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| Open AccessThe miR-144/Hmgn2 regulatory axis orchestrates chromatin organization during erythropoiesis
Differentiation of stem and progenitor cells is a highly regulated process. Here, the authors uncover miR-144 and its target Hmgn2 as the backbone of the genetic regulatory circuit that controls the terminal differentiation of erythrocytes in vertebrates.
- Dmitry A. Kretov
- , Leighton Folkes
- & Daniel Cifuentes
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Article
| Open AccessDeterminants of mosaic chromosomal alteration fitness
Here, the authors use passenger mutations to quantify expansion rate in ~6,000 people with mosaic chromosomal alterations in the NHLBI TOPMed cohort, finding associations between growth rate and blood counts along with germline genetic modulators of growth rate.
- Yash Pershad
- , Taralynn Mack
- & Alexander G. Bick
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Article
| Open Accessp53 regulates diverse tissue-specific outcomes to endogenous DNA damage in mice
DNA repair deficiency can cause tissue-specific phenotypes in humans and mice. Here, the authors find that p53 drives different, but tissue-specific responses despite the same defect in DNA repair. p53 drives blood stem cell loss but restrains liver polyploidisation in the absence of Ercc1.
- Ross J. Hill
- , Nazareno Bona
- & Gerry P. Crossan
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Article
| Open AccessAutophagy regulates the maturation of hematopoietic precursors in the embryo
The production of hematopoietic stem cells in the embryo is precisely regulated by various intrinsic and extrinsic factors. Here, the authors find that autophagy is involved in the maturation of hematopoietic precursors through nucleolin pathways.
- Yumin Liu
- , Linjuan Shi
- & Zhuan Li
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Article
| Open AccessDeregulated protein homeostasis constrains fetal hematopoietic stem cell pool expansion in Fanconi anemia
In this manuscript, the authors show deregulated protein synthesis as a novel, noncanonical defect in Fanconi Anemia. The observed deficits reflect the impact of proteostasis during fetal hematopoietic stem cell expansion and define the origins of hematopoietic failure in this disorder.
- Narasaiah Kovuru
- , Makiko Mochizuki-Kashio
- & Peter Kurre
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| Open AccessCis inhibition of NOTCH1 through JAGGED1 sustains embryonic hematopoietic stem cell fate
Notch signaling is critical for HSC emergence. Here, the authors identify a sub-set of hemogenic endothelial cells with high Notch activity that it is gradually shut down through cis inhibition of NOTCH1 by JAG1, and report that this process sustains HSC.
- Roshana Thambyrajah
- , Maria Maqueda
- & Anna Bigas
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Article
| Open AccessIncreased iron uptake by splenic hematopoietic stem cells promotes TET2-dependent erythroid regeneration
The cues guiding hematopoietic stem cells (HSCs) to regenerate specific cell types lost due to injury remain elusive. This study shows that iron instructs erythroid differentiation of HSCs during anemia in a Tet2-dependent manner.
- Yu-Jung Tseng
- , Yuki Kageyama
- & Daisuke Nakada
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Article
| Open AccessNlrc3 signaling is indispensable for hematopoietic stem cell emergence via Notch signaling in vertebrates
The emergence of hematopoietic stem and progenitor cells is finely tuned by a variety of signaling pathways. Here, the authors find that Nlrc3 is highly expressed during hematopoietic differentiation in vivo and in vitro, activates the Notch pathway, and acts downstream of NF-kB signaling.
- Shuyang Cai
- , Honghu Li
- & He Huang
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Article
| Open AccessNod1-dependent NF-kB activation initiates hematopoietic stem cell specification in response to small Rho GTPases
The signals that enable endothelial cells to switch to hemogenic to generate hematopoietic stem cells are poorly understood. Here, the authors identify an intracellular sensor of pathogens as an inductive developmental cue that primes this switch.
- Xiaoyi Cheng
- , Radwa Barakat
- & Raquel Espin-Palazon
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Article
| Open AccessCRISPR-Cas9 engineering of the RAG2 locus via complete coding sequence replacement for therapeutic applications
RAG2-SCID is a primary immunodeficiency caused by mutations in Recombination-activating gene 2 (RAG2). Here the authors report a RAG2 correction strategy that replaces the entire endogenous coding sequence (CDS) to maintain the endogenous spatiotemporal gene regulation and locus architecture.
