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| Open AccessQuinacrine-CASIN combination overcomes chemoresistance in human acute lymphoid leukemia
Chemoresistance and relapse are main limitations in the treatment of acute lymphoblastic leukemia (ALL). Here, the authors identify Quinacrine (QC) as a sensitizer for Cytarabine (AraC) and establish a QC-CASIN regimen to improve leukemia eradication in ALL.
- Limei Wu
- , Srinivas Chatla
- & Wei Du
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Article
| Open AccessHematopoiesis under telomere attrition at the single-cell resolution
The molecular mechanisms that drive hematopoietic stem cell functional decline under conditions of telomere shortening are not completely understood. Here the authors demonstrate that hematopoietic stem cells with short telomeres induced by mutations affecting telomerase complex genes undergo differentiation towards megakaryopoiesis through the activation of the IFI16-mediated interferon response.
- Natthakan Thongon
- , Feiyang Ma
- & Simona Colla
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Article
| Open AccessDiscrete regulatory modules instruct hematopoietic lineage commitment and differentiation
Lineage differentiation and commitment is driven by transcription regulators and chromatin changes. Here the authors report daily profiling of chromatin accessibility and transcriptome changes during human erythropoiesis, relating these changes to lineage potential between erythropoiesis and megakaryopoieis.
- Grigorios Georgolopoulos
- , Nikoletta Psatha
- & Jeff Vierstra
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Article
| Open AccessOncogene-induced senescence in hematopoietic progenitors features myeloid restricted hematopoiesis, chronic inflammation and histiocytosis
BRAF-MAPK activating mutations are reported in histiocytoses—hematological neoplasms with widespread pro-inflammatory myeloid cells. Here, the authors show that an activating mutant BRAF in haematopoietic stem and progenitor cells causes an oncogene-induced senescence response leading to myeloid restricted haematopoiesis, inflammation and histiocytosis.
- Riccardo Biavasco
- , Emanuele Lettera
- & Eugenio Montini
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Article
| Open AccessA connexin/ifi30 pathway bridges HSCs with their niche to dampen oxidative stress
Reactive oxygen species (ROS) are metabolic by-products which in excess can be toxic for hematopoietic stem and progenitor cells (HSPCs). Here the authors show that toxic ROS are transferred by expanding HSPCs to the zebrafish developmental niche via connexin Cx41.8, where Ifi30 promotes their detoxification.
- Pietro Cacialli
- , Christopher B. Mahony
- & Julien Y. Bertrand
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Article
| Open AccessReactivation of a developmentally silenced embryonic globin gene
Globin loci harbor genes that are expressed embryonically and silenced postnatally. Here the authors show that zeta-globin silencing depends upon selective hypoacetylation of its TAD subdomain, which blocks its interaction with the alpha-globin super-enhancer, and zeta-globin can be reactivated by acetylation.
- Andrew J. King
- , Duantida Songdej
- & Christian Babbs
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Article
| Open AccessNon-conditioned bone marrow chimeric mouse generation using culture-based enrichment of hematopoietic stem and progenitor cells
Bone marrow chimaeric mice are a valuable tool in research, but require myeloablative conditioning. Here the authors demonstrate efficient FACS-free enrichment of haematopoietic stem and progenitor cells for transplantation into unconditioned recipient mice, as well as for genetic engineering using polyvinyl alcohol based media.
- Kiyosumi Ochi
- , Maiko Morita
- & Satoshi Yamazaki
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Article
| Open AccessNicotinamide riboside attenuates age-associated metabolic and functional changes in hematopoietic stem cells
Aged hematopoietic stem cells (HSC) are characterised by reduced regenerative potential and a loss of quiescence. Here, the authors show nicotinamide riboside treatment shrinks the age-enlarged stem cell pool and shifts aged HSC functionally, metabolically and molecularly towards the young state.
