sign in sign up
<<
Home , B cell, Haematopoietic system, Macrophage, Marginal zone

Haematopoietic stem cells, niches and differentiation pathways Thomas Graf and Andreas Trumpp Haematopoietic stem cells (HSCs) continuously replenish cells that are lost by transcription factors, the activity of which is orchestrated by extrinsic and intrinsic signals. attrition or tissue damage. They are capable of self-renewal and are currently the only The study of changes in regulatory networks during haematopoietic differentiation has adult stem-cell type routinely used in clinical settings to replace lost cells. HSCs are mostly long served as a paradigm for basic processes of cell-fate specification and its aberrations, quiescent but can be mobilized from their niche to proliferate and differentiate into such as those that occur in leukaemia. The easy accessibility and transplantability of normal lineages of the innate and adaptive , as well as into red blood cells and and leukaemic haematopoietic cells has led to the discovery of , oncogenes and . Cell-fate decisions are initiated and maintained by specific combinations of stem cells and to some of the most celebrated successes of targeted drug design.

Guide through the poster HSC niches The upper left region of the poster shows a mouse Yolk sac marrow embryo with its haematopoietic anlagen. Although the Sinusoid G-CSF Erythrocyte C/EBPα extent of yolk-sac contribution to the formation of adult Mesenchymal HSC precursors HSCs are transiently present Endothelial cell GFI1 HSCs is controversial, most HSCs are probably formed in in the placenta (E11–E15) TPO EPO IL-5 IL-3 GATA1 GATA1 GATA2 GATA2 M-CSF PU.1hi the aorta–gonad–mesonephros (AGM) region. From here, Thymic rudiment Vas cul ar niche α α PU.1hi EGR1/2 IRF8 FOG1 FOG1 C/EBP C/EBP α Mouse embryo ETS1 EKLF C/EBP MAFB C/EBPα stem cells seed the fetal , where they expand and From E10 onwards, AGM-derived CXCL12-e xpres sing HSCs colonize the fetal liver, reticul ar ce ll differentiate into myeloid and lymphoid lineages. where they expand and mature. MEP CMP GMP / Subsequently, HSCs exit the liver and populate HSCs are generated in the Approximately at birth, HSCs start AGM between E8.5 and E.11.5 to migrate to the bone marrow, specialized bone-marrow microenvironments (niches) in IL-3 ID2 which becomes the main site of Activat ed LT-HSC ST-HSC MPP GM-CSF which they gradually become quiescent. As shown in the in the adult. SPIB IL-4 LT-HS C lower left panel, dormant HSCs are mostly located close FLT3L SCF ID2 to the lining of the trabecular bone, the endosteal niche. PU.1 SPIB DC DC DC Fetal liver Homeo stasis (rare) This niche contains osteoblasts and CXC- Injury (frequent) IL-7 ligand 12 (CXCL12)-expressing reticular (CAR) cells. F-HSC Dividing HSC SCF FLT3L E2A CXCL12 preBCR BCR IgM FLT3L CXCL12 EBF PAX5 RAG RAG Several cell molecules, together with short- Fibrobl ast range signalling molecules, control HSC lodging and Endo st e a l niche ECM MPP LMPP CLP Pre/pro- Pro- Pre-B cell Immature B cell maintenance (lower left panel). In response to specific MBT B cell Low O2 signals, it is thought that HSCs are recruited to vascular Differenti ation, CXCL12-e xpres sing Erythrocyte Neutrophil Macrophage Megakaryocyte CXCL12- NK cell reticul ar cell e xpres sing migration and niches — that are comprised of CAR cells and re ticul ar ce ll e xpansion fenestrated sinusoidal endothelial cells — where they Dormant TSP MT NK MB LT-HSC Osteoblast begin to divide, differentiate and enter the circulation. T-cell development B-cell development Bone-marrow-derived -seeding progenitors Osteocyte in the thymus Notch1 in the Ikaros (TSPs) seed the thymus and become committed to the Bone IL-15 Ikaros IL-2 ETS1 IgM+ T-cell lineage (lower right panel). In the thymus, the cells ID2 PU.1 travel from the cortex through the subcapsular zone to Macrophage/ B cell ETP/ NK cell neutrophil DN1 Immature the medulla, encountering different epithelial niches B cell (T1) that guide them through several developmental stages. IL-7 TCF + + FLT3L PU.1 Fetal precursor Finally, CD4 and CD8 T cells enter the circulation and E2A GATA3 CXCL12- Dormant HSC Nucleus differentiate into mature effector and helper T cells in expressing Phenotypes of HSCs the spleen and nodes. B-lineage cells become – + + – – + DN2 Mouse: Lin Sca1 Kit CD34 CD48 CD150 Notch- IgMlow committed in the bone marrow and, after immature Sonic Human: LIN–CD34+CD38–THY1lowKIT+ + Patched ligand TCRβ IgD hedgehog DLL4- B cells enter the circulation and home to the spleen, GATA3 IL-7 B-1a/b cell Mature Effect on self-renewal capacity producing RAG RAG (In peritoneum Notch2 B cell (T2) they mature into -secreting memory B cells and cortical SOX13 BAFF + (Promote HSC maintenance and/or quiescence): BMI1, FOXO, GFI1, STAT5, ATM, p57, HOXB4 as well as in spleen) plasma cells (lower right panel). epithelial DN3 γδ T cell Weak BCR – (Promote HSC proliferation and/or differentiation): cMYC, cMYB, JUNB, β-catenin, p18, p27 cell signal The differentiation pathways are shown beginning Smoothened β TCR GATA3 hi with HSCs and ending with mature cells. Dotted lines Notch1 RAG IgM Survival IgDlow represent transitions in which the origin of the more Self-renewal MCL1 mature cell is not clear. Arrows indicate points of DN4 BAFF TPO Dormancy Adhesion Self-renewal, Dormancy, Self-renewal Lodging Self-renewal Migration stimulation, Marginal-zone Strong BCR migration of circulating cells (with the exception of the MPL helper T-cells B cell signal Survival adhesion TCF GATA3 HSC synapse panel). It is likely that the early stages of CXCL12 E2A RAG Non-canonical HSC development represent a continuum. There are still ? ? Migration RAC WNT signalling β-catenin ? uncertainties about several parts of the pathways. The ? DP TCRα TReg cell poster shows multipotent progenitors (MPPs) branching CXCR4 GATA3 Calcium IL-15 ThPOK β into megakaryocyte/erythroid progenitors (MEPs) and KIT TIE2 Notch Frizzled TCRα TGF Short-lived low SCA1 α FOXP3 IgM TCR IgDhi lymphoid-primed multipotent progenitors (LMPPs). RUNX3 RUNX1 VLA5 CD44 CD44 LMPPs either become common lymphoid progenitors VLA4 LRP5 (CLPs) or common myeloid progenitors (CMPs) and 2+ or LRP6 + Antigen IL-6 /macrophage progenitors (GMPs). However, Ca NKT cell SP CD8+ SP CD4 stimulation, BLIMP1 GMPs can also generate , and mast WNT helper T-cells STAT3 CXCL12 Cadherins APRIL/BAFF NF-κB OPN PAX5 cells and it is possible that more than one pathway to BMP PTH T-cell development γ BCL6 Hyaluronic IFN and exists. Finally, there are in the periphery SP CD8+ IL-12 SP CD4+ ECM acid IL-6 controversies about the developmental origin of the