- Daniel Allen
- , Orli Knop
- & Ayal Hendel
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Article
| Open AccessEbf3+ niche-derived CXCL12 is required for the localization and maintenance of hematopoietic stem cells
CAR cells act as HSC niche cells. Here the authors show that CXCL12 ablation in half CAR cells attracts HSCs from affected CAR cells to intact CAR cells whereas CXCL12 ablation in all CAR cells depletes balanced HSCs producing B cells at high levels.
- Taichi Nakatani
- , Tatsuki Sugiyama
- & Takashi Nagasawa
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| Open AccessFertility-preserving myeloablative conditioning using single-dose CD117 antibody-drug conjugate in a rhesus gene therapy model
Successful engraftment of human hematopoietic stem cells during gene therapy requires myeloablative conditioning of the recipient, at the expense of toxicity. Authors show here that a single-dose of anti-CD117 antibody-drug conjugate achieves similar engraftment results as traditional multi-dose busulfan conditioning but preserves fertility in a non-human primate model.
- Naoya Uchida
- , Ulana Stasula
- & John F. Tisdale
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Article
| Open AccessProteogenetic drug response profiling elucidates targetable vulnerabilities of myelofibrosis
Myelofibrosis is a form of myeloproliferative neoplasm with few treatment options available. Here, the authors profiled drug responses and proteomics ex vivo and identify molecularly-guided treatment strategies, including HDAC and BET inhibitors for CALR mutant myelofibrosis patients.
- Mattheus H. E. Wildschut
- , Julien Mena
- & Berend Snijder
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Article
| Open AccessPerivascular niche cells sense thrombocytopenia and activate hematopoietic stem cells in an IL-1 dependent manner
Hematopoietic stem cells (HSCs) replenish blood cells. Here, Luis et al., identify a feedback mechanism by which IL-1 secreted by activated platelets signals through niche Lepr+ cells to activate HSCs and restore platelet homeostasis.
- Tiago C. Luis
- , Nikolaos Barkas
- & Sten Eirik W. Jacobsen
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Article
| Open AccessGATA2 mitotic bookmarking is required for definitive haematopoiesis
Most transcription factors detach from chromatin during mitosis, but some are retained and bookmark genomic sites. Here, the authors show that GATA2-mediated mitotic bookmarking is critical for definitive haematopoiesis.
- Rita Silvério-Alves
- , Ilia Kurochkin
- & Carlos-Filipe Pereira
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Article
| Open AccessMeis1 establishes the pre-hemogenic endothelial state prior to Runx1 expression
Hematopoietic stem cell formation via the endothelial-to-hematopoietic transition is initiated by a complex rewiring of the aortic endothelium. Here the authors identify Meis1 as an early driver of hemogenic specification of this arterial endothelium.
- Patrick Coulombe
- , Grace Cole
- & Aly Karsan
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Article
| Open AccessHematopoietic reconstitution dynamics of mobilized- and bone marrow-derived human hematopoietic stem cells after gene therapy
Scala et al. show that mobilized peripheral blood hematopoietic stem/progenitor cells are more enriched in repopulating stem cells than bone marrow. Moreover, the quantity and type of infused subsets correlated with gene therapy outcome in humans.
- Serena Scala
- , Francesca Ferrua
- & Alessandro Aiuti
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Article
| Open AccessRNA binding protein SYNCRIP maintains proteostasis and self-renewal of hematopoietic stem and progenitor cells
Hematopoietic stem cells (HSCs) are essential for long-term repopulation after secondary transplantation. Here they show that SYNCRIP safeguards HSC self-renewal during regenerative stress by maintaining both proteostasis and CDC42-regulated cell polarity.
- Florisela Herrejon Chavez
- , Hanzhi Luo
- & Michael G. Kharas
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Article
| Open AccessExpansion of human megakaryocyte-biased hematopoietic stem cells by biomimetic Microniche
An effective expansion system for therapeutic megakaryocyte-biased hematopoietic stem cells has not been developed. Here the authors present a microniche-based system that supports scalable expansion of human Mk-biased HSCs and identify their immune phenotype.
- Yinghui Li
- , Mei He
- & Yingdai Gao
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Article
| Open AccessDRAG in situ barcoding reveals an increased number of HSPCs contributing to myelopoiesis with age
Using in situ single cell lineage tracing technology DRAG, we show that, unlike emergency myelopoiesis post-transplantation, aged HSPCs do not functionally decline in the number of myeloid cells that they produce.
