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| Open AccessMulti-night cortico-basal recordings reveal mechanisms of NREM slow-wave suppression and spontaneous awakenings in Parkinson’s disease
Using at-home intracranial DBS recordings in PD participants, the authors found subcortical beta has an inverse effect on cortical slow-wave in NREM sleep, rises before awakenings and found >88% accuracy in NREM vs Wake classification in brief 5 s epochs.
- Md Fahim Anjum