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| Open AccessCell-specific proteome analyses of human bone marrow reveal molecular features of age-dependent functional decline
Ageing causes an inability to replace damaged tissue. Here, the authors perform proteomics analyses of human haematopoietic stem cells and other cells in the bone marrow niche at different ages and show changes in central carbon metabolism, reduced bone marrow niche function, and enhanced myeloid differentiation.
- Marco L. Hennrich
- , Natalie Romanov
- & Anthony D. Ho
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Article
| Open AccessLnk/Sh2b3 deficiency restores hematopoietic stem cell function and genome integrity in Fancd2 deficient Fanconi anemia
Loss of Fancd2 leads to replication stress intolerance and Fanconi Anemia, where haematopoietic stem cell (HSC) function is compromised. Here, the authors show that Lnk/Sh2b3 loss restores HSC proliferation and survival in Fancd2 knockout mice and ameliorates replication stress in a cytokine/JAK2 signaling dependent manner.
- Joanna Balcerek
- , Jing Jiang
- & Wei Tong
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Article
| Open AccessMed23 serves as a gatekeeper of the myeloid potential of hematopoietic stem cells
Hematopoietic stem cells (HSCs) in the bone marrow are quiescent, but are activated in response to stress. Here, the authors show that loss of Med23 leads to greater activation and enhanced myeloid potential of HSCs in response to stress, also Med23 maintains stemness gene expression and suppresses myeloid genes.
- Xufeng Chen
- , Jingyao Zhao
- & Xiaolong Liu
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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 AccessNeutralizing negative epigenetic regulation by HDAC5 enhances human haematopoietic stem cell homing and engraftment
Enhancement of haematopoietic stem cell (HSC) homing and engraftment is critical for haematopoietic cell transplantation. Here, the authors find that HDAC5 inhibition enhances HSC homing and engraftment by increasing p65 acetylation and enhancing NF-kB mediated CXCR4 transcription.
- Xinxin Huang
- , Bin Guo
- & Hal E. Broxmeyer
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Article
| Open AccessSingle-cell transcriptomics reveal the dynamic of haematopoietic stem cell production in the aorta
Haematopoietic stem cells (HSCs) are generated from haemogenic endothelial (HE) cells in vertebrate embryo aortas. Here, the authors perform single-cell RNA-sequencing of cells isolated from embryonic mouse aortas to identify genes and transcription factor networks activated during the endothelial-to-haematopoietic switch.
- Chloé S. Baron
- , Lennart Kester
- & Catherine Robin
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Article
| Open AccessStem cell factor is selectively secreted by arterial endothelial cells in bone marrow
Endothelial cells (EC) are known to contribute to haematopoietic stem cell (HSC) maintenance in the bone marrow (BM). Here the authors demonstrate that arterial ECs can be distinguished from sinusoidal ECs by podoplanin and Sca-1 expression, and that specifically arterial, but not sinusoidal ECs maintain HSCs by secreting SCF.
- Chunliang Xu
- , Xin Gao
- & Paul S. Frenette
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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 AccessA revised road map for the commitment of human cord blood CD34-negative hematopoietic stem cells
Single CD34 negative haematopoietic stem cells (HSCs) can fully reconstitute lympho-myeloid hematopoiesis in mice. Here, using single cell transplantation and gene expression analyses, the authors show that CD34 negative HSCs lie at the apex of haematopoiesis in human cord blood and that they can give rise to erythroid megakaryocytic progenitors.
- Keisuke Sumide
- , Yoshikazu Matsuoka
- & Yoshiaki Sonoda
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Article
| Open AccessHematopoietic stem cells can differentiate into restricted myeloid progenitors before cell division in mice
Dependence of hematopoietic stem cell (HSC) fate on the phase of the cell cycle has not been demonstrated in vivo. Here, the authors find that HSCs can differentiate into a downstream progenitor without physical division, even before progressing into the S phase of the cell cycle.