- Jos Urbanus
- , Jason Cosgrove
- & Leïla Perié
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Article
| Open AccessHigh ploidy large cytoplasmic megakaryocytes are hematopoietic stem cells regulators and essential for platelet production
Not all megakaryocytes are created equal, with sub-populations identified that generate platelets and differentially regulate blood stem cells. These sub-populations, conserved in humans, are important in treating blood and clotting disorders.
- Shen Y. Heazlewood
- , Tanveer Ahmad
- & Susan K. Nilsson
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| Open AccessRestoring bone marrow niche function rejuvenates aged hematopoietic stem cells by reactivating the DNA Damage Response
Aging is associated with a loss of blood stem cell fitness in part due to defects in stem cell-supportive niches. Here, the authors demonstrate that restoring niche function by treatment with Netrin-1 is able to rejuvenate aged blood stem cells.
- Pradeep Ramalingam
- , Michael C. Gutkin
- & Jason M. Butler
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| Open AccessLongitudinal single-cell profiling of chemotherapy response in acute myeloid leukemia
Relapse within acute myeloid leukaemia may be driven by the presence of leukaemia stem cells. Here, the authors use single cell RNA-seq seq to characterise leukemia stem cells, and show miR-126 as a potential marker of resistance.
- Matteo Maria Naldini
- , Gabriele Casirati
- & Bernhard Gentner
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Article
| Open AccessAlcam-a and Pdgfr-α are essential for the development of sclerotome-derived stromal cells that support hematopoiesis
The early ontogeny of hematopoietic niches is largely unknown. This article shows that the sclerotome compartment of somites provides Alcam and Pdgfr-α dependent mesenchymal cells that are essential at every step of the development of hematopoiesis.
- Emi Murayama
- , Catherine Vivier
- & Philippe Herbomel
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Article
| Open AccessA genome-wide relay of signalling-responsive enhancers drives hematopoietic specification
Defining cis-regulatory elements is an important goal in understanding how gene expression is regulated. Here the authors show blood cell-specific gene expression is controlled by the action of thousands of differentiation stage-specific sets of cis-elements that respond to cytokine signals terminating at signaling responsive transcription factors.
- B. Edginton-White
- , A. Maytum
- & C. Bonifer
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Article
| Open AccessTherapeutic adenine base editing of human hematopoietic stem cells
Here, Liao and colleagues apply adenine base editor ABE8e and its PAM-less variant ABE8e-SpRY to β-thalassemia patient hematopoietic stem cells in the form of ribonucleoprotein complexes, resulting in efficient long-term editing and β-thalassemia alleviation.
- Jiaoyang Liao
- , Shuanghong Chen
- & Yuxuan Wu
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Article
| Open AccessEndogenous IL-1 receptor antagonist restricts healthy and malignant myeloproliferation
Enhanced IL-1β signaling pathway causes hematopoietic stem cell (HSC) to differentiate into myeloid cells and contributes to malignant hematopoiesis. Here the authors reveal that HSC differentiation is controlled by balanced levels of IL-1 receptor antagonist (IL-1rn) and IL-1β under steady-state, and that IL-1rn protects against pre-leukemic myelopoiesis by repressing IL-1β signaling.
- Alicia Villatoro
- , Vincent Cuminetti
- & Lorena Arranz
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Article
| Open AccessMyeloid cells promote interferon signaling-associated deterioration of the hematopoietic system
Innate and adaptive immune cells function in the homeostasis of haematopoietic stem cells (HSC). Here the authors show that myeloid cells are able to reduce the function of HSCs via interferon signaling through a neutrophil-NK cell dependent process.
- Jacqueline Feyen
- , Zhen Ping
- & Marc H. G. P. Raaijmakers
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Article
| Open AccessThe transcription factor DDIT3 is a potential driver of dyserythropoiesis in myelodysplastic syndromes
Myelodysplastic syndromes (MDS) are age-related pathologies in which alterations of hematopoietic stem cells lead to abnormal formation of blood cells. Here, the authors study the lesions that these cells undergo in aging and disease, characterizing a factor whose alteration in MDS leads to abnormal blood cell production.
- Nerea Berastegui
- , Marina Ainciburu
- & Felipe Prosper
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Article
| Open AccessA Myb enhancer-guided analysis of basophil and mast cell differentiation
The transcription factor MYB has been shown to regulate haematopoietic stem cells but there could be lineage specific enhancers. Here, using lineage tracing and single cell sequencing the authors characterise a Myb −68 enhancer that regulates the differentiation of mast cells and basophils.
