive
(Nestin+) cells and reduced HSC maintenance factors in the microenvironment,
such as CXCL12, resulting in peripheral mobilization of HSCs and accelerated
MPN cell expansion in the BM (Price and Sipkins 2014 ) The perivascular cells in
the vascular niche include CXCL12-abundant reticular (CAR) cells (Sugiyama
et al. 2006 ), Nestin+ MSCs (Méndez-Ferrer et al. 2010 ) and leptin receptor-positive
(LepR+) MSCs (Ding et al. 2012 ) exhibiting significant overlap and expressing
multiple soluble and membrane-bound factors that regulate stem cell self-renewal
and retention (Doan and Chute 2012 ). The conditional deletion of stem cell factor
from LepR+ perivascular stromal cells, including Nestin+ MSCs and CAR cells,
significantly reduces the number of HSCs (Adams et al. 2006 ).
Multiple mature hematopoietic cells including T-regulatory (Treg) cells, macro-
phages, and megakaryocytes also participate in regulation of the BM microenvironment
3 Leukemia Stem Cells Microenvironment