- Tatyana Grinenko
- , Anne Eugster
- & Ben Wielockx
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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 AccessReconstruction of complex single-cell trajectories using CellRouter
Single cell analysis provides insight into cell states and transitions, but to interpret the data, improved algorithms are needed. Here, the authors present CellRouter as a method to analyse single-cell trajectories from RNA-sequencing data, and provide insight into erythroid, myeloid and lymphoid differentiation.
- Edroaldo Lummertz da Rocha
- , R. Grant Rowe
- & George Q. Daley
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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 AccessDiabetes impairs wound healing by Dnmt1-dependent dysregulation of hematopoietic stem cells differentiation towards macrophages
Type 2 diabetes is associated with impaired wound healing, which can lead to limb loss. Here, the authors show that in Type 2 diabetic mouse models, Dnmt1 is upregulated in hematopoietic stem cells, leading to impaired differentiation towards macrophages, reduced macrophage infiltration in the wound and skewed M1/M2 polarization.
- Jinglian Yan
- , Guodong Tie
- & Louis M. Messina
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Article
| Open AccessSingle-cell RNA-sequencing uncovers transcriptional states and fate decisions in haematopoiesis
Traditionally marker-based approaches are used to define haematopoietic cell type or state. Here, the authors use single-cell RNA-seq to establish a cellular hierarchy of lineage development in zebrafish haematopoiesis, and propose a refined model of developmental progression of haematopoietic cells.
- Emmanouil I. Athanasiadis
- , Jan G. Botthof
- & Ana Cvejic
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Article
| Open AccessThe telomere binding protein Pot1 maintains haematopoietic stem cell activity with age
Repeated cell divisions induce DNA damage in haematopoietic stem cells (HSC) and telomeres are sensitive to this damage. Here, the authors show in murine HSCs that the telomere binding protein POT1a inhibited the production of reactive oxygen species, and rejuvenated aged HSCs.
- Kentaro Hosokawa
- , Ben D. MacArthur
- & Fumio Arai
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Article
| Open AccessEditing an α-globin enhancer in primary human hematopoietic stem cells as a treatment for β-thalassemia
β-thalassemia is characterised by the presence of an excess of α-globin chains, which contribute to erythrocyte pathology. Here the authors use CRISP/Cas9 to reduce α-globin expression in hematopoietic precursors, and show effectiveness in xenograft assays in mice.
- Sachith Mettananda
- , Chris A. Fisher
- & Douglas R. Higgs
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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 AccessEssential role of FBXL5-mediated cellular iron homeostasis in maintenance of hematopoietic stem cells
The iron-regulated F-box protein FBXL5 regulates iron homeostasis by mediating the degradation of iron regulatory protein 2 (IRP2). Here the authors show that FBXL5 and its regulation of IRP2 are required for HSC self-renewal and reconstitution capability.
- Yoshiharu Muto
- , Masaaki Nishiyama
- & Keiichi I. Nakayama
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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 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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Article
| Open Accessp190-B RhoGAP and intracellular cytokine signals balance hematopoietic stem and progenitor cell self-renewal and differentiation
The success of hematopoietic stem cell (HSC) transplantation relies on understanding what regulates the fate decision to self-renew. Here, the authors show using bothin vitro assays and in vivotransplantation that loss of the RhoGAP p190-B enhances self-renewal by inhibiting TGFβ/p38 signalling.
- Ashwini Hinge
- , Juying Xu
- & Marie-Dominique Filippi
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Article
| Open AccessEndothelial-specific inhibition of NF-κB enhances functional haematopoiesis
The complex microenvironmental signalling pathways that govern haematopoietic stem cell (HSC) activity remain poorly defined. Here, the authors identify endothelial NF-κB signalling as regulating regenerative HSC function, accelerating haematopoietic recovery following myelosuppressive injury in mice.
