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| Open AccessTFPI from erythroblasts drives heme production in central macrophages promoting erythropoiesis in polycythemia
The role of coagulation system in erythropoiesis is not clear. Here, the authors report that an anticoagulant protein TFPI from erythroblasts directs central macrophages to synthesize heme, which in turn promotes erythropoiesis in bone marrow.
- Jun-Kai Ma
- , Li-Da Su
- & Xin-Jiang Lu
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Article
| 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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| Open AccessA let-7 microRNA-RALB axis links the immune properties of iPSC-derived megakaryocytes with platelet producibility
The authors pioneered the iPSC-derived platelet transfusion in human. Here they employ miRNA switches, identifying RALB as a determinant of immune megakaryocytes and a marker for quality control, advancing standardization of iPSC-platelet production.
- Si Jing Chen
- , Kazuya Hashimoto
- & Koji Eto
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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 AccessComparative transcriptomics coupled to developmental grading via transgenic zebrafish reporter strains identifies conserved features in neutrophil maturation
Maturation of innate immune cells is a graded stereotypic process which is often conserved across species. Here authors label distinct neutrophil leukocyte developmental stages via generating combinations of transgenic zebrafish reporter strains, followed by transcriptome analysis of different neutrophil maturation stages and comparison to the gene expression profile of developing neutrophils from humans and mice.
- Stefanie Kirchberger
- , Mohamed R. Shoeb
- & Martin Distel
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Article
| Open AccessRunx1+ vascular smooth muscle cells are essential for hematopoietic stem and progenitor cell development in vivo
Hematopoietic stem cells are supported by niche cells that help balance stem cell self-renewal and differentiation. Here they show that Runx1 deletion in the embryonic perivascular HSC niche impairs hematopoietic development in vivo and causes transcriptional changes in pericytes/vSMCs, endothelial cells and hematopoietic cells in the murine AGM.
- Zaniah N. Gonzalez Galofre
- , Alastair M. Kilpatrick
- & Mihaela Crisan
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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 AccessVEXAS syndrome is characterized by inflammasome activation and monocyte dysregulation
Acquired mutations of the gene UBA1 occurring in myeloid cells that result in the expression of impaired isoforms of the enzyme E1 have been described in patients with a severe adult onset auto-inflammatory syndrome called VEXAS. Here the authors profile patients with UBA1 mutations presenting with or without VEXAS disease and show VEXAS disease is characterized by inflammasome activation and monocyte dysregulation.
- Olivier Kosmider
- , Céline Possémé
- & Benjamin Terrier
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Article
| Open AccessCebp1 and Cebpβ transcriptional axis controls eosinophilopoiesis in zebrafish
Eosinophils are innate immune cells critical for protection from parasites, but their developmental origin remains under studied. Here they analyze development of eosinophils in zebrafish and find that eosinophilic lineage commitment and differentiation are regulated by the Cebp1-Cebpβ axis.
- Gaofei Li
- , Yicong Sun
- & Yiyue Zhang
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Article
| Open AccessAn IL-10/DEL-1 axis supports granulopoiesis and survival from sepsis in early life
Neutrophils play critical roles in response to infection, and the limit of available neutrophils in neonates and young infants can impact responses to infections, including sepsis. Here the authors identify that the IL-10/DEL-1 axis is involved in emergency granulopoiesis in neonates and suggest a link to sepsis survival in early life.
- Eleni Vergadi
- , Ourania Kolliniati
- & Christos Tsatsanis
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Article
| Open AccessDNMT3A clonal hematopoiesis-driver mutations induce cardiac fibrosis by paracrine activation of fibroblasts
This study uncovers a critical link between DNMT3A-driven CHIP and heart failure and, in particular, it shows that DNMT3A inactivation in monocytes boosts the release of HB-EGF, which activates fibroblasts inducing diffuse fibrosis in the heart.
- Mariana Shumliakivska
- , Guillermo Luxán
- & Stefanie Dimmeler
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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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| 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 AccessClonal hematopoiesis related TET2 loss-of-function impedes IL1β-mediated epigenetic reprogramming in hematopoietic stem and progenitor cells
The expansion of cells with TET2 mutations within the blood is associated with increased risk for all-cause mortality, development of leukemia and cardiovascular disease. Here authors show IL1 promotes the clonal expansion TET2 knockout cells, enhancing their self-renewal, promoting their myeloid bias and impairing an IL1 driven loss of methylation at lymphoid and erythroid regulatory elements.
- J. McClatchy
- , R. Strogantsev
- & A. Agarwal
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Article
| Open AccessOVOL2 sustains postnatal thymic epithelial cell identity
The molecular mechanisms that maintain thymic epithelial cell (TEC) identity throughout life are incompletely understood. Here, the authors demonstrate that the transcription factor, Ovol2, maintains post-natal TECs by preventing their epithelial-to-mesenchymal transition.
