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C H A P T E R 11

HEMATOPOIETIC MICROENVIRONMENT

David Scadden and Lev Silberstein

EVOLUTION OF THE NICHE CONCEPT The hematopoiesis-promoting factors may be either produced by the
placental trophoblast cells or enter via maternal circulation. Hemato-
In 1868, Ernest Neumann first suggested that blood cells are being poietic progenitors appear in the placenta at E9, but their number
replenished throughout postnatal life, and this proposal led to the declines by E13. The cells and local factors providing placental hema-
attempts to localize the place of hematopoiesis. His hypothesis that topoietic support are currently unknown, but mesenchymal/stromal
blood cell production takes place in the bone marrow (BM) was cells have been suggested as candidates. Placental microenvironment is
experimentally validated by selective lead shielding of limbs in irradi- thought to be geared toward supporting the expansion or maturation
ated animals almost a century later. Notably these and other studies of HSPCs without their concomitant differentiation.
showed that differentiation pathways of immature blood cells are In the fetal liver, the HSPCs are first detected on day 9 of mouse
determined by their location and are different between the spleen and embryonic development, and large expansion of the HSPCs occurs
the BM. Based on this difference between BM and spleen, Schofield between days 12 and 15 before migration to the bone on day 18.
first proposed that there is a specialized place or niche where stem cells Stromal cell lines obtained from the fetal liver are able to support
reside and are governed. He succinctly posed in 1978 that “stem cell primitive hematopoietic cells in ex vivo cultures. Some of these cells
is seen in association with other cells which determine its behavior.” (termed myelosupportive stroma) are able to differentiate in vitro into
Trentin further clarified how different sites affected hematopoietic mesenchymal components (osteoblasts, chondrocytes, and adipo-
stem/progenitor cell (HSPC) differentiation. Although both spleen and cytes). Although the nature of fetal liver cells participating in the
marrow support multiple cell lineages (erythropoietic and granulocy- HSPC niche remains enigmatic, recent studies point to a nonhema-
topoietic, for example), the ratios of differentiating cells were distinct: topoietic hepatic population that express Dlk-1, a member of delta-
spleen favored erythropoiesis, but BM predominantly supported like family of cell surface transmembrane proteins, and stem cell
granulopoiesis. This controlling influence of the surrounding cells factor, and can be prospectively isolated based on the expression of
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was further illustrated by implanting BM stroma into the spleen and these molecules. These cells express angiopoietin ligand 3 and
showing that hematopoietic cells abruptly changed from erythropoiesis CXCL12, and in combination with stem cell factor, thrombopoietin,
to granulopoiesis at the spleen–BM demarcation. These observations FGF1 and FGF2, and either angiopoietin ligand 2 or 3 are able to
suggest that immature differentiating progenitors require interactions produce more than 30-fold expansion of the murine HSPCs in
with other specific cell types in a defined microenvironment. culture.
This chapter reviews the current knowledge of the hematopoietic Despite the differences in the hematopoietic microenvironment
microenvironment during development and in postnatal life in between the sites of fetal and adult hematopoiesis, the key compo-
normal hematopoiesis and in myelodysplasia and leukemia. The nents of the molecular milieu are likely to be shared, as evidenced by
opportunities for therapeutic manipulation of the niche in the treat- successful (although limited) engraftment of HSPCs across develop-
ment of these disorders are also discussed. For the related topics on mental barriers. For example, AGM- or fetal liver–derived HSPCs
stem cell mobilization, hematopoietic cytokines and the role of are able to engraft in the adult BM. Notably, they have a competitive
microenvironment in lymphoid malignancies, plasma cell disorders, advantage over their BM-derived counterparts, with the long-term
and myeloproliferative conditions, readers are referred to other repopulating ability exceeding that of the BM by fivefold. Vice versa,
chapters of this book. BM HSPCs engraft in fetal liver when transplanted in utero, although
at low efficiency (<5% for the whole BM and 0.43% for highly
HEMATOPOIETIC MICROENVIRONMENT DURING enriched HSPCs), which may be partly attributable to the absence
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of pretransplant conditioning.
DEVELOPMENT Multilineage hematopoiesis during development occurs largely by
the virtue of sequential HSPC migration from the AGM region to
In mammals, hematopoiesis during development takes place in dis- the fetal liver and the BM, as opposed to de novo HSPC generation.
tinct extraembryonic and embryonic sites. Sequentially, it moves Failure of migration to the “next niche,” as exemplified by the targeted
from the yolk sac to the aorta-gonad-mesonephros (AGM) region, disruption of the guanine-nucleotide–binding protein stimulatory
fetal liver, placenta, and BM (for details, see Chapter 26). α-subunit (GS-α), calcium-sensing receptor, or CXCL12/CXCR4
The first definitive adult HSPCs emerge from the floor of the axis (discussed in detail in Chapter 14 on HSPC migration) leads to
dorsal aorta, more precisely from AGM region in midgestation mouse severe impairment in hematopoiesis. This suggests even in the absence
embryo, and the HSPC clusters appear in close association with the of cell-intrinsic HSPC defects, proper progression of blood cell
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aortic endothelium. Recent reports indicate that phenotypically production throughout development critically depends on the ability
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defined HSPCs (Sca1 c-kit § CD41 ) arise directly from ventral of the HSPC to sequentially move to the appropriate microenviron-
aortic endothelial cells and that fluid shear stress may be important mental compartments.
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for this process. Although direct cellular interactions during the
emergence of hematopoietic stem cells (HSC) in the embryo remain
to be dissected, bone morphogenetic protein 4 (BMP4), fibroblast ADULT BONE MARROW MICROENVIRONMENT
growth factor (FGF), transforming growth factor (TGF), and vascular
endothelial growth factor (VEGF)-Flk1 signaling pathways are Niches for Hematopoietic Stem and Progenitor Cells
involved in early mouse hematopoiesis.
Recently placenta has been identified as a hematopoietic organ Location of the HSPC Niche
during development. Placenta is known to produce hormones that
influence vascularization and therefore may affect blood cell produc- In mammals, BM is a major site of hematopoiesis throughout life.
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tion because hematopoiesis and vasculogenesis are tightly coupled. The niche preserves and dynamically regulates the HSPC pool by
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