- Michael G. Poulos
- , Pradeep Ramalingam
- & Jason M. Butler
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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 AccessOutside-in integrin signalling regulates haematopoietic stem cell function via Periostin-Itgav axis
Integrins regulate haematopoietic stem cell (HSC) homeostasis and engraftment into the bone marrow (BM) niche upon transplantation. Here, the authors show that HSC quiescence and function in the BM is regulated by the interaction of PERIOSTIN and INTEGRIN αv and subsequent increase in p27Kip1.
- Satish Khurana
- , Sarah Schouteden
- & Catherine M. Verfaillie
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Article
| Open AccessReprogramming mouse fibroblasts into engraftable myeloerythroid and lymphoid progenitors
Direct reprogramming of closely-related lineages can generate hematopoietic stem cells. Here, the authors show hematopoietic transcription factors Scl, Lmo2, Runx1 and Bmi1 can reprogram fibroblasts into induced hematopoietic progenitors (iHPs), which are engraftable blood progenitors.
- Hui Cheng
- , Heather Yin-Kuan Ang
- & Bing Lim
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Article
| Open AccessSemi-automated closed system manufacturing of lentivirus gene-modified haematopoietic stem cells for gene therapy
Current methods for haematopoietic stem cell gene therapy are laborious and require special licensed facilities. Here the authors develop a semi-automated protocol using a commercially available device to allow for benchtop generation of gene-modified blood cell products for transplantation, that meet current standards.
- Jennifer E. Adair
- , Timothy Waters
- & Hans-Peter Kiem
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Article
| Open AccessSpecification of haematopoietic stem cell fate via modulation of mitochondrial activity
Haematopoietic stem cells rely on glycolysis for their energy demands but whether this affects their fate is unknown. Here, the authors show that forcing the cells to rely on glycolysis is important for self-renewal and that this involves a reduction in mitochondrial mass.
- Nicola Vannini
- , Mukul Girotra
- & Matthias P. Lutolf
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Article
| Open AccessIdentification of a common mesenchymal stromal progenitor for the adult haematopoietic niche
How the environment of the niche regulates haematopoietic stem cells (HSC) is unclear. Here, the authors identify a mesenchymal stromal progenitor hierarchy and identify Sca1+ cells as common progenitors for mesenchymal stromal cells in the adult niche that provide a supportive environment for hematopoiesis.
- Xingbin Hu
- , Mayra Garcia
- & Ching-Cheng Chen
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Article
| Open AccessLECT2 drives haematopoietic stem cell expansion and mobilization via regulating the macrophages and osteolineage cells
How extramedullar cytokines regulate hematopoietic stem cell (HSC) homeostasis is unclear. Here, the authors show that the cytokine leukocyte cell-derived chemotaxin 2 regulates HSC expansion and mobilisation via tumour necrosis factor and interaction with CD209a in macrophages.
- Xin-Jiang Lu
- , Qiang Chen
- & Jiong Chen
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Article
| Open AccessHigh-resolution imaging and computational analysis of haematopoietic cell dynamics in vivo
It is difficult to image haematopoietic stem cells (HSC) in their niche. Here, the authors present a new high-throughput computational approach to visualise HSCs in vivoat a high spatial and temporal resolution and also use a Msi2-reporter to label endogenous HSCs and progenitors, enabling cell tracking
- Claire S. Koechlein
- , Jeffrey R. Harris
- & Tannishtha Reya
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| Open AccessDNMT3A R882 mutants interact with polycomb proteins to block haematopoietic stem and leukaemic cell differentiation
DNMT3A mutations are known to cause acute myeloid leukaemia. Here, Koya et al. show that DNMT3A R882H mutation causes monoblastic transformation and haematopoietic stem cell accumulation in a methylation-independent manner, by suppressing the polycomb repressive complex 1, causing transcriptional silencing.