- Xuan Sun
- , Benjamin Cao
- & Susan K. Nilsson
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Article
| Open AccessMAEA is an E3 ubiquitin ligase promoting autophagy and maintenance of haematopoietic stem cells
Haematopoietic stem cells (HSCs) are metabolically quiescent, with balanced myeloid and lymphoid potential. Here the authors show that MAEA is required in HSCs for ubiquitination and downregulation of surface cytokine receptors via autophagy; MAEA loss leads to impaired HSC quiescence and a myeloproliferative disorder.
- Qiaozhi Wei
- , Sandra Pinho
- & Paul S. Frenette
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Article
| Open AccessIndispensable role of Galectin-3 in promoting quiescence of hematopoietic stem cells
Long term haematopoitic stem cells (LT-HSCs) are in a quiescent state during homeostasis, which is critical for their maintenance. Here, the authors show that Gal-3 expression in LT-HSCs is induced in response to Tie2 and Mpl and is both necessary and sufficient for LT-HSC quiescence through regulation of p21.
- Weizhen Jia
- , Lingyu Kong
- & Nobuyuki Takakura
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Article
| Open AccessMutant ASXL1 induces age-related expansion of phenotypic hematopoietic stem cells through activation of Akt/mTOR pathway
ASXL1 mutations are frequently found in age-related clonal haemaotopoiesis (CH), but how they drive CH is unclear. Here the authors show that expression of C-terminal truncated ASXL1 in haematopoietic stem cells (HSCs) leads to Akt de-ubiquitination, activated Akt/mTOR signaling, and aberrant HSC proliferation.
- Takeshi Fujino
- , Susumu Goyama
- & Toshio Kitamura
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Article
| Open AccessLong-term lymphoid progenitors independently sustain naïve T and NK cell production in humans
Gene therapy (GT) using haematopoietic stem cells (HSCs) provides an opportunity to trace cell fates in humans, in vivo. Here the authors present evidence in GT patients for a long term lymphoid progenitor population, surviving and maintaining de novo T and NK cell production for years, independently from HSCs.
- Natalia Izotova
- , Christine Rivat
- & Luca Biasco
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Article
| Open AccessDeep learning-based enhancement of epigenomics data with AtacWorks
ATAC-seq measures chromatin accessibility as a proxy for the activity of DNA regulatory regions across the genome. Here the authors present AtacWorks, a deep learning tool to denoise and identify accessible chromatin regions from low cell count, low-coverage, or low-quality ATAC-seq data.
- Avantika Lal
- , Zachary D. Chiang
- & Jason D. Buenrostro
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Article
| Open AccessFacilitative lysosomal transport of bile acids alleviates ER stress in mouse hematopoietic precursors
Mutations in ENT3, encoded by SLC29A3, result in anaemia and erythroid hypoplasia, suggesting roles in erythropoiesis. Here the authors show that ENT3 acts as a lysosomal bile acid transporter, and mutation compromises taurine conjugated bile acid transport in erythroid progenitors leading to ER stress, and anaemia.
- Avinash K. Persaud
- , Sreenath Nair
- & Rajgopal Govindarajan
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Article
| Open AccessLIGHT/LTβR signaling regulates self-renewal and differentiation of hematopoietic and leukemia stem cells
Regulation of self-renewal is critical during steady state and stress in haematpoietic stem cells (HSCs), and underlies leukaemia pathology. Here, the authors show that LIGHT and its receptor LTβR promote quiescence and self-renewal of HSCs and that LTβR deficiency promotes survival in a mouse leukaemia model.
- S. S. Höpner
- , Ana Raykova
- & A. F. Ochsenbein
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Article
| Open AccessCas9-AAV6 gene correction of beta-globin in autologous HSCs improves sickle cell disease erythropoiesis in mice
CRISPR mediated gene correction of sickle cell disease (SCD) in patient-derived hematopoietic stem cells is a promising avenue for therapy. Here the authors use a humanized SCD mouse model to study gene editing in the context of autologous transplantation.