- Xue Zhong
- , Nagesh Peddada
- & Bruce Beutler
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Article
| Open AccessA transcriptional network governing ceramide homeostasis establishes a cytokine-dependent developmental process
Bioactive small molecules mediate transcription factor functions to control cellular processes. Here, Liao et al. discover that a GATA1-regulated metabolic enzyme controls ceramide homeostasis to commission vital cytokine signaling for erythropoiesis.
- Ruiqi Liao
- , Abiola Babatunde
- & Emery H. Bresnick
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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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Article
| Open AccessNotch and retinoic acid signals regulate macrophage formation from endocardium downstream of Nkx2-5
A subset of endocardial cells gives rise to hematopoietic cells which are important for the formation of cardiac valves. In this follow up study, authors report the molecular regulatory mechanisms behind the formation of macrophages in the heart.
- Norika Liu
- , Naofumi Kawahira
- & Atsushi Nakano
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| Open AccessA genome-wide association study of blood cell morphology identifies cellular proteins implicated in disease aetiology
The authors identify genetic variation associated with properties of the internal biological structures of blood cells in hundreds of genes and show how such discoveries can be used to improve understanding of cellular mechanisms causing disease.
- Parsa Akbari
- , Dragana Vuckovic
- & William J. Astle
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Article
| Open AccessOntogenetically distinct neutrophils differ in function and transcriptional profile in zebrafish
Neutrophil ontogeny in zebrafish may be a continuum or consist of distinct lineages. Here the authors characterise neutrophils derived from rostral blood island and caudal haematopoietic tissue lineages and show differential gene expression and function in steady state and during wound healing.
- Juan P. García-López
- , Alexandre Grimaldi
- & Carmen G. Feijoo
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| 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 AccessSingle cell transcriptomics clarifies the basophil differentiation trajectory and identifies pre-basophils upstream of mature basophils
Single cell sequencing can be used to better characterize immune cell progenitors. Here the authors characterize CLEC12Ahi pre-basophils downstream of pre-basophil and mast cell progenitors (pre-BMPs) but upstream of mature basophils and this population includes basophil progenitors (BaPs).
- Kensuke Miyake
- , Junya Ito
- & Hajime Karasuyama
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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 AccessPrimitive haematopoiesis in the human placenta gives rise to macrophages with epigenetically silenced HLA-DR
The generation of primitive macrophages remains a poorly understood process in humans. Here, the authors identify placental erythro-myeloid progenitors that give rise to foetal macrophages in the early human placenta and demonstrate that epigenetic silencing of the class II transactivator leads to downregulation of HLA-DR in these cells.
- Jake R. Thomas
- , Anna Appios
- & Naomi McGovern
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Article
| Open AccessTesticular macrophages are recruited during a narrow fetal time window and promote organ-specific developmental functions
How testis resident macrophages develop and influence tissue function is not fully understood. Here the authors use mouse lineage tracing methods to document the haematopoietic source, development and recruitment of early testicular macrophages, support of foetal testis differentiation, and interaction with, and promotion of steroidogenesis in, Leydig cells.
- Xiaowei Gu
- , Anna Heinrich
- & Tony DeFalco
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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 AccessIn vivo clonal tracking reveals evidence of haemangioblast and haematomesoblast contribution to yolk sac haematopoiesis
The lineage relationship between blood and endothelial cells has been difficult to examine due to the multiphasic timing of hematopoiesis in the embryo. Here the authors use using in vivo barcoding technology to assess cell ancestry and show that blood and endothelial cells emerge through common (haemangioblast) or separate (mesenchymoangioblasts and haematomesoblasts) progenitors in the yolk sac.
- C. Biben
- , T. S. Weber
- & S. Taoudi
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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 AccessPCGF1-PRC1 links chromatin repression with DNA replication during hematopoietic cell lineage commitment
Here the authors show that a Polycomb Repressive Complex 1 (PRC1) containing PCGF1 prevents excessive loading of transcriptional activators and chromatin remodelers on nascent DNA, allowing proper deposition of nucleosomes immediately after the passage of the DNA replication fork to optimize downstream chromatin configurations in hematopoietic stem and progenitor cells (HSPCs).
- Junichiro Takano
- , Shinsuke Ito
- & Tomokatsu Ikawa
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| 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 AccessReprogramming of myeloid cells and their progenitors in patients with non-medullary thyroid carcinoma
Myeloid cells contribute to the tumor microenvironment of thyroid cancers, but their functional relevance is lesser known. Here authors show that myeloid cells infiltrating non-medullary thyroid carcinomas upregulate their antigen presentation-related genes, release less cytokines and over-produce reactive oxygen species, with transcriptional changes already present in extra-tumoral myeloid cells.
