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Chapter 11 Hematopoietic Microenvironment 121

expressing extracellular matrix (ECM) protein osteocalcin and even- by sinusoidal endothelial cells also plays a role in the retention and
tually to osteocytes. self-renewal of HSPC in BM. 13
Several lines of in vivo evidence support a functional role of the
OLCs in regulation of primitive hematopoietic cells. In the studies
providing the first experimental evidence for a mammalian niche Perivascular Cells
in vivo, mice with genetically modified OLCs had an increase in
the number of activated OLCs and a corresponding increase in the The observation that HSPCs colocalize with the marrow vasculature
number of HSPCs. 10,11 This effect was associated with an increased raised the possibility that perivascular cells may also play a role in the
trabecular bone area and an elevated number of trabecular osteoblasts HSPC regulation by the niche. So far, three types of perivascular cells
that expressed the Notch ligand Jagged 1. When the OLCs were have been characterized: CXCL 12-abundant reticular cells (CAR
+
+
dim
depleted, there was a reduction in the BM cellularity and migration cells), nestin-GFP /leptinR MSCs and nestin-GFP bright /NG2
of hematopoiesis to the extramedullary sites. Thus, OLCs play a role pericytes.
in regulation of HSPC pool size. In addition, OLCs participate in CAR cells were identified in a mouse model in which GFP was
controlling HSPC quiescence through contributing to production of driven by CXCL12 promoter. Similar to the other components of the
CXCL12, Angiopoietin 1, thrombopoietin, paninhibitor of canonical niche, CAR cells are found in a close proximity to HSPCs. It is likely
low
Wnt signaling Dickkopf1 (Dkk1), noncanonical Wnt ligands and that they are genetically and phenotypically related to nestin-GFP
ECM protein osteopontin. Finally, OLCs govern HSPC localization cells (see later) because their ablation also severely impaired adipo-
by controlling their egress into blood and return to the BM, a process genic and osteogenic differentiation of nonhematopoietic BM cells
that forms the basis for clinical peripheral blood stem cell collection in addition to reducing the number of HSPCs. Notably, the effect of
for transplantation. When mature OLCs are deleted from bone, there deletion was not limited to HSPCs but also affected mature lineages,
is an increase in the number of circulating progenitors and a decrease such as lymphoid cells, indicating a wider role for these cells in
in the mobilization of HSPC with granulocyte colony-stimulating hematopoietic support.
factor (G-CSF) indicating that OLC-derived signals retain primi- MSCs are located in the perisinusoidal BM space and have been
tive hematopoietic cells in the marrow. Following G-CSF–induced initially defined by low expression of green fluorescent protein (GFP)
mobilization, the OLCs in the trabecular bone adapt a flattened driven by gene regulatory elements of intermediate filament protein
low
low 14
morphology with short projections, which is associated with HSPC Nestin (nestin-GFP ). Nestin-GFP cells express the genes associ-
egress from the niche. Similar changes are seen after treatment with ated with HSPC retention in the niche (Cxcl12, VCAM-1), which
nonsteroidal antiinflammatory drugs (NSAIDs), which are known are downregulated upon G-CSF mobilization. Selective deletion of
to enhance G-CSF–induced HSPC mobilization. When CXCL12, a Nestin-positive cells in mice resulted in 50% reduction in the number
major HSPC chemoattractant and retention factor, is deleted from of long-term HSPCs and their relocation to the spleen, although it
the osteoprogenitors using osterix-Cre promoter, increased HSPC is not clear whether this effect was mediated directly by Nestin-
mobilization is also observed. Thus, OLCs participate in the BM positive cells or through their more differentiated downstream
niche by regulating HSPC number, quiescence and retention in the progeny. Subsequent studies revealed that a population that largely
low
BM space. overlaps with nestin-GFP cells can be also defined by expression of
Despite the evidence presented earlier, several studies have leptin receptor. Specific deletion of known HSPC regulators (stem
argued against the role of OLCs in the niche, citing the absence cell factor, CXCL12) specifically from MSCs using Cre-recombinase
of HSPC changes either in genetic models associated with reduced driven by leptin receptor gene regulatory elements lead to reduction
OLC number or following OLC-specific deletion of HSPC regula- in the HSPC number and long-term repopulating capacity, further
tors such as kit-ligand or CXCL12. Several experimental factors delineating the functional significance of MSCs in the HSPC niche.
are likely to account for this discrepancy, including developmental Careful analysis of HSPC distribution within BM sections led to
adaptation when the genetic modification is present throughout the discovery of another perivascular cell subset (termed nestin-GFP high ),
15
ontogeny, or inability of genetic tools to target a specific subset which is closely associated with arterioles. Cell deletion experiments
within the OLC compartment that serves as a nodal point of the demonstrated the role for nestin-GFP high in maintaining HSPC
HSPC regulation: several studies suggest that immature OLCs quiescence. Interestingly, nestin-GFP high cells are preferentially found
are important for the niche function, whereas mature OLCs are close to the endosteum leading to a model that denotes the endosteal
low
dispensable. surface as a quiescent niche and central BM (where nestin-GFP
form the niches around sinusoidal vessels) as a proliferative niche,
with the two being involved in a dynamic interaction with each
Endothelial Cells other.
Endothelial cells are known to secrete hematopoietic cytokines and
express several adhesion molecules such as E-selectin, P-selectin, Adipocytes
vascular cell adhesion molecule 1 (VCAM-1), and intercellular adhe-
sion molecule 1 (ICAM-1) which have been shown to participate in An observation that adipocyte-rich vertebrae in mice contained sig-
cellular interactions within HSPC niche. The existence of vascular nificantly fewer cycling HSPCs compared with adipocyte-poor tho-
16
niche for the HSPCs has been suggested by in vivo imaging studies racic vertebrae led to the discovery of their role in HSPC regulation.
showing early homing of transplanted BM progenitors to specific In a genetic mouse model of lipoatrophy (i.e., a condition with
subdomains of the vascular tree as well as by histologic assessment of reduced adipocyte number), posttransplant hematopoietic recovery
the BM using CD150 antibody when HSPCs were found to be in a was accelerated, although a concomitant increase in trabecular bone
close proximity to the BM sinusoids. could have contributed to this result.
Endothelium-derived factors have diverse effects on HSPCs in
vivo. For example, E-selectin (which is expressed exclusively in the
endothelial cells) negatively regulates HSPC quiescence; consequently, Osteoclasts
HSPCs from E-selectin knockout (KO) mice are more quiescent and
12
resistant to irradiation. On the other hand, endothelial-specific Osteoclasts are BM-derived cells that are located in close proximity to
deletion of stem cell factor or CXCL12 lead to the respective reduc- stem cell–rich endosteum and play a critical role in bone remodeling.
tion of the HSPC pool and loss of repopulating capacity. Similar During stress and G-CSF–induced mobilization, the activity of the
changes are seen upon endothelial-specific deletion of Notch ligand osteoclasts increases and is accompanied by secretion of proteolytic
Jagged 1, which in contrast to E-selectin, promotes HSPC quiescence. enzymes and reduction in the endosteal niche components, as
The heparin-binding growth factor, pleiotrophin, which is produced evidenced by downregulation of the osteopontin expression by the