- Adam C. Wilkinson
- , Daniel P. Dever
- & Matthew H. Porteus
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Article
| Open AccessNiche derived netrin-1 regulates hematopoietic stem cell dormancy via its receptor neogenin-1
Haematopoietic stem cells (HSCs) are characterized by their self-renewal potential and associated dormancy. Here the authors show that niche produced netrin-1 preserves HSC quiescence and self-renewal via neogenin-1, and that decline of netrin-1 production during ageing leads to decreased Neo1 mediated HSC self-renewal.
- Simon Renders
- , Arthur Flohr Svendsen
- & Andreas Trumpp
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| Open AccessThe TRACE-Seq method tracks recombination alleles and identifies clonal reconstitution dynamics of gene targeted human hematopoietic stem cells
Genetic barcoding has been used to track clonal dynamics of cells. Here, the authors develop a Tracking Recombination Alleles in Clonal Engraftment using sequencing (TRACE-Seq), to barcode repaired alleles by introducing silent mutations or outside of coding regions, to show clonal complexity of edited CD34 + cells following engraftment.
- Rajiv Sharma
- , Daniel P. Dever
- & Ravindra Majeti
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Article
| Open AccessA clinically applicable and scalable method to regenerate T-cells from iPSCs for off-the-shelf T-cell immunotherapy
T-cell immunotherapies, such as CAR-T immunotherapy, are being developed against a wide variety of diseases. Here the authors report the feeder-free, scalable differentiation of human induced pluripotent cells (iPSCs) to T-cells with T-cell receptor dependent anti-tumour function in vitro and in vivo.
- Shoichi Iriguchi
- , Yutaka Yasui
- & Shin Kaneko
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Article
| Open AccessSingle-cell transcriptome maps of myeloid blood cell lineages in Drosophila
How the Drosophila lymph gland hemocytes develop and are regulated at a single-cell level is unclear. Here, the authors use single-cell RNA sequencing to show heterogeneity of developing hemocytes in the lymph gland and how they react to wasp infestation, and compare hemocytes from two independent origins.
- Bumsik Cho
- , Sang-Ho Yoon
- & Jiwon Shim
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Article
| Open AccessMicro-environmental sensing by bone marrow stroma identifies IL-6 and TGFβ1 as regulators of hematopoietic ageing
Ageing of the haematopoietic system is accompanied by declining erythropoiesis and lymphopoiesis. Here the authors uncover upregulated IL-6 and TGFβ signalling in aged bone marrow stroma; inhibition of these signals reverses age-related haematopoietic defects, re-balancing haematopoietic stem cell lineage output.
- Simona Valletta
- , Alexander Thomas
- & Claus Nerlov
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| Open AccessEx vivo editing of human hematopoietic stem cells for erythroid expression of therapeutic proteins
A platform for systemic therapeutic transgene expression independent of patient mutations needs a safe and highly transcribed locus. Here the authors ex vivo edit HPSCs using CRISPR-Cas9 to integrate transgenes under the α-globin promoter to achieve erythroid specific expression.
- Giulia Pavani
- , Marine Laurent
- & Mario Amendola
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Article
| Open AccessSpinal cord injury causes chronic bone marrow failure
Spinal cord injury (SCI) often leads to immune dysfunction, but mechanistic insights are still lacking. Here the authors show that SCI alters chemokine signaling and induces long, persisting defects in hematopoietic stem and progenitor cell migration, thereby entrapping them in the bone marrow and disrupting peripheral immune homeostasis.
- Randall S. Carpenter
- , Jessica M. Marbourg
- & Phillip G. Popovich
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Article
| Open AccessDiaphanous-related formin mDia2 regulates beta2 integrins to control hematopoietic stem and progenitor cell engraftment
Bone marrow engraftment of haematopoietic stem and progenitor cells (HSPCs) requires homing and lodgement to the niche. Here, the authors show that mDia2 is required for HSPC polarization, nuclear MAL, and SRF-induced beta2 integrin expression during transendothelial migration of HSPCs required for engraftment.
