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Environments of Haematopoiesis and B-Lymphopoiesis in Foetal Liver K

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Environments of Haematopoiesis and B-Lymphopoiesis in Foetal Liver K Environments of haematopoiesis and B-lymphopoiesis in foetal liver K. Kajikhina1, M. Tsuneto1,2, F. Melchers1 1Max Planck Fellow Research Group ABSTRACT potent myeloid/lymphoid progenitors on “Lymphocyte Development”, In human and murine embryonic de- (MPP), and their immediate progeny, Max Planck Institute for Infection velopment, haematopoiesis and B-lym- common myeloid progenitors (CMP) Biology, Berlin, Germany; phopoiesis show stepwise differentia- and common lymphoid progenitors 2Department of Stem Cell and Developmental Biology, Mie University tion from pluripotent haematopoietic (CLP) soon thereafter (10). The first Graduate School of Medicine, Tsu, Japan. stem cells and multipotent progenitors, T- or B-lymphoid lineage-directed pro- Katja Kajikhina over lineage-restricted lymphoid and genitors appear at E12.5-13.5, for T- Motokazu Tsuneto, PhD myeloid progenitors to B-lineage com- lymphocytes in the developing thymus Fritz Melchers, PhD mitted precursors and finally differenti- (11), for B-lymphocytes in foetal liver Please address correspondence to: ated pro/preB cells. This wave of dif- (12). Time in development, therefore, Fritz Melchers, ferentiation is spatially and temporally separates and orders these different Max Planck Fellow Research Group organised by the surrounding, mostly developmental haematopoietic stages. on “Lymphocyte Development”, non-haematopoietic cell niches. We re- Three-dimensional imaging of progen- Max Planck Institute for Infection Biology, view here recent developments and our itors and precursors indicates that stem Chariteplatz 1, current contributions on the research D-10117 Berlin, Germany. cells are mainly found inside the em- E-mail: [email protected] on blood cell development. bryonic blood vessel, and are attracted Received and accepted on August 28, 2015. to vascular endothelium at the early Introduction stage of tissue colonisation at E10.5- Clin Exp Rheumatol 2015; 33 (Suppl. 92): S91-S93. Human and murine haematopoietic E11.5 (13). stem cells generate their progeny, eryth- © Copyright CLINICAL AND EXPERIMENTAL RHEUMATOLOGY 2015. roid, megakaryocytic, myeloid and Haematopoietic stem cells and lymphoid lineage cells continuously progenitors on their way to B cells Key words: foetal liver, throughout life in bone marrow. These We have chosen foetal liver as an em- haematopoiesis, migration, progenitors and differentiated lineage bryonic site, where myeloid and B-lym- B-lymphopoiesis, stromal cell niches cells are guided in their development by phoid cells develop in a timely ordered microenvironments (niches) consisting fashion (4). Our analyses of the com- of mostly non-haematopoietic stromal position and kinetics of CD45+ haema- cells. Because of this continuous cell topoietic cells show that the foetal liver development during life bone marrow is colonised with less than 1000 pHSC contains a mixture of all haematopoi- at E13.5, which are characterised as etic cell stages in their environments lin-c-kit+Sca1+CD150+CD48+ or CD48- at any given time (1-3). Furthermore, cells, while lin- c-kit+Sca1+Flt3+CD48+ the three-dimensional complexity of MPP and lin-c-kit+IL7Rα+ CLP are the cavities, in which marrow is local- 10-fold, and lin-c-kit+IL7Rα-c-fms+ ised in bone, complicates histological myeloid progenitors (MP) 100-fold as analyses of spatial ordering of haemat- frequent. It is notable that the absolute opoietic niches. Foetal liver is easily ac- numbers of MPP, MP and CLP increase cessible for histological sectioning and, only slightly with increasing time of therefore, for the localisation of haema- gestation between E13.5 and E16.5. topoietic niches and their relationship At the same time the numbers of dif- in time of development (4). ferentiated SLC+CD19+preB cells, the Embryonic development of the mouse immediate precursors of SLC-IgM+ B starts to generate haematopoietic pro- cells, undergo an over 400-fold expan- genitors with limited erythroid/my- sion within 4 days (Fig. 1). eloid capacities in yolk sac at E8.5 (5, 6), while pluripotent haematopoietic Environments of haematopoiesis Funding: this work was in part supported stem cells (pHSC) are generated in the in foetal liver by a DFG Kosellek Grant (ME 2764/1-1. aorta-gonad-mesonephros area of the On the other side, the microenviron- Competing interests: none declared. embryo at around E10.5 (7-9), multi- ments, in which pHSCs, MPPs, MPs S-91 Haematopoiesis in foetal liver / K. Kajikhina et al. Fig. 1. Develop- than 10% were still in contact with ment of haemato- LYVE-1high cells. By contrast, half of poietic progenitor subsets and B cell them were now in contact with mesen- high precursors in wild- chymal ALCAM liver cells (11). type murine foetal This change in the histologically de- livers from E12.5 tectable neighborhood of the MPPs and to E16.5 CLPs, their chemokine receptor expres- sion and migration responsiveness, and the chemokine and cytokine expression profiles of the non-haematopoietic cells suggested that