- Katrin Rabold
- , Martijn Zoodsma
- & Romana T. Netea-Maier
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Article
| Open AccessDifferential ABC transporter expression during hematopoiesis contributes to neutrophil-biased toxicity of Aurora kinase inhibitors
Patients treated with Aurora kinase inhibitors experience dose-limiting neutropenia while other cytopenias are rare. Here, Chou et al. show that this cell-type specific side effect is partly explained by loss of drug efflux pump expression during neutrophil differentiation.
- David B. Chou
- , Brooke A. Furlong
- & Donald E. Ingber
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Article
| Open AccessLoss of Zfp335 triggers cGAS/STING-dependent apoptosis of post-β selection thymocytes
T cell development involves extensive proliferation of developing thymocytes. Here, the authors demonstrate that the transcription factor Zfp335 regulates the survival post-β-selection thymocytes via the cGAS/STING pathway.
- Jeremy J. Ratiu
- , William E. Barclay
- & Yuan Zhuang
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Article
| Open AccessIdentification of distinct functional thymic programming of fetal and pediatric human γδ thymocytes via single-cell analysis
Knowledge about the ontogeny of T cells in the thymus relies heavily on mouse studies because of difficulty to obtain human material. Here the authors perform a single cell analysis of thymocytes from human fetal and paediatric thymic samples to characterise the development of human γδ T cells in the thymus.
- Guillem Sanchez Sanchez
- , Maria Papadopoulou
- & David Vermijlen
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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 AccessClonal hematopoiesis of indeterminate potential, DNA methylation, and risk for coronary artery disease
Clonal hematopoiesis, often caused by mutations in DNMT3A and TET2, is associated with blood cancer and coronary artery disease. Here, the authors conduct an epigenome-wide association study, finding that clonal hematopoiesis caused by DNMT3A vs. TET2 mutations has directionally opposing changes in DNA methylation profiles, with both promoting stem cell self-renewal.
- M d Mesbah Uddin
- , Ngoc Quynh H. Nguyen
- & Karen N. Conneely
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Article
| Open AccessCompetition between hematopoietic stem and progenitor cells controls hematopoietic stem cell compartment size
Hematopoietic stem cells (HSCs) rely on a combination of paracrine signals produced by their niche, including SCF. Here the authors show that HSCs and hematopoietic progenitors compete for limited amounts of membrane-bound SCF.
- Runfeng Miao
- , Harim Chun
- & João P. Pereira
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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 AccessNotch, RORC and IL-23 signals cooperate to promote multi-lineage human innate lymphoid cell differentiation
Innate lymphoid cells (ILC) are effector cells that rapidly respond to immune evading stimuli, and despite their functional diversity arise from common precursors. Authors here show how the Notch signalling pathway orchestrates ILC development from circulating human ILC precursors via RORC and its target IL-23R.
- Carys A. Croft
- , Anna Thaller
- & James P. Di Santo
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Article
| Open AccessDiscovering the drivers of clonal hematopoiesis
Identifying the genetic drivers of clonal haematopoiesis (CH) has been challenging due to their low frequencies and a lack of adequate tools. Here, the authors use a reverse calling to detect blood somatic mutations and the IntOGen pipeline to identify CH drivers in large cancer genomics data sets based on signals of positive selection.
- Oriol Pich
- , Iker Reyes-Salazar
- & Nuria Lopez-Bigas
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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 AccessLy6D+Siglec-H+ precursors contribute to conventional dendritic cells via a Zbtb46+Ly6D+ intermediary stage
The ontogeny of conventional and plasmacytoid dendritic cells (DC) and how these two cell types are related is not fully known. Here the authors identify a pool of bone marrow precursor cells expressing Ly6D Siglec-H and Zbtb46 that can differentiate into either cDC or pDC and show that type I IFN can limit cDC and favor pDC output from these precursors.
- Konstantin Lutz
- , Andrea Musumeci
- & Anne B. Krug
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Article
| Open AccessIntegrative epigenomic and transcriptomic analysis reveals the requirement of JUNB for hematopoietic fate induction
Here they perform an integrative analysis of the epigenetic landscape of human pluripotent stem cell hematopoietic differentiation and show that JUNB is an indispensable transcription factor for hemogenic endothelium development.
- Xia Chen
- , Peiliang Wang
- & Jie Na
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Article
| Open AccessRobust temporal map of human in vitro myelopoiesis using single-cell genomics
The myeloid lineage is central to homeostasis and immunity. The authors provide an atlas of human iPSC-to-myeloid cell differentiation and demonstrate that the in vitro system recapitulates yolk sac differentiation, opening new avenues to human myelopoiesis.
- Clara Alsinet
- , Maria Nascimento Primo
- & Roser Vento-Tormo
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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