Bone marrow niches and HSC fates

Evgenia V. Verovskaya, Timothy B. Campbell and Emmanuelle Passegué

Self-renewing and multipotent haematopoietic stem cells (HSCs) generate
all mature blood cells. Adult HSCs exist in highly specialized bone marrow
niches. These niches have crucial roles in regulating the fate of HSCs in
terms of quiescence, mobilization into the peripheral blood and
differentiation in response to steady-state and emergency cues. HSC fate is
influenced by diverse types of stromal and haematopoietic cells that make
up the bone marrow niche and provide signals in the form of soluble factors,
direct cell–cell contact and cell-surface ligands. In stress conditions, such as
during an inflammatory response, bone marrow niches respond by
regulating the balance of downstream HSC fates. In the case of myeloid
malignancies, bone marrow niches can be remodelled to create an
environment that supports malignant stem cells but impairs the
maintenance of normal HSCs. Understanding the signalling pathways of
the bone marrow niche will aid the therapeutic use and targeting of HSCs,
as well as provide more general insights into stem cell regulation and the
function and composition of stem cell niches.

Diverse bone marrow Bone Arteriole Endosteum Central bone marrow Identification of bone marrow niche cell types in mice
niches influence HSC fate VCAM1
Bone marrow niche cells have been characterized by protein expression (cell-surface
The bone marrow contains a dense and intracellular), by genetic labelling and by lineage tracing. Expression patterns
neurovascular network that is often correlate with specialized locations of niche cells in vascular bone marrow
Articular cartilage HSC mobilization Sympathetic niches (capillaries, arterioli or sinusoids), particularly for MSCs and endothelial cells.
innervated by sympathetic nerves and E-selectin Latent TGFβ1 nerve
– VCAM1
includes an enrichment of arterioles Endothelial cell CXCL12
and capillaries in the endosteum, as Haematopoietic cells Stromal cells
well as large sinusoids located Bone Active TGFβ1
Sinusoid HSCs Endothelial Arterioli MSCs
throughout the endosteum and central Lineage– FLT3 – cells
Endosteum SCA1+ PDGFRA+ CD45– CD105+ CD51+
bone marrow cavity. Cellular bone HSC quiescence Macrophage SCA1+ CD150+ PDGFRB+ CD31– TER119–
CD31 +
TJP1hi
marrow niches are closely associated and maintenance KIT+ PROCR+ MECA32 +
CD144hi
Non-myelinating CD48– CD34– Prx1 Gli1
with this neurovascular network and Nutrient CXCL12 + TGFβ1 VEGFR2 +
Nestin
Schwann cell CD105+ Laminin+ Periarteriolar Perisinusoidal
contain stromal elements including artery TPO Noradrenaline Sinusoids
CXCL4 α-catulin Tie2 SCA1+ LEPR+
perivascular mesenchymal stromal Nutrient Macrophage VEGFR3+
vein Latent TPO CXCL4 SCF HoxB5 Capillaries Ng2 Cxcl12
cells (MSCs), endothelial cells (of TGFβ1 CD144low +
CXCL12 Tie2 Nestin–GFP (high) Scf
Endomucin+ TJP1low
arterioles, capillaries and ANGPT1 Gremlin Nestin–GFP (dim)
sinusoids), differentiated Central bone marrow Sinusoid Foxc1
Perisinusoidal MSC – E-selectin
osteoprogenitors and Periarteriolar SCF Megakaryocytes
Arteriole MSC CXCL12 SinusoidSinusoid CD61+ Osteoblasts
adipocytes. Haematopoietic Periostial capillary
CXCL12 Perisinusoidal VWF+ ALCAM+
cells of the bone marrow niche Osteoblast CXCL4+
Sinusoid MSC Collagen 1
include megakaryocytes, ANGPT1 HSC cycling and SCF Endothelial cell CD41+ Osterix
macrophages and osteoclasts. Arteriole differentiation Clec2 Osteocalcin
Arteriole
These diverse cell types Osteoclast + IL-7
provide crucial signals to HSCs Central vein/sinusoid
EPO Notch Osteoprogenitors
in the form of soluble factors, Notch ligands ligand CD31–
Adiponectin FGF1
direct cell–cell contact and cell- Central artery CD45–
Macrophages
surface ligands that influence fates Osteoprogenitor TER119–
Sympathetic nerve TNF CD169+ CD115int CD51+
such as mobilization, quiescence and Adipocyte FGF1 F4/80+ GR1– PDGFRA+
IL-7
differentiation. Megakaryocyte Adipocytes Osterix
Osteoclasts Perilipin+ Nestin
EPO Protein Genetic
TRAP+ Caveolin+ Cxcl12
expression labelling