- Takayoshi Matsumura
- , Haruhito Totani
- & Toshio Suda
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Article
| Open AccessBase-editing-mediated dissection of a γ-globin cis-regulatory element for the therapeutic reactivation of fetal hemoglobin expression
Antoniou and colleagues used base editing to generate a variety of mutations inducing γ-globin and rescue the β-hemoglobinopathy phenotype. This strategy was safe and effective in long-term repopulating hematopoietic stem/progenitor cells.
- Panagiotis Antoniou
- , Giulia Hardouin
- & Annarita Miccio
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Article
| Open AccessMurine fetal bone marrow does not support functional hematopoietic stem and progenitor cells until birth
Relatively little is known about the first hematopoietic stem and progenitor cells to arrive in the fetal bone marrow. Here they characterize the frequency, function, and molecular identity of fetal BM HSPCs and their bone marrow niche, and show that most BM HSPCs have little hematopoietic function until birth.
- Trent D. Hall
- , Hyunjin Kim
- & Shannon McKinney-Freeman
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Article
| Open AccessGermline-somatic JAK2 interactions are associated with clonal expansion in myelofibrosis
Myelofibrosis is a risk factor for the development of Acute Myeloid Leukaemia. Here, the authors carry out an integrated genomic investigation of 933 myelofibrosis patients, and identified interactions between germline and somatic variation in patients who required haematopoietic cell transplantation.
- Derek W. Brown
- , Weiyin Zhou
- & Mitchell J. Machiela
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Article
| Open AccessTaz protects hematopoietic stem cells from an aging-dependent decrease in PU.1 activity
Immune system function declines with age, a consequence of defects in hematopoietic stem cells (HSCs). Here the authors show that TAZ buffers age-related loss of PU.1 activity to maintain HSC functionality and identify the surface protein Clca3a1 as a marker of “young-like” HSCs, even in old mice.
- Kyung Mok Kim
- , Anna Mura-Meszaros
- & Björn von Eyss
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Article
| Open AccessUltra-deep sequencing validates safety of CRISPR/Cas9 genome editing in human hematopoietic stem and progenitor cells
As CRISPR-based therapies enter the clinic, evaluation of safety remains a critical and active area of study. Here the authors use next generation sequencing to achieve high sequencing depth and demonstrate that clinically relevant delivery of high-fidelity Cas9 to primary HSPCs and ex vivo culture up to 10 days does not introduce or enrich for tumorigenic variants.
- M. Kyle Cromer
- , Valentin V. Barsan
- & Matthew H. Porteus
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Article
| Open AccessFate mapping of hematopoietic stem cells reveals two pathways of native thrombopoiesis
Hematopoietic stem cells produce diverse cell lineages. Here, the authors apply single-cell RNA-seq, computational integration of non-perturbative approaches for fate-mapping, and mitotic tracking to chart lineage decisions in native hematopoiesis and identify megakaryocyte progenitors that directly link HSCs to megakaryocytes.
- Mina N. F. Morcos
- , Congxin Li
- & Alexander Gerbaulet
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Article
| Open AccessTranscription factor-driven coordination of cell cycle exit and lineage-specification in vivo during granulocytic differentiation
Here the authors show that differentiation of haematopoietic stem cells into mature blood cells is primed by cell type-specific transcription factors at the enhancer level during early differentiation, before they confere promoter-driven growth arrest, and activate post-mitotic terminal differentiation.
- Kim Theilgaard-Mönch
- , Sachin Pundhir
- & Bo T. Porse
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Article
| Open AccessEpigenetic traits inscribed in chromatin accessibility in aged hematopoietic stem cells
Haematopoietic stem cells (HSCs) exhibit considerable cell-intrinsic changes with age. Here the authors demonstrate that differentially accessible regions in aged HSC chromatin are enriched for stress-responsive enhancers and act as an epigenetic hub to augment transcriptional responses of aged HSCs to external stimuli.
- Naoki Itokawa
- , Motohiko Oshima
- & Atsushi Iwama
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Article
| Open AccessRunx1 and Runx2 inhibit fibrotic conversion of cellular niches for hematopoietic stem cells
The transcription factors, Runx1 and Runx2 are critical embryonically for generation of HSCs and osteoblasts, respectively. Here the authors show that adult mice lacking Runx1 and Runx2 in HSC-supporting CAR cells displayed an increase in fibrosis with reduced HSCs in bone marrow.