Cadherins (spleen and T-bet β ) STAT4 TGF different types of dendritic cells and B cells. The poster ANG1 RUNX3 RORγt IgG+ also shows lineage-instructive signals such as , IL-4 Plasma GATA3 cell cytokines and transcription factors at the points where Osteoblast BMPR1A ICAM1 or Membrane- Jagged PTHR STAT6 they are required. The definition of a lineage-instructive VCAM1 bound SCF HSC synapse Effector T cell TH1 cell TH2 cell TH17 cell factor is complex and is ideally based on gene ablation, cell-type-specific gene inactivation and gain-of-function experiments. Since this applies only to a fraction of the factors shown here, the information provided is We have over 30,000 in our catalogue. Quality and honesty are our top priorities. Our Abpromise Abbreviations ETS1, v-ets erythroblastosis E26 oncogene homologue 1; MPP, multipotent progenitor; MT, myeloid/T-cell precursor; somewhat speculative. Also, only transcription factors Abcam Stem Cell antibodies you can rely on! F-HSC, fetal HSC; FLT3L, FMS-related-tyrosine-kinase-3 ligand; NF-κB, nuclear factor-κB; NK, natural killer; OPN, ; Our Stem Cell Markers range includes over 2000 antibodies to: guarantees full technical support from our experienced team. AGM, aorta–gonad–mesonephros; ANG1, 1; FOG1, friend of GATA 1; FOX, forkhead box; GATA1, GATA- PAX5, paired box gene/ 5; PTH, parathyroid hormone; that act dominantly during lineage commitment are Abcam supplies primary and secondary antibodies and reagents If an antibody doesn’t work as it says on our datasheet we will APRIL, a proliferation-inducing ligand; ATM, ataxia-telangiectasia binding protein 1; G-CSF, granulocyte colony-stimulating factor; PTHR, parathyroid hormone receptor; PU.1, transcription factor listed, but not those that need to be silenced. • Embryonic Stem Cells γ to researchers worldwide. We ship direct to over 60 countries give you a full refund or replacement if you tell us within mutated; BAFF, B-cell-activating factor; BCL, B-cell ; GFI1, growth-factor independent 1; GM-CSF, granulocyte/ PU.1; RAG, recombination-activating gene 1; ROR t, retinoic- • Embryonic Germ Cells BCR, B-cell receptor; BLIMP1, B--induced macrophage CSF; GMP, granulocyte/macrophage progenitor; acid-receptor-related orphan receptor-γt; RUNX, runt-related and have offices in the UK, US and Japan, as well as offering 90 days. We publish everything we know about every product maturation protein 1; BMP, bone morphogenetic protein; HOXB4, homeobox B4; HSC, haematopoietic stem cell; ICAM1, transcription factor; SCA1, stem-cell antigen 1; SCF, stem- Thomas Graf is an ICREA investigator at the Centre for Genomic Regulation, • Endothelial progenitors Dr Aiguader 88, E08003 Barcelona, Spain. e-mail: [email protected] customer support in English, French, German and Japanese. on our datasheets and our catalogue is web-based. This allows BMPR1A, bone morphogenetic protein receptor, type 1 A; intercellular adhesion molecule 1; ID2, inhibitor of DNA cell factor; SOX13, SRY box 13; SPIB, Spi-B transcription • Hematopoietic progenitors C/EBPα, CCAAT/enhancer-binding protein α; CLP, common binding 2; IFNγ, -γ; IL, ; IRF8, interferon- factor; STAT, signal transducer and activator of transcription; daily updates and far more information than in any printed Andreas Trumpp is at the Swiss Institute for Experimental Cancer Research (ISREC) We are rapidly developing and expanding our range, looking for • Mesenchymal Stem Cells lymphoid progenitor; CMP, common myeloid progenitor; regulatory factor 8; LIN, lineage; LMPP, lymphoid primed MPP; ST-HSC, short-term repopulating HSC; T1, 1; and the Ecole Polytechnique Fédérale de Lausanne (EPFL), Chemin des Boveresses new targets and improving our existing antibodies. To help us with catalogue, including customer reviews, technical enquiries and CXCL12, CXC-chemokine ligand 12; CXCR4, CXC-chemokine LRP5, low-density-lipoprotein-receptor-related protein 5; TCF, T-cell factor; TCR, T-cell receptor; TGFβ, transforming 155, 1066 Epalinges, Lausanne, Switzerland. e-mail: [email protected] • Neural Stem Cells β receptor 4; DC, ; DLL4, delta-like ligand 4; LT-HSC, long-term repopulating HSC; MB, myeloid/B-cell - ; TH, T helper; ThPOK, T helper-inducing this, we actively attend, support and help organise conferences on links to publication references. Visit our website today and see DN, double negative; DP, double positive; E2A, transcription precursor; MBT, myeloid, T- and B-cell precursor; MCL1, POZ/Kruppel factor; TIE2, tyrosine kinase receptor 2; Supplementary information (glossary terms and background reading) is associated • Neural Crest Stem Cells with the online version of this poster. www.nature.com/nri/posters/hsc Stem Cell research. Find out more on our Stem Cells resource page: for yourself: factor E2A; EBF, early B-cell factor; ECM, ; myeloid-cell leukaemia sequence 1; M-CSF, macrophage TPO, thrombopoietin; TReg, T regulatory; TSP, thymus-seeding • Ectoderm, Mesoderm and Endoderm lineages EGR1, early-growth response; EKLF, erythroid Kruppel-like colony-stimulating factor; MEP, megakaryocyte/erythroid progenitor; VCAM1; vascular cell-adhesion molecule 1; Edited by Elaine Bell; copy edited by Marta Tufet; designed by Neil Smith and www.abcam.com/stemcells • Wnt, TGF-β, Hedgehog and Notch signaling pathways www.abcam.com/stemcells factor; EPO, erythropoietin; ETP, early T-cell-lineage progenitor; progenitor; MPL, myeloproliferative leukaemia virus oncogene; VLA, very late antigen. Simon Fenwick. © 2007 Nature Publishing Group. Glossary Haematopoietic stem cells Bone-marrow and/or HSC transplantation (HSCs). Cells that are capable of reconstituting all lineages of the A procedure involving injection of HSCs or bone marrow into after transplantation into lethally irradiated irradiated hosts to determine the cell’s biological potential. In the mice. Long-term repopulating HSCs (LT-HSCs) do this life-long and clinic it is a life-saving procedure after or radiation after secondary transplantations into irradiated hosts, whereas therapy that destroys the haematopoietic system. Bone-marrow short-term repopulating HSCs (ST-HSCs) only show multilineage transplantation typically requires to prevent repopulation for a few weeks. LT- and ST-HSCs can be identified graft rejection due to tissue mismatch. and isolated by on the basis of their expression of specific cell-surface . Cord-blood stem cells These are fetal HSCs present in the umbilical cord of newborns. Lineage commitment They are used clinically as an alternative to bone-marrow-derived Also known as cell-fate determination; a process whereby HSCs HSCs. If stored frozen and thawed years later, they can be useful for become specialized while losing their self-renewal capacity. regenerating the haematopoietic system of the donor, obviating the danger of tissue rejection of mismatched transplants. Progenitor cells Also known as precursor cells; are intermediates between HSCs and Dormancy and mobilization differentiated cells with restricted differentiation potential, high Although HSCs self-renew, they are mostly quiescent, dividing proliferative capacity, but little or no self-renewal capacity. They approximately once a month. Proliferation can be activated in are probably equivalent to the transit amplifying cells of other adult response to injury or injection of cytokines, such as granulocyte stem-cell systems. colony-stimulating factor (G-CSF). G-CSF also induces the exit of HSCs from their niches and mobilization of the cells into the Myeloid cells circulation, a procedure that is used clinically to obtain HSCs from a A term variously used to define non-lymphoid cells or cells of the patient’s blood. monocyte–macrophage compartment (known as myelomonocytic cells). Cytokines and chemokines Secreted that stimulate cell growth, survival and Granulocytes differentiation. A group of cells including , eosinophils, and basophils, but the term is often used for neutrophils only. Colony-forming assay If seeded in semi-solid medium, blood-cell precursors form colonies Stem-cell niches in the presence of appropriate cytokines. This assay is widely Specialized microenvironments that control stem-cell dormancy used to define a cell’s differentiation potential and to identify and the balance between stem-cell self-renewal and differentiation. biologically active molecules.