- Junji Koya
- , Keisuke Kataoka
- & Mineo Kurokawa
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| Open AccessSingle-cell RNA sequencing reveals molecular and functional platelet bias of aged haematopoietic stem cells
With age, haematopoietic stem cells (HSCs) produce more myeloid than lymphoid cells, affecting adaptive immunity. By combining HSC single cell transcriptomics with functional studies, Grover et al. find that platelet production is also increased in old murine HSCs and show that the FOG-1 transcription factor contributes to the age-dependent platelet bias.
- Amit Grover
- , Alejandra Sanjuan-Pla
- & Claus Nerlov
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Article
| Open AccessTherapeutic targeting and rapid mobilization of endosteal HSC using a small molecule integrin antagonist
Mobilizing haematopoietic stem cells to the peripheral blood has largely replaced bone marrow transplants as a strategy in the clinic. Here, Cao et al. report the use of an α9β1/α4β1integrin antagonist to induce rapid mobilization of blood stem cells from the bone marrow in a humanized mouse model.
- Benjamin Cao
- , Zhen Zhang
- & Susan K. Nilsson
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Article
| Open AccessInductive interactions mediated by interplay of asymmetric signalling underlie development of adult haematopoietic stem cells
It is unclear how the microenvironment of the aorta-gonad-mesonephros influences haematopoietic stem cell (HSC) production early in mouse development. Here, Souilhol et al. use an in vitroaggregate system as a tool to understand how several pathways, BMP, SCF and Shh, may regulate HSC production.
- Céline Souilhol
- , Christèle Gonneau
- & Alexander Medvinsky
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Article
| Open AccessHaematopoietic ESL-1 enables stem cell proliferation in the bone marrow by limiting TGFβ availability
Hematopoietic stem and progenitor cell (HSPCs) proliferation is controlled by signals from the niche. Here, Leivaet al. show in vivoin mice that deletion of E-selectin ligand 1 causes quiescence of HSPCs and a reduction in niche size, which is mediated by changes of TGFß levels in the bone marrow.
- Magdalena Leiva
- , Juan A. Quintana
- & Andrés Hidalgo
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Article
| Open AccessSF3B1 mutant MDS-initiating cells may arise from the haematopoietic stem cell compartment
Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders with diverse phenotypes and can derive from hematopietic stem cells after the acquisition of specific somatic aberrations. In this study, the authors show that MDS initiating cells in some cases of sideroblastic anemia with SF3B1 mutations, can arise from hematopoietic stem cells.
- Syed A. Mian
- , Kevin Rouault-Pierre
- & Ghulam J. Mufti
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Article
| Open AccessSTAT5-regulated microRNA-193b controls haematopoietic stem and progenitor cell expansion by modulating cytokine receptor signalling
MicroRNAs regulate haematopoietic stem cell (HSC) development to ensure the correct generation of blood cells. Haetscher et al. show in mice that miR-193b controls the life-long self-renewal ability of HSCs via AKT and STAT5 pathways, with loss of miR-193b accelerating HSC expansion and reducing differentiation.
- Nadine Haetscher
- , Yonatan Feuermann
- & Michael A. Rieger
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Sleep disruption impairs haematopoietic stem cell transplantation in mice
How can you increase the success of hematopoietic stem cell (HSC) transplantation? In mice, Rolls et al. identify sleep in the donor as an important factor, finding that less sleep leads to 50% lower HSC engraftment, via miR-19b and suppressor of cytokine signaling genes, which prevent HSC homing.
- Asya Rolls
- , Wendy W. Pang
- & Luis de Lecea
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Article
| Open AccessReplication stress caused by low MCM expression limits fetal erythropoiesis and hematopoietic stem cell functionality
What causes hematopoietic stem cell loss of functionality? Here, Alvarez et al. show that loss of origin licensing factor MCM3 induces replicative stress (RS), causing aberrant erythrocyte maturation, but mice strains with higher tolerance to RS can overcome this defect.
