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Article
| Open AccessTRADD regulates perinatal development and adulthood survival in mice lacking RIPK1 and RIPK3
Programmed cell death regulates early development but how various factors (for example, TRADD, FADD and RIPKs) regulate this is unclear. Here, the authors show that a single allele of Tradd is essential for survival, when both Ripk3 and Ripk1 are knocked out in mice, and RIPK1 protects thymocytes from TNF-induced apoptosis.
- John P. Dowling
- , Mohamed Alsabbagh
- & Jianke Zhang
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Article
| Open AccessFetal-derived macrophages dominate in adult mammary glands
Tissue-resident macrophages are highly specialized phagocytes that serve multiple functions. Here, using high-dimension analyses and fate-mapping experiments, the authors show that fetal liver-derived macrophages dominate the mammary gland in neonatal and adult, and display characteristic phenotypes and functions.
- Norma Jäppinen
- , Inês Félix
- & Marko Salmi
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Article
| Open AccessA miR-150/TET3 pathway regulates the generation of mouse and human non-classical monocyte subset
A decrease in the fraction of non-classical monocytes is a hallmark of chronic myelomonocytic leukaemia. Taking advantage of this abnormal situation, the authors identify a mechanistic link between miR-150 and TET3 as being involved in monocyte subset generation.
- Dorothée Selimoglu-Buet
- , Julie Rivière
- & Eric Solary
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Article
| Open AccessMurine hematopoietic stem cell activity is derived from pre-circulation embryos but not yolk sacs
The source of where definitive hematopoietic stem cells (dHSCs) develop in the mouse embyro has been much debated. Here, the authors identify that dHSCs arise from the intra-embyronic region by using murine embryonic explant transplantation but not from the yolk sac.
- Miguel Ganuza
- , Ashley Chabot
- & Shannon McKinney-Freeman
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Article
| Open AccessSCL/TAL1 cooperates with Polycomb RYBP-PRC1 to suppress alternative lineages in blood-fated cells
Mechanisms that operate during embryonic development to restrict cell fate are currently under investigation. Here the authors characterise the role of SCL/TAL1 at the onset of blood specification in embryonic development using mouse EB differentiation culture as a model system.
- Hedia Chagraoui
- , Maiken S. Kristiansen
- & Catherine Porcher
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Article
| Open AccessCSF1R regulates the dendritic cell pool size in adult mice via embryo-derived tissue-resident macrophages
Dendritic cells (DC) are important regulators of both innate and adaptive immunity, but how the DC pool is homeostatically maintained in vivo is unclear. Here the authors show that combined deficiency of FLT3 and CSF1R impedes the differentiation of spleen macrophages of embryonic origin that are required for DC homeostasis.
- Gulce Itir Percin
- , Jiri Eitler
- & Claudia Waskow
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Article
| Open AccessTrisomy silencing by XIST normalizes Down syndrome cell pathogenesis demonstrated for hematopoietic defects in vitro
Individuals with Down Syndrome have hematopoietic abnormalities including high risk of leukaemia. Here the authors show that transcriptional silencing of one chromosome 21 by XIST effectively corrects cell function and development to prevent excessive production of megakaryocytes and erythroids, shown during hematopoietic differentiation of human iPSCs in culture.
- Jen-Chieh Chiang
- , Jun Jiang
- & Jeanne B. Lawrence
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Article
| Open AccessCrosstalks between mTORC1 and mTORC2 variagate cytokine signaling to control NK maturation and effector function
The metabolic regulator protein family, mTOR, regulate natural killer (NK) cell development and function, but the underlying mechanism is unclear. Here, the authors show that Raptor/mTORC1 and Rictor/mTORC2 form a feedback crosstalk network to variegate cytokine and cellular signaling and modulate NK maturation and effector functions.