- Yoshiki Omatsu
- , Shota Aiba
- & Takashi Nagasawa
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Article
| Open AccessRegulation of chromatin accessibility by the histone chaperone CAF-1 sustains lineage fidelity
Cell fate commitment involves transcription factor activity and changes in chromatin architecture. Here the authors show that CAF-1 maintains lineage fidelity by controlling chromatin accessibility at specific sites; suppressing CAF-1 triggers differentiation of myeloid stem and progenitor cells into a mixed lineage state.
- Reuben Franklin
- , Yiming Guo
- & Sihem Cheloufi
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Article
| Open AccessSingle cell analyses identify a highly regenerative and homogenous human CD34+ hematopoietic stem cell population
The trajectories of hematopoietic stem cells (HSCs) during lineage commitment are complex. Here, the authors use single cell RNA-sequencing and xenotransplantation to uncover CD34 + EPCR + (CD38/CD45RA)- HSCs, which high repopulating and self-renewal properties.
- Fernando Anjos-Afonso
- , Florian Buettner
- & Dominique Bonnet
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Article
| Open AccessEngineering a niche supporting hematopoietic stem cell development using integrated single-cell transcriptomics
Here, the authors use single cell RNA-sequencing to generate an atlas of signaling interactions regulating embryonic hematopoietic stem cell (HSC) development and apply this knowledge to engineer a niche sufficient to support HSC maturation in vitro.
- Brandon Hadland
- , Barbara Varnum-Finney
- & Irwin D. Bernstein
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Article
| Open AccessA specialized bone marrow microenvironment for fetal haematopoiesis
The colonization of bone marrow by haematopoietic stem and progenitor cells is critical for lifelong blood cell formation. Here the authors report distinct features of fetal bone marrow and show that artery-derived signals promote haematopoietic colonization.
- Yang Liu
- , Qi Chen
- & Ralf H. Adams
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Article
| Open AccessMulti-modal profiling of human fetal liver hematopoietic stem cells reveals the molecular signature of engraftment
During human embryonic development, haematopoietic stem cells of the foetal liver undergo expansion, while retaining engraftment capacity. Here the authors apply CITE-seq to profile single cells from a human foetal liver, identifying a molecular signature of engraftment potential
- Kim Vanuytsel
- , Carlos Villacorta-Martin
- & George J. Murphy
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Article
| Open AccessCholinergic signals preserve haematopoietic stem cell quiescence during regenerative haematopoiesis
The sympathetic nervous system has been shown to respond to stress and activate haematopoietic stem cells. Here they show that cholinergic signals in the bone marrow preserve haematopoietic stem cell quiescence and self-renewal under proliferative stress.
- Claire Fielding
- , Andrés García-García
- & Simón Méndez-Ferrer
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Article
| Open AccessQuantification of bone marrow interstitial pH and calcium concentration by intravital ratiometric imaging
The fate of hematopoietic stem cells can be controlled by factors such as calcium ion concentration. Here the authors report an intravital ratiometric analysis method to measure extracellular calcium ion concentrations and absolute pH in mouse bone marrow.
- S-C. A. Yeh
- , J. Hou
- & C. P. Lin
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Article
| Open AccessFree fatty-acid transport via CD36 drives β-oxidation-mediated hematopoietic stem cell response to infection
Hematopoietic stem cells (HSCs) rapidly expand upon infection, switching their metabolic profile to increase OXPHOS. Here, the authors show in mouse models that infection promotes uptake of long-chain free fatty acids via CD36, which is required for a protective response.
- Jayna J. Mistry
- , Charlotte Hellmich
- & Stuart A. Rushworth
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Article
| Open AccessEzh2 is essential for the generation of functional yolk sac derived erythro-myeloid progenitors
Yolk sac erythro-myeloid progenitors (EMPs) are critical for embryo viability and a major source of adult tissue-resident macrophages. Here, the authors show an essential stage-specific role for Ezh2 in modulating Wnt signaling during EMP generation.
- Wen Hao Neo
- , Yiran Meng
- & Georges Lacaud
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Article
| Open AccessNeuropilin 1 regulates bone marrow vascular regeneration and hematopoietic reconstitution
Ionizing radiation and chemotherapy deplete haematopoietic stem cells and damage the vascular niche. Here the authors show that irradiation induces SEMA3A secretion from bone marrow endothelial cells (ECs), inducing EC apoptosis via NRP1 and that NRP1 inhibition promotes vascular regeneration and R spondin 2 dependent hematopoietic regeneration.
- Christina M. Termini
- , Amara Pang
- & John P. Chute