- Yang Mei
- , Xu Han
- & Peng Ji
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Article
| Open AccessA missense mutation in the MLKL brace region promotes lethal neonatal inflammation and hematopoietic dysfunction
Necroptosis is a regulated form of inflammatory cell death driven by activated MLKL. Here, the authors identify a mutation in the brace region that confers constitutive activation, leading to lethal inflammation in homozygous mutant mice and providing insight into human mutations in this region.
- Joanne M. Hildebrand
- , Maria Kauppi
- & John Silke
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Article
| Open AccessEngineered niches support the development of human dendritic cells in humanized mice
Classical human dendritic cells (cDCs) are rare sentinel cells specialized in regulating adaptive immunity. Here, the authors show that expression of membrane bound FLT3L, along with stem cell factor (SCF) and CXCL12 in stromal cells induces specification of pre/AS-DCs, type 1 and type2 cDC from haematopoietic stem cells.
- Giorgio Anselmi
- , Kristine Vaivode
- & Pierre Guermonprez
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Article
| Open AccessHyperTRIBE uncovers increased MUSASHI-2 RNA binding activity and differential regulation in leukemic stem cells
The identification of mRNA targets for RNA binding proteins (RBP) in stem cells is difficult due to the limited number of available cells. Here, as a proof-of-principle, the authors adapt the HyperTRIBE method to find that an RBP, MSI2, has increased RNA binding in leukemic compared with normal stem cells for selective regulation of oncogenic genes.
- Diu T. T. Nguyen
- , Yuheng Lu
- & Michael G. Kharas
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Article
| Open AccessChromatin accessibility promotes hematopoietic and leukemia stem cell activity
Chromatin accessibility is a key mediator of gene expression and mutations in chromatin modifiers are frequently seen in cancers. Here, the authors show that the chromatin accessibility regulator HMGN1 - which is frequently mutated by amplification in leukemias - acts by blocking myeloid differentiation.
- Lucia Cabal-Hierro
- , Peter van Galen
- & Andrew A. Lane
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Article
| Open AccessChronic activation of endothelial MAPK disrupts hematopoiesis via NFKB dependent inflammatory stress reversible by SCGF
Myelosuppressive injuries lead to chronic MAPK activation and impair blood reconstitution. Here, the authors show that chronic activation endothelial MAPK impairs hematopoietic stem cell (HSC) function through NFkB signaling, and that post-myelosuppressive HSC defects can be reversed by administration of Stem Cell Growth Factor SCGFa.
- Pradeep Ramalingam
- , Michael G. Poulos
- & Jason M. Butler
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Article
| Open AccessSingle-cell transcriptomics identifies CD44 as a marker and regulator of endothelial to haematopoietic transition
The endothelial to haematopoietic transition (EHT) is the process where haemogenic endothelium differentiates into haematopoietic stem and progenitor cells (HSPCs). Here the authors use single cell transcriptomics and antibody screening to identify CD44 as a marker of EHT that is required for EHT and HSPC development.
- Morgan Oatley
- , Özge Vargel Bölükbası
- & Christophe Lancrin
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Article
| Open AccessMutant p53 drives clonal hematopoiesis through modulating epigenetic pathway
Ageing is associated with clonal hematopoiesis of indeterminate potential (CHIP), which is linked to increased risks of hematological malignancies. Here the authors uncover an epigenetic mechanism through which mutant p53 drives clonal hematopoiesis through interaction with EZH2.
- Sisi Chen
- , Qiang Wang
- & Yan Liu
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Article
| Open AccessIL-27 receptor-regulated stress myelopoiesis drives abdominal aortic aneurysm development
Immune cells contribute to the aortic wall destruction during abdominal aortic aneurysm (AAA) development. Here, Peshkova et al. show that cytokine signaling through interleukin-27 receptor is required for Angiotensin II-induced myelopoiesis and mature myeloid cells production, thus contributing to their aortic accumulation and aneurysm progression
- Iuliia O. Peshkova
- , Turan Aghayev
- & Ekaterina K. Koltsova
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| Open AccessFunctional profiling of single CRISPR/Cas9-edited human long-term hematopoietic stem cells
Previous gene editing in haematopoietic stem cells (HSCs) has focussed on a heterogeneous CD34+ population. Here, the authors demonstrate high efficiency CRISPR/Cas9-based editing of purified long-term HSCs using non-homologous end joining and homology-directed repair, by directing isoform-specific expression of GATA1.