- Fangjie Wang
- , Meng Meng
- & Youcai Deng
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Article
| Open AccessBi-directional signaling by membrane-bound KitL induces proliferation and coordinates thymic endothelial cell and thymocyte expansion
c-Kit receptor–Kit ligand complex signaling is known to activate c-Kit and is essential for tissue development. Here, Buono et al. show that membrane-bound KitL signaling induces proliferation via CAML-Akt-CREB pathway activation, establishing a role for bidirectional signaling in tissue expansion.
- Mario Buono
- , Marie-Laëtitia Thézénas
- & Claus Nerlov
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Article
| Open AccessLong non-coding RNA-dependent mechanism to regulate heme biosynthesis and erythrocyte development
LncRNAs modulate diverse physiological cellular processes, however, their involvement in heme-dependent processes are not yet clear. Here the authors reveal the role of lncRNA UCA1 in erythroid cell development.
- Jinhua Liu
- , Yapu Li
- & Lihong Shi
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Article
| Open AccessVariants in exons 5 and 6 of ACTB cause syndromic thrombocytopenia
Genetic variants in ACTB and ACTG1 have been associated with Baraitser-Winter Cerebrofrontofacial syndrome. Here, the authors report of a syndromic thrombocytopenia caused by variants in ACTB exons 5 or 6 that compromise the organization and coupling of the cytoskeleton, leading to impaired platelet maturation.
- Sharissa L. Latham
- , Nadja Ehmke
- & Nataliya Di Donato
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Article
| Open AccessMyelo-lymphoid lineage restriction occurs in the human haematopoietic stem cell compartment before lymphoid-primed multipotent progenitors
Human blood cells all develop from haematopoietic stem cells (HSCs), classically thought to be multipotent. Here the authors show, using single-cell RNA-seq and functional assays, that loss of erythroid potential and commitment to the myelo-lymphoid lineage occurs within the purest HSC compartment to date.
- Serena Belluschi
- , Emily F. Calderbank
- & Elisa Laurenti
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Article
| Open AccessP38α/JNK signaling restrains erythropoiesis by suppressing Ezh2-mediated epigenetic silencing of Bim
Erythropoietin (EPO) stimulates erythropoiesis and is commonly used to treat anemia. Here Hu et al. find that P38α/JNK signaling restrains erythropoiesis independently of EPO by regulating epigenetic silencing of the proapoptotic protein Bim, and thus identify putative targets for the treatment of anemic disorders resistant to EPO.
- Ping Hu
- , Angel R. Nebreda
- & Reuben Kapur
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Article
| Open AccessA metabolic interplay coordinated by HLX regulates myeloid differentiation and AML through partly overlapping pathways
HLX transcription factor regulates haematopoietic stem and progenitor cell (HSPC) differentiation and is overexpressed in acute myeloid leukemia. Here the authors show that HLX overexpression leads to myeloid differentiation block in zebrafish and human HSPCs by direct regulation of metabolic pathways.
- Indre Piragyte
- , Thomas Clapes
- & Eirini Trompouki
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Article
| Open AccessLineage marker synchrony in hematopoietic genealogies refutes the PU.1/GATA1 toggle switch paradigm
The timing of cell fate choices is usually unknown, because we have to rely on indirect evidence of their molecular basis. Here, the authors introduce a method to infer decision times from marker onset in cell genealogies, and find evidence refuting the paradigmatic PU.1/GATA1 cell fate switch.
- Michael K. Strasser
- , Philipp S. Hoppe
- & Carsten Marr
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Article
| Open AccessSystemic control of immune cell development by integrated carbon dioxide and hypoxia chemosensation in Drosophila
In mammals, crosstalk between O2 and CO2 sensing central and peripheral chemoreceptors has been linked to functions of the hematopoietic system. Here, the authors show an evolutionarily relevant cascade involving multiple organs that links CO2- and O2-chemosensation to immune cell maturation in Drosophila.
