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Page 4 of 14 Tosato et al. J Cancer Metastasis Treat 2021;7:52 https://dx.doi.org/10.20517/2394-4722.2021.120

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[21]
[22]
matrix protein collagen-1 ; and Kitl/SCF from Nestin mesenchymal stem cells and arteriolar endothelial
[4]
cells . However, the recovery of quiescent HSC near sinusoids questions a clear distinction between HSC in
the arteriolar/endosteal and sinusoidal niches , suggesting instead the existence of different types of
[2]
quiescent HSC and other spatially distinct niches/niche factors for maintenance of HSC quiescence. The
most quiescent HSC in aged mice reside in sinusoidal niches, which appear critical to protecting HSC from
aging; endothelial-derived Jag2 may be an essential sinusoidal niche factor . However, single-cell RNAseq
[23]
results have indicated Jag2 expression in arterial endothelial cells of bone marrow . Consistent with the
[7]
possibility of different types of HSC niches, hematopoietic progenitor cells committed to lymphoid
differentiation are found preferentially in the arteriolar niche whereas myeloid-biased progenitors are found
in the sinusoidal niche . It is interesting that aging is associated with a decline in B-cell production and an
[24]
increased propensity for myeloid cell production in mice and man [25,26] . In addition, Cxcl12-abundant
reticular cells, most abundant near sinusoids in the central bone marrow but also present in the endosteal
[27]
niche , can promote HSC quiescence through Cxcl12 secretion and CXCR4 signaling in the HSC [9,15] . Non-
myelinating Schwan cells that wrap around small axons, which localize in the central and endosteal bone
marrow , are reported to produce transforming growth factor beta (TGF-β), which activates SMAD-
[27]
induced quiescence in the adjacent HSC . In addition, megakaryocytes, which are broadly distributed in
[28]
the bone marrow , are reported to regulate HSC quiescence through secretion of CXCL4 (also named
[29]
platelet factor 4) , TGF-β , and thrombopoietin . Thus, niches for quiescent HSC may not be spatially
[31]
[29]
[30]
segregated to the periosteal bone marrow. Different quiescent HSC subsets may exist with distinct lineage
commitment potential. Quiescent stem cells may be a dynamic and migratory cell pool capable of changing
residence in the bone marrow, switching between quiescence/growth/differentiation in response to niche-
derived signals. Although quiescence is believed to represent an essential property of HSC to maintain their
self-renewal potential in the bone marrow [14-21,32] , stem cells in various other tissues do not require
[33]
quiescence for stemness .
Despite these uncertainties, the importance of niche cells and factors for the maintenance of HSC is
supported by the substantial reduction of the HSC pool after depleting stem cell factor (SCF/Kitl) from
Tie2 endothelial cells or from leptin receptor (LepR)-expressing mesenchymal cells [7,8,34,35] and depleting
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+
[34]
Cxcl12 from nestin , but not from Lepr mesenchymal cells . In addition, depleting nerve/glial antigen 2
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(NG2) (Cspsg4) mesenchymal cells, but not Lepr mesenchymal cells, reduced the number of HSC and
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altered HSC localization in the bone marrow .
[34]
CONTRIBUTION OF BONE MARROW NICHES TO HEMATOLOGICAL MALIGNANCIES
Appreciation of the importance of niche cells and factors in physiologic hematopoiesis suggested that
“derangements” in bone marrow “stroma” may contribute to clonal selection of bone marrow
malignancies [Figure 1]. Neoplastic hematopoietic cells could induce change in the bone marrow stroma
[36]
or “morph into” stroma resulting in improved growth conditions for the tumor cells. Alternatively, stromal
lesions could be the inducers of malignant transformation of hematopoietic cells [36-38] .

Experimental mouse models have explored the possibility that non-hematopoietic niche factors contribute
to the initiation of bone marrow malignancy. Proof-of-principle came from genetic disruption of Dicer1
ribonuclease in osterix osteo-lineage progenitors. The mutant mice displayed impaired osteoblast
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differentiation and myelodysplasia associated with leukopenia when the mice were 4-6 weeks old. A
proportion of these mice developed acute myeloid leukemia (AML) and rapidly died . Dicer1 was not
[39]
disrupted in the leukemic cells, which instead displayed other genetic abnormalities, providing evidence that
Dicer1 depletion from osteo-lineage cells caused myelodysplasia and AML in mice. The Schwachman-
Bodian-Diamond syndrome (Sbds) gene was expressed at significantly lower levels in the osteo-lineage cells