- Elvin Wagenblast
- , Maria Azkanaz
- & Eric R. Lechman
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Article
| Open AccessDevelopment of a forward-oriented therapeutic lentiviral vector for hemoglobin disorders
Vectors used in gene therapy for hemoglobin disorders carry globin in a reverse-orientation to prevent the loss of key regulatory elements by RNA splicing, but this limits their efficiency. Here, the authors develop a vector carrying β-globin in a forward orientation and show that it has improved titers and transduction efficiency in humanized mice and nonhuman primates.
- Naoya Uchida
- , Matthew M. Hsieh
- & John F. Tisdale
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Article
| Open AccessPTPσ inhibitors promote hematopoietic stem cell regeneration
Protein tyrosine phosphatase sigma (PTPσ) deficient haematopoietic stem cells (HSCs) demonstrate increased engraftment following transplantation. Here the authors identify a small molecule inhibitor of PTPσ that promotes murine and human haematopoietic stem cell regeneration via induction of the RAC pathway and BCL-XL.
- Yurun Zhang
- , Martina Roos
- & John P. Chute
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Article
| Open AccessBlood stem cell-forming haemogenic endothelium in zebrafish derives from arterial endothelium
HSCs emerge from haemogenic endothelium (HE) in the dorsal aorta but whether these tissues share a common lineage is unclear. Here, the authors use a zebrafish runx1 reporter to show that HE maintains an arterial gene expression profile in the absence of Runx1, suggesting the aortic endothelium as a precursor of HE.
- Florian Bonkhofer
- , Rossella Rispoli
- & Roger Patient
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Article
| Open AccessPhc2 controls hematopoietic stem and progenitor cell mobilization from bone marrow by repressing Vcam1 expression
Mobilization of hematopoietic stem and progenitor cells (HSPCs) into the circulation is essential for maintaining homeostasis. Here, the authors show that Phc2 in bone marrow stromal cells represses the cell adhesion molecule Vcam1 and facilitates mobilization of HSPCs through regulation of epigenetic marks.
- Joonbeom Bae
- , Sang-Pil Choi
- & Taehoon Chun
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Article
| Open AccessAdult stem cell deficits drive Slc29a3 disorders in mice
Mutations in equilibrative nucleoside transporter 3 (ENT3), encoded by SLC29A3, cause a spectrum of human genetic disorders. Here, the authors show altered haematopoietic stem cell and mesenchymal stem cell fates in ENT3-deficient mice, due to misregulation of the AMPK-mTOR-ULK axis.
- Sreenath Nair
- , Anne M. Strohecker
- & Rajgopal Govindarajan
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Article
| Open AccessMutant H3 histones drive human pre-leukemic hematopoietic stem cell expansion and promote leukemic aggressiveness
The role of histone mutations in leukemogenesis remains largely unexplored. In this study of AML, the authors show that histone mutations are early events that drive a more aggressive phenotype.
- Meaghan Boileau
- , Margret Shirinian
- & Kolja Eppert
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Article
| Open AccessA comprehensive single cell transcriptional landscape of human hematopoietic progenitors
Human Hematopoietic stem and progenitor cells (HSPCs) are commonly defined by CD34 expression. Here, the authors map single-cell RNA states both inside and outside the CD34 compartment, uncovering previously unappreciated branchpoints and validating CD164 as an efficient marker for early HSPCs.
- Danilo Pellin
- , Mariana Loperfido
- & Luca Biasco
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Article
| Open AccessPrimary cilia regulate hematopoietic stem and progenitor cell specification through Notch signaling in zebrafish
Haematopoietic stem and progenitor cells (HSPCs) produce all blood lineages and arise from the haemogenic endothelium (HE) during embryogenesis. Here the authors show that genes specific to cilia formation are required for HSPC development in the HE in zebrafish through transduction of Notch signal.