- Bumsik Cho
- , Carrie M. Spratford
- & Jiwon Shim
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Article
| Open AccessTCR signal strength controls thymic differentiation of iNKT cell subsets
Invariant natural killer T (iNKT) cells can be subsetted by their cytokine profiles, but how they develop in the thymus is unclear. Here the authors show, by analysing mice carrying mutant Zap70 genes, that T cell receptor signaling strength induces epigenetic changes of genes to modulate iNKT lineages.
- Kathryn D. Tuttle
- , S. Harsha Krovi
- & Laurent Gapin
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Article
| Open AccessAltered thymic differentiation and modulation of arthritis by invariant NKT cells expressing mutant ZAP70
Invariant natural killer T (iNKT) cells can be subsetted based on their cytokine productions. Here the authors show, using Zap70 mutant mice, that interferon-γ secreting (IFN-γ) iNKT cells may be induced by hampered T cell receptor signallings to help ameliorate interleukin-17-mediated joint inflammation.
- Meng Zhao
- , Mattias N. D. Svensson
- & Mitchell Kronenberg
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Article
| Open AccessQuantitative spatial analysis of haematopoiesis-regulating stromal cells in the bone marrow microenvironment by 3D microscopy
The bone marrow microenvironment modulates haematopoiesis, stem cell maintenance and differentiation. Here, the authors use 3D microscopy to map the topography of haematopoietic stem cell niche stromal components.
- Alvaro Gomariz
- , Patrick M. Helbling
- & César Nombela-Arrieta
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Article
| Open AccessThe Wave2 scaffold Hem-1 is required for transition of fetal liver hematopoiesis to bone marrow
Hematopoietic stem cells (HSCs) migrate from the fetal liver to the bone marrow (BM) during embryogenesis. Here the authors show that the WAVE2 complex scaffold Hem1 is required for engraftment of HSCs in BM, not through its canonical role regulating actin polymerization, but through c-Abl survival signaling.
- Lijian Shao
- , Jianhui Chang
- & Robert A. Hromas
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Article
| Open AccessNOTCH signaling specifies arterial-type definitive hemogenic endothelium from human pluripotent stem cells
It is unclear whether arterial specification is required for hematopoietic stem cell formation. Here, the authors use a chemically defined human pluripotent stem cell (hPSC) differentiation system to show the role of NOTCH signaling in forming arterial-type hemogenic endothelial cells.
- Gene I. Uenishi
- , Ho Sun Jung
- & Igor I. Slukvin
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Article
| Open AccessLipoprotein lipase regulates hematopoietic stem progenitor cell maintenance through DHA supply
Lipoprotein lipase (LPL) hydrolyzes triglycerides to supply free fatty acids (FFAs) to muscle for energy and adipocytes for storage. Here, the authors demonstrate that Lpl and its product, the FFA docosahexaenoic acid (DHA) are required for haematopoietic stem progenitor cell expansion during zebrafish embryogenesis.
- Chao Liu
- , Tianxu Han
- & Yury I. Miller
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Article
| Open AccessBreast and pancreatic cancer interrupt IRF8-dependent dendritic cell development to overcome immune surveillance
Tumors escape the immune system through many mechanisms. Here the authors show that certain tumors inhibit anti-tumor immunity by stopping the production of conventional dendritic cells (cDCs) in the bone marrow, therefore depleting the pool of cDCs available to present antigen to CD8+ T cells.
- Melissa A. Meyer
- , John M. Baer
- & David G. DeNardo
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Article
| Open AccessIkaros family zinc finger 1 regulates dendritic cell development and function in humans
IKZF1 is a transcription factor known to regulate mammalian B-cell development. Here the authors show that IKZF1 is required for human pDC development and regulation of DC cytokine production in patients with IKZF1 haploinsufficiency, findings which are recapitulated in lenalidomide-induced IKZF1 deficiency.