transendothelial migra- tion of these progenitors at E13.5 into foetal liver is mediated by CXCR3- CXCL10 interactions. MPPs and CLPs and CLPs, precursor B (preB) and im- towards CXCL10 in vitro and to ex- then migrate through the LYVE-1high mature and mature B-lymphocytes de- press the proper chemokine receptor vascular endothelium to ALCAMhigh velop in foetal liver during embryonic CXCR3 and, furthermore, to migrate to mesenchyme, attracted by CXCL10 development of the mouse between CXCL12, since these cells co-express and CXCL12 produced by this hepat- E13.5 and 16.5, are still largely un- the receptor CXCR4. ic environment. Once in contact with known. We analysed enzymatically At the same early times the ALCAMhigh mesenchymal cells MPPs, CLPs (pos- dissociated CD45+Ter119+ haemat- non-haematopoietic liver mesenchymal sibly also MPs) and their progenitors opoietic and CD45-TER119-VCAM-1+ cells produce CXCL10 and CXCL12, become resident and begin their further non-haematopoietic foetal liver cells as well as the cytokines SCF, Flt3L, differentiation toward B-lymphoid and by flow cytometry. Two subpopula- M-CSF and IL-7. Therefore these non- myeloid cell lineages, induced by the tions among the non-haematopoietic haematopoietic stromal cells produce cytokines M-CSF and IL7 produced in cells were identified that were either the chemokines necessary to attract this ALCAMhigh niche. It is interesting CD105high LYVE-1high or CD105low- the progenitors to this second site, as that in vitro migration assays at E15.5 ALCAMhigh (14). The LYVE-1high cells well as the cytokines required to in- showed that differentiated B-progeni- were shown to co-express the endothe- duce further differentiation along the tors had lost their migration capacity to- lial markers CD31, Tie-2 and VEGFR3. myeloid and lymphoid pathways. It is ward CXCL10, but remained sensitive The ALCAMhigh cells displayed hepatic well known that B cell development to CXCL12, although they retained the and mesenchymal markers DLK1, in the bone marrow as well as in foetal expression of the corresponding recep- BP-1 and CD133. liver requires IL-7 and CXCL12 (17), tor, CXCR3, on their surface. It needs By RT-PCR and histological analysis of whereas M-CSF drives myeloid line- to be clarified whether signalling via IL7-GFP reporter mice (15) we checked age choice and differentiation (13,14). CXCR3 has been abandoned by preB in these two types of non-haematopoi- Therefore, ALCAMhigh cells appear to cells, or whether the quality of signal etic cells for gene expression programs be capable to support both B-lymphoid transduction has changed from migra- that could be involved in the chemokine and myeloid differentiation of early tion to residence, survival and prolif- mediated progenitor migration, and for progenitors. eration at the second, mesenchymal site their cytokine profiles for support of of B-lymphoid development. proliferation, survival and differentia- Migration from embryonic blood For the development of B-lineage cells tion of haematopoietic and B-lymphoid to foetal liver these observations suggest that MPPs progenitors. The location of IL-7Rα+ haematopoietic and CLPs with Ig gene loci in germline At E13.5 and E14.5 LYVE-1high en- progenitors in the endothelial, LYVE-1+ configuration enter the developing foe- dothelial cells produce CXCL10. The and mesenchymal ALCAM+ microenvi- tal liver at E13.5 through the vascular LYVE-1high endothelial cells do not ronments of foetal liver was investigated endothelium and then migrate within a produce M-CSF, one major myeloid by immuno-fluorescence in histological day to an ALCAMhigh liver mesenchy- cytokine, nor IL7, the major lymphoid sections between E13.5 and E16.5. mal cell microenvironment. It is known cytokine. They express SCF, the ligand At E13.5, but not later, these analyses that proB and preB cells are chemo- for c-kit, which is expressed on pHSCs, found three of four IL-7Rα+-stainable attracted in vitro towards CXCL12 and MPPs, MPs and CLPs, and they also (CD19-c-kit+SLC-) progenitors, pos- that non-haematopoietic stroma cells express Flt3L, active with Flt3 on the sibly a mixture of MPPs and CLPs, control the early stages of differen- surface of MPPs, MPs and CLPs, and in contact with vascular endothelial- tiation to DHJH-rearranging, surrogate required for further myeloid and lym- type LYVE-1high cells. One day later, light chain-expressing pro B and preBI phoid differentiation (16). these c-kit+IL-7Rα+ cells developed to cells (4, 20). We see this when, between At the same developmental stage the CD19- and +, SLC-expressing, DHJH- E15.5 and E16.5, preBI cells expand early progenitors are seen to migrate rearranged pro and preBI cells. Less 10-fold in continued contact with AL- S-92 Haematopoiesis in foetal liver / K. Kajikhina et al. CAMhigh cells, begin VH- to DHJH-re- References Produced by Thymic Epithelial Cells Plays arrangements, but fail to express IgµH- 1. KIEL MJ, YILMAZ OH, IWASHITA T, YILMAZ a Major Role in the Development of Thymo- OH, TERHORST C, MORRISON SJ: SLAM cytes and TCRγδ+ Intraepithelial Lympho- chains and preB cell receptors before family receptors distinguish hematopoietic cytes.
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