- Zhibin Liu
- , Haiqing Tu
- & Feng Liu
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Article
| Open AccessGene correction for SCID-X1 in long-term hematopoietic stem cells
Gene correction in hematopoietic stem cells could be a powerful way to treat monogenic diseases of the blood and immune system. Here the authors develop a strategy using CRISPR-Cas9 and an aAdeno-Associated vVirus(AAV)-delivered IL2RG cDNA to correct X-linked sSevere Ccombined iImmunodeficiency (SCID-X1) with a high success rate.
- Mara Pavel-Dinu
- , Volker Wiebking
- & Matthew H. Porteus
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Article
| Open AccessGfi1b regulates the level of Wnt/β-catenin signaling in hematopoietic stem cells and megakaryocytes
Gfi1b regulates cellularity of haematopoietic stem cells (HSCs) and megakaryocytes (MKs) as well as spreading of MKs on matrix. Here the authors show that Gfi1b regulates this behaviour by recruiting LSD1 and β-catenin to Wnt/β-catenin signalling targets.
- Peiman Shooshtarizadeh
- , Anne Helness
- & Tarik Möröy
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Article
| Open AccessRegnase-1-mediated post-transcriptional regulation is essential for hematopoietic stem and progenitor cell homeostasis
Regnase-1 is known to mediate post-trasncriptional regulatory activity through degradation of target mRNAs. Here, the authors show that Regnase-1 regulates self-renewal of haematopoietic stem and progenitor cells through modulation of the stability of Gata2 and Tal1 mRNA.
- Hiroyasu Kidoya
- , Fumitaka Muramatsu
- & Nobuyuki Takakura
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Article
| Open AccessHematopoietic chimerism and donor-specific skin allograft tolerance after non-genotoxic CD117 antibody-drug-conjugate conditioning in MHC-mismatched allotransplantation
Transplantation of allogeneic bone marrow helps establish chimerism that may induce tolerance to tissue grafts. Here the authors show that a CD117-antibody-drug-conjugate helps precondition the recipients for inducing mixed chimerism and allo-tolerance without clear adverse effects or the need for chronic immune suppression.
- Zhanzhuo Li
- , Agnieszka Czechowicz
- & Philip M. Murphy
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Article
| Open AccessSelective hematopoietic stem cell ablation using CD117-antibody-drug-conjugates enables safe and effective transplantation with immunity preservation
Hematopoietic stem cell (HSC) transplantation is a desirable treatment for many non-malignant and malignant diseases, but its use requires preconditioning of recipients with irradiation or chemotherapy that often induces high toxicity. Here the authors show that antibody-drug-conjugate to CD117, a HSC marker, allows specific and efficient preconditioning for HSC therapy.
- Agnieszka Czechowicz
- , Rahul Palchaudhuri
- & Derrick J. Rossi
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Article
| Open AccessHigh-fat diet disturbs lipid raft/TGF-β signaling-mediated maintenance of hematopoietic stem cells in mouse bone marrow
High fat diets (HFD) are thought to perturb murine hematopoiesis as a result of obesity. Here the authors find that short-term HFD reduces hematopoietic stem cells (HSC), disrupts lipid rafts and TGF-β1 signalling. Injecting HFD-fed mice with recombinant TGF-β1 can rescue HSC loss.
- François Hermetet
- , Anne Buffière
- & Ronan Quéré
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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 AccessLin−CCR2+ hematopoietic stem and progenitor cells overcome resistance to PD-1 blockade
Brain tumors are difficult to treat using existing immunotherapeutic strategies. Here, the authors show that in brain tumors resistant to PD-1 blockade, HSCs expressing CCR2+ can reverse treatment resistance and sensitizes mice to immunotherapy.
- Catherine T. Flores
- , Tyler J. Wildes
- & Duane A. Mitchell