- Urszula Cytlak
- , Anastasia Resteu
- & Venetia Bigley
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Article
| Open AccessBone marrow lympho-myeloid malfunction in obesity requires precursor cell-autonomous TLR4
Obesity can affect bone marrow cell differentiation and the generation of myeloid and lymphoid cells. Here, the authors show that diet and obesity, as well as low-dose lipopolysaccharide, can alter Toll-like receptor 4 signaling bone marrow cells to skew the myeloid-lymphoid homeostasis in mice.
- Ailing Liu
- , Minhui Chen
- & Lisa Borghesi
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Article
| Open AccessThe tumour microenvironment creates a niche for the self-renewal of tumour-promoting macrophages in colon adenoma
Tissue-resident F4/80hi macrophages can be found both in normal gut as well as in intestinal tumours. Here the authors show that in the colon these macrophages are CCR2-dependent, while in tumours they gain the ability to self-renew, relying on CSF1 and promoting cancer progression.
- Irene Soncin
- , Jianpeng Sheng
- & Christiane Ruedl
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Article
| Open AccessYolk sac macrophage progenitors traffic to the embryo during defined stages of development
Tissue-resident macrophages are derived from yolk sac progenitors but how and when these progenitors enter is unclear. Here the authors use fate mapping and intravital microscopy to track the movement of resident macrophage precursors from the yolk sac to fetal tissues during development.
- C. Stremmel
- , R. Schuchert
- & C. Schulz
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Article
| Open AccessHEB is required for the specification of fetal IL-17-producing γδ T cells
The γδ T cell pool includes abundant IL-17-producing cells that protect mucosal surfaces, but the signals that control γδ T cell specification are unclear. Here the authors identify a role for the transcription factor HEB, and antagonistic activity of Id3, in the development of these cells.
- Tracy S. H. In
- , Ashton Trotman-Grant
- & Michele K. Anderson
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Article
| Open AccessCritical role of the HDAC6–cortactin axis in human megakaryocyte maturation leading to a proplatelet-formation defect
Histone deacetylase (HDAC) inhibitors, a class of cancer therapeutics, cause thrombocytopenia via an unknown mechanism. Here, the authors show that HDAC6 inhibition impairs proplatelet formation in human megakaryocytes, and show that this is linked to hyperacetylation of the actin-binding protein cortactin.
- Kahia Messaoudi
- , Ashfaq Ali
- & Najet Debili
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Article
| Open AccessCheckpoint kinase 1 is essential for normal B cell development and lymphomagenesis
Checkpoint kinase 1 (CHK1) is critical for intrinsic cell cycle control and coordination of cell cycle progression. Here the authors show that CHK1 loss or chemical inhibition impacts on normal B cell development, lymphomagenesis and cancer cell survival.
- Fabian Schuler
- , Johannes G. Weiss
- & Andreas Villunger
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Article
| Open AccessSuppression of SRCAP chromatin remodelling complex and restriction of lymphoid lineage commitment by Pcid2
Haematopoiesis and the generation of lymphoid cell subsets are controlled by delicate genetic programs enforced via epigenetic regulation. Here the authors show that Pcid2 interacts with ZNHIT1, a component of the SRCAP chromatin remodelling complex, to critically modulate the differentiation of multipotent progenitors.
- Buqing Ye
- , Benyu Liu
- & Zusen Fan
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Article
| Open AccessPLCγ-dependent mTOR signalling controls IL-7-mediated early B cell development
IL-7R activation drives early B cell development, but the signalling is unclear. Here the authors show PLCγ is involved in IL-7R-induced mTOR activation via a DAG/PKC-dependent pathway, and that double deficiency of the two PLCγ isoforms arrests B cell development at the pre-pro-B stage in mice.