- Silvia Alvarez
- , Marcos Díaz
- & Juan Méndez
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Article
| Open AccessNotch signal strength controls cell fate in the haemogenic endothelium
It is unclear how Notch1 signals regulate both the maintenance of the endothelial fate and the endothelial-to-hematopoietic transition in the embryonic aorta. Here the authors show that those cells in which Notch1 ligand Jag1 is out-competed by Dll4 remain endothelial, while higher Jag1 activity leads to generation of hematopoietic stem cells.
- Leonor Gama-Norton
- , Eva Ferrando
- & Anna Bigas
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Article
| Open AccessBMP signalling differentially regulates distinct haematopoietic stem cell types
How bone morphogenetic proteins (BMPs) regulate haematopoietic stem cells (HSCs) later in development is unclear. Crisan et al.show that long-term repopulating HSCs in murine fetal liver and the bone marrow are of two types: either BMP activated or non-BMP activated, which correlate with different lineage outputs.
- Mihaela Crisan
- , Parham Solaimani Kartalaei
- & Elaine Dzierzak
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An MTCH2 pathway repressing mitochondria metabolism regulates haematopoietic stem cell fate
Changes in the metabolic state of stem cells can trigger a shift from quiescence into cell cycle entry. Here Maryanovichet al. identify mitochondrial carrier homolog 2 (MCH2) as a negative regulator of mitochondrial oxidative phosphorylation in haematopoietic stem cells, maintaining their homeostasis.
- Maria Maryanovich
- , Yehudit Zaltsman
- & Atan Gross
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Article
| Open AccessRepression of arterial genes in hemogenic endothelium is sufficient for haematopoietic fate acquisition
The first haematopoietic stem and progenitor cells arise from the hemogenic endothelium of arterial vascular beds. Here the authors describe the mechanism that regulates the endothelial-to-haematopoietic transition and show that Sox17 and Notch1, genes critical to arterial endothelium identity, are also crucial repressors of haematopoietic fate.
- Carlos O. Lizama
- , John S. Hawkins
- & Ann C. Zovein
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Wip1 deficiency impairs haematopoietic stem cell function via p53 and mTORC1 pathways
Aging leads to impaired differentiation and increased pool size of hematopoietic stem cells (HSCs). Here, the authors show that wild-type p53-induced phosphatase 1 (Wip1), a negative regulator of DNA damage response pathways, regulates aging-associated HSC differentiation and expansion viap53 and mTORC1 pathways, respectively.
- Zhiyang Chen
- , Weiwei Yi
- & Zhenyu Ju
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Small-molecule inhibitors targeting INK4 protein p18INK4C enhance ex vivo expansion of haematopoietic stem cells
The cyclin-dependent kinase inhibitors p18 and p27 confer advantage to the propagation of haematopoietic stem cells (HSCs). In this manuscript, the authors demonstrate that p18 is a potent negative regulator of HSC self-renewal, and identify novel small molecules putatively inhibiting p18 that promote HSC growth in culture and mouse transplant assays.
- Yingdai Gao
- , Peng Yang
- & Xiang-Qun Xie
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Primitive macrophages control HSPC mobilization and definitive haematopoiesis
Haematopoietic stem/progenitor cells (HSPCs) transform from aortic endothelium into migratory cells that move through stroma and enter circulation to colonize haematopoietic tissues. Here the authors show that HSPCs' passage is facilitated by primitive macrophages that secrete extracellular matrix-degrading enzymes.
- Jana Travnickova
- , Vanessa Tran Chau
- & Karima Kissa
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Vasculopathy-associated hyperangiotensinemia mobilizes haematopoietic stem cells/progenitors through endothelial AT2R and cytoskeletal dysregulation
Increased levels of haematopoietic stem and progenitor cells in the blood have been linked to some forms of organ failure. Here, the authors show that the hormone angiotensin II increases mobilization of haematopoietic stem and progenitor cells by inducing cytoskeletal changes in bone marrow cells.
- Kyung Hee Chang
- , Ramesh C Nayak
- & Jose A Cancelas