Plasticity Cancer and/or leukaemia stem cells The capacity of defined cell types to acquire new identities. The These are self-renewing cells capable of generating leukaemia extent of plasticity of HSCs and haematopoietic progenitors under after transplantation. They can give rise to more differentiated physiological conditions is controversial and probably quite limited. cells comprising the bulk of the leukaemia. Cancer stem cells, However, re-specification of cell fate can be induced by enforced first identified in acute myeloid leukaemia, are critical targets for transcription factor expression, cell fusion or nuclear transfer. intervention.

Self-renewal Lineage The ability of cells to repeatedly generate at least one identical The promiscuous expression of myeloid–erythroid lineage daughter cell. associated markers in HSCs.

Background reading

Wilson, A. & Trumpp, A. Bone-marrow haematopoietic-stem-cell Takahama Y. Journey through the thymus: stromal guides for T-cell niches. Nature Rev. Immunol. 6, 93–106 (2006). development and selection. Nature Rev. Immunol. 6, 127–135 (2006).

Rothenberg E.V. Cell lineage regulators in B and T cell development. Cumano, A. & Godin, I. Ontogeny of the hematopoietic system. Nature Immunol. 8, 441–444 (2007). Annu Rev. Immunol. 25, 745–785 (2007).

Laiosa C.V., Stadtfeld, M. & Graf, T. Determinants of lymphoid- Nagasawa T. Microenvironmental niches in the bone marrow myeloid lineage diversification. Annu. Rev. Immunol. 24, 705–738 required for B-cell development. Nature Rev. Immunol. 6, 107–116 (2006). (2006).