- Mei Yu
- , Yuhong Chen
- & Demin Wang
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Article
| Open AccessKSRP specifies monocytic and granulocytic differentiation through regulating miR-129 biogenesis and RUNX1 expression
RNA-binding proteins (RBPs) regulate RNA activity and are implicated in haematopoietic malignancies, but their role in myeloid cell specification is unclear. Here, the authors show a role for the RBP KSRP in promoting granulocyte fate over monocyte fate through the biogenesis of miR-129 and a decrease in RUNX1.
- Hongmei Zhao
- , Xiaoshuang Wang
- & Jia Yu
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Article
| Open AccessA CRISPR screen identifies genes controlling Etv2 threshold expression in murine hemangiogenic fate commitment
How haematopoietic and endothelial cell lineages are specified is unclear. Here, the authors identify the forkhead transcription factor Foxh1 as regulating FLK1+ mesoderm formation in mouse embryonic stem cells, which in turn specifies hemangiogenic fate via Etv2.
- Haiyong Zhao
- & Kyunghee Choi
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Article
| Open AccessIL-7Rα glutamylation and activation of transcription factor Sall3 promote group 3 ILC development
Innate lymphoid cells (ILC) are important regulators of mucosal immunity, but how their development and homeostasis are modulated is still unclear. Here the authors show that the differentiation of group 3 ILCs is controlled by the glutamylation of IL-7Rα and the induction of transcription factor Sall3.
- Benyu Liu
- , Buqing Ye
- & Zusen Fan
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Article
| Open AccessSingle-cell analyses identify bioengineered niches for enhanced maintenance of hematopoietic stem cells
Haematopoietic stem cell (HSC) self-renewal is not sufficiently understood to recapitulate in vitro. Here, the authors generate gene signature and cell cycle hallmarks of single murine HSCs, and use identified endothelial receptors Esam and JamC as substrates to enhance HSC growth in engineered niches.
- Aline Roch
- , Sonja Giger
- & Matthias P. Lutolf
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Article
| Open AccessLet-7 microRNA-dependent control of leukotriene signaling regulates the transition of hematopoietic niche in mice
Hematopoietic stem and progenitor cells are generated first from the vascular endothelium of the dorsal aorta and then the fetal liver but what regulates this switch is unknown. Here, the authors show that changing miRNA biogenesis and leukotriene B4 signaling in mice modulates this switch in the niche.
- Xuan Jiang
- , John S. Hawkins
- & Akiko Hata
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Article
| Open AccessDisruption of the C/EBPα—miR-182 balance impairs granulocytic differentiation
C/EBPα is a critical transcription factor involved in myelopoiesis and its inactivation is associated with acute myeloid leukemia (AML). Here the authors show a negative feedback loop between C/EBPα and miR-182 and identify this miRNA as a marker of high-risk AML.
- Alexander Arthur Wurm
- , Polina Zjablovskaja
- & Gerhard Behre
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Article
| Open AccessHif-1α regulates macrophage-endothelial interactions during blood vessel development in zebrafish
The molecular mechanism regulating macrophage interaction with endothelial cells during development is unclear. Here, the authors show that in zebrafish mutation of hypoxia-inducible factor-1α impairs macrophage mobilization from the aorta-gonad-mesonephros, causing defects in angiogenesis and vessel repair.
- Claudia Gerri
- , Rubén Marín-Juez
- & Didier Y R. Stainier
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Article
| Open AccessFoxp3+ regulatory T cells maintain the bone marrow microenvironment for B cell lymphopoiesis
Treg cells suppress peripheral immune responses, but their function in haematopoiesis is unclear. Here the authors show they modulate the bone marrow microenvironment to sustain haematopoietic stem cell-driven generation of mature B cells.
- Antonio Pierini
- , Hidekazu Nishikii
- & Robert S. Negrin
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Article
| Open AccessThe Pu.1 target gene Zbtb11 regulates neutrophil development through its integrase-like HHCC zinc finger
Neutrophils are increased in response to injury and infection but how they form from a common granulocyte-macrophage progenitor is unclear. Here, the authors identify a role for the transcriptional repressor ZBTB11 in zebrafish, which is regulated by master myeloid regulators and repressesTP53.
- Maria-Cristina Keightley
- , Duncan P. Carradice
- & Graham J. Lieschke
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Article
| Open AccessIL-15 sustains IL-7R-independent ILC2 and ILC3 development
ILC2 and ILC3 are generally thought to require IL-7. Here the authors use IL-7 ko mice and provide side-by-side comparison of ILCs from different tissues to show that IL-7 signalling is not required for intestinal ILC maintenance or function and that IL-15 can compensate for absence of IL-7.
- Michelle L. Robinette
- , Jennifer K. Bando
- & Marco Colonna
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Article
| Open AccessClonal reversal of ageing-associated stem cell lineage bias via a pluripotent intermediate
Age-associated decline in tissue function has been linked to alterations in adult stem cells, with implications for organ homeostasis and cellular therapy. Here, the authors study the heterogeneity of ageing mouse haematopoietic stem cells (HSCs) and find that the compromised blood cell-forming potential of individual and functionally defined aged HSCs can be reset by reprogramming.
- Martin Wahlestedt
- , Eva Erlandsson
- & David Bryder
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Review Article
| Open AccessThe molecular basis of endothelial cell plasticity
Vascular endothelium possesses remarkable plasticity in response to cues from its surroundings, leading to great heterogeneity of endothelial cells in different vascular beds. Here the authors explain the molecular basis of endothelial plasticity during embryogenesis and in various diseases.
- Elisabetta Dejana
- , Karen K. Hirschi
- & Michael Simons
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Article
| Open AccessThioredoxin-interacting protein regulates haematopoietic stem cell ageing and rejuvenation by inhibiting p38 kinase activity
The processes regulating the ageing of stem cells are not clearly defined. Here, the authors report that in haematopoietic stem cells (HSC) thioredoxin-interacting protein, known to regulate the cell cycle, binds to p38 mitogen-activated protein kinase and regulates HSC ageing and rejuvenation.
- Haiyoung Jung
- , Dong Oh Kim
- & Inpyo Choi
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Article
| Open AccessEndoglin integrates BMP and Wnt signalling to induce haematopoiesis through JDP2
How both BMP and Wnt signalling pathways regulate lineage specification early in development is unclear. Here, the authors show that endoglin via Jdp2, an AP-1 family member, modulates BMP and Wnt signalling to commit mesodermal progenitors to a haematopoietic fate at the expense of the cardiac lineage.
- June Baik
- , Alessandro Magli
- & Rita C. R. Perlingeiro
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Article
| Open AccessRegulation of monocyte cell fate by blood vessels mediated by Notch signalling
Circulating Ly6Clo monocytes are thought to be derived from Ly6Chi subset. Here the authors show that Notch signalling is activated in Ly6Clocells and is required for their differentiation, and that Notch ligands that initiate this signalling are provided by a subset of endothelial cells.
- Jaba Gamrekelashvili
- , Roberto Giagnorio
- & Florian P. Limbourg
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Article
| Open AccessMEF2C protects bone marrow B-lymphoid progenitors during stress haematopoiesis
MEF2C is a transcription factor required for B-cell proliferation. Here the authors show that MEF2C is also needed in B-cell development and recovery from stress by inducing expression of DNA repair factors that prevent double stranded breaks and enable VDJ recombination.
- Wenyuan Wang
- , Tonis Org
- & Hanna K. A. Mikkola
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Article
| Open AccessLTβR controls thymic portal endothelial cells for haematopoietic progenitor cell homing and T-cell regeneration
Lymphoid progenitors migrate from the bone marrow into the thymus to give rise to T and NK cell lineages. Here the authors characterize a lymphotoxin receptor beta-dependent population of thymic endothelial cells that guide lymphoid progenitor homing in the thymus.
- Yaoyao Shi
- , Weiwei Wu
- & Mingzhao Zhu