H e m a t o lo g y E d u c a t io n - European Hematology Association

D. Lucas 1
A. Chow 1,2
P.S. Frenette 1
1 Ruth L. and David S. Gottesman
Institute for Stem Cell
and Regenerative Medicine
Research, Albert Einstein
College of Medicine, NY;
2 Department of Gene and Cell
Medicine, Mount Sinai School
of Medicine, New York
Hematology Education:
the education program for the
annual congress of the European
Hematology Association
2011;5:140-145
Hematopoietic stem cells
Neural and immune regulation of the hematopoietic
stem cell niche
Introduction
In the adult, blood-forming hematopoietic
stem cells (HSC) reside in the bone marrow
(BM), but retain migratory properties. HSC
continuously circulate from the BM to blood
and tissues, 1–3 where they may participate in
immunity 1 and tissue regeneration. 2,4 In the
BM, HSC reside in defined areas that maintain,
support, and regulate them. 5–10 The specific
microenvironment is now commonly
referred to as the HSC “niche”, as initially
proposed in 1978 by Schofield. 11 Although
the HSC niche has been extensively studied
in murine models, there are notable anatomical
differences between human and murine
hematopoiesis. For example, murine
hematopoiesis is sustained throughout life in
the marrow of long bones, whereas in
humans, after puberty, hematopoiesis is progressively
lost from the epiphyseal portion
of long bones and persists in parts of long
bone metaphyses and the axial skeleton. 12
In the past decade, our knowledge of the
major cellular components that form the niche
and of how these cells regulate HSC function
has increased dramatically. However, the
understanding of how the niche is regulated
and integrates signals from the periphery is
much more limited. Parallels between the
healthy and dysregulated niche may shed
insights on the development and propagation
of malignancies. 13–15 Here, we review the putative
cellular constituents of the HSC niche and
discuss recent data showing that the sympathetic
nervous and the innate immune systems
regulate the niche in an antagonistic
manner to direct HSC trafficking.
Cellular components of the
hematopoietic stem cell niche
Studies of the HSC niche have been hampered
by its enclosure in bone, making direct
A B S T R A C T
Hematopoietic stem cells (HSC) reside in specific bone marrow areas often referred to as niches.
These niches regulate the proliferation, differentiation and migration of HSC. The cellular constituents
comprising this niche are the subject of active investigations. Here we briefly review current knowledge
on the major candidate cellular components, and discuss its regulation by the sympathetic nervous
system and bone marrow macrophages, which exert antagonistic functions in HSC retention within
the niche.
observation difficult. Advances have been
made through imaging of microenvironments
and genetic models, in which specific
cells and molecules have been deleted in vivo.
Several recent excellent reviews discuss the
different components of the niche and of
how it regulates HSC. 5–10 In this section, we
will provide an overview of the major candidate
niche cells.
The osteoblast
The fact that HSC localize within bone
structures suggests a role for specific bone
constituents in their maintenance. Studies
decades ago suggested that progenitor activity
was enriched in proximity to the endosteal
surface 16,17 and, after transplantation, preferentially
home to BM endosteal areas. 18
Further, osteoblasts can support HSC expansion
in vitro. 19,20 These observations led to the
hypothesis that cells belonging to the
osteoblastic lineage were niche cells. This
hypothesis was supported through in vivo
experiments. 21,22 Mice in which the Collagen
a1 (Cola1) gene promoter directs the expression
of an activated form of the parathyroid
hormone receptor in osteoblastic cells
showed an increase in the number of trabeculae
and this was associated with an increase
in total HSC numbers. 21 Further, treatment of
wild-type mice with PTH also led to
increased trabecular bone and HSC, presumably
by activating Jagged-1, a Notch ligand,
in osteoblastic cells. 21 Similarly, conditional in
vivo inactivation of bone morphogenetic protein
receptor IA (Bmpr1a) in total bone marrow
cells led to increased trabeculae and HSC
numbers. 22 Moreover, in vivo ablation of
osteoblastic cells with gancyclovir treatment
of Col2.3Δtk transgenic mice caused a progressive
reduction in HSC numbers. 23,24 Cells
of the osteoblastic lineage can also synthesize
factors that promote HSC maintenance,
such as CXCL12 (SDF-1a), 25 Angiopoietin-1
(Angpt1), 26 Thrombopoietin 27,28 and Osteopontin,
which affect HSC quiescence. 29 These data
| 140 | Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1)