Viral infection Bacterial infection Malignancy

Stress signals alter HSC fates Haematopoietic cell-driven malignancies Niche-driven
The active roles of bone
Inflammation Diverse stressors and insults to the bone marrow, malignancies marrow niches in malignancy
such as bacterial and viral infection and BCR–ABL-driven CML JAK2V617F-driven MPN MLL–AF9-driven AML Bone marrow niches have an active role in
IFNα/β IFNγ IL- 1 G-CSF malignancy, create an inflammatory milieu that the initiation and progression of myeloid
controls HSC fate via cell-surface receptors. malignancies. In BCR–ABL-driven CML,
Macrophage Inflammatory factors can act on HSCs and their remodelled endosteal MSCs differentiate to
Leukocytes Neuropathy
downstream progenitors through various Loss of osteoblast lineage cells that deposit collagen I
T cell G-CSF Endosteal IL1 nestin+
mechanisms that are illustrated by the collagen 1 at the endosteal surface, creating a hostile
Monocyte MSC Loss of
NK cell prototypical examples of type I and type II fibrosis MLL–AF9 environment for normal HSCs. In JAK2V617F-
Fibroblast MSC NG2+ MSC
blasts
Arteriole interferons (IFNs; IFNα/β and IFNγ, respectively), Osteoprogenitors Arteriole
Primary Inflammation driven MPN, neuropathy and loss of nestin+
HSC driver
IL-1 and G-CSF. IFNs are produced preferentially MSCs are hallmarks of disease progression,
mutation
IFNγ IL-1 CXCL12 by haematopoietic cells and act directly on HSCs mediated by IL-1-driven inflammation.
Sinusoid to direct downstream differentiation and In MLL–AF9-driven AML, sympathetic
IFNα/β ANGPT1 Non-functional HSC
proliferation. IL-1 is produced under stress CXCL12 Nestin+ neuropathy leads to the depletion of
Quiescent HSC Quiescent HSC IL-1 Loss of osteoprogenitor Transformation
SCF conditions by stromal and haematopoietic cells nestin+ MSC periarteriolar NG2+ MSCs but expands the
and acts directly on HSCs to drive an emergency CCL3 TPO MSC population of remodelled osteoblast-primed
TLR myeloid response. G-CSF is produced by stromal Leukaemic nestin+ MSCs through a mechanism dependent
Impaired
Mobilized and haematopoietic cells and acts indirectly on Remodelled differentiation stem cell on β-adrenergic signalling. Primary driver
Cycling HSC Cycling HSC Quiescent HSC Neuropathy
HSC HSCs by downregulating the production of endosteal mutations in bone marrow niche cells,
CXCL12 Malignant
stromal cell-derived factors, which affects HSC MSC myeloid particularly osteoprogenitor cells, can initiate
Megakaryocyte ANGPT1
quiescence and mobilization, and by the Leukaemic Malignant cells myeloid malignancies within the
Myeloid Myeloid Sinusoid
stem cell myeloid SCF
Apoptotic HSC cells cells Cycling HSC induction of TLR signalling, which leads to HSC haematopoietic compartment by establishing
cells
proliferation. an inflammatory milieu.

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Abbreviations
ALCAM, activated leukocyte cell adhesion molecule;
AML, acute myeloid leukaemia; ANGPT1, angiopoietin 1;
Clec2, C-type lectin domain family 2; CML, chronic
myeloid leukaemia; CXCL, CXC-chemokine ligand; EPO,
erythropoietin; FGF1, fibroblast growth factor 1; FLT3,
Fms-related tyrosine kinase 3; Foxc1, Forkhead box c1;
GFP, green fluorescent protein; G-CSF, granulocyte
colony- stimulating factor; IL, interleukin; LEPR, leptin
receptor; MPN, myeloproliferative neoplasm;
PDGFRA, platelet-derived growth factor receptor A;
PROCR, protein C receptor; SCF, stem cell factor;
TGFβ1, transforming growth factor β1; TJP1, tight
junction protein 1; TLR, Toll-like receptor; TNF, tumour
necrosis factor; TPO, thrombopoietin; TRAP, tartrate-
resistant acid phosphatase; VCAM1, vascular cell
adhesion molecule 1; VEGFR, vascular endothelial
growth factor receptor; VWF, von Willebrand factor.
Affiliations
Evgenia V. Verovskaya, Timothy Campbell and
Emmanuelle Passegué are at the Eli and Edythe Broad
Center of Regeneration Medicine and Stem Cell
Research, University of California San Francisco,
California 94143, USA. Evgenia V. Verovskaya and
Emmanuelle Passegué are relocating to the
Columbia Stem Cell Initiative, Columbia University
Medical Center, New York 10032, USA.
Correspondence to E.P.
e-mail: ep2828@cumc.columbia.edu
The authors declare no competing interests.
Edited by Kirsty Minton; designed by Caio Bracey.
© 2017 Macmillan Publishers Limited, part of
Springer Nature. All rights reserved.
http://www.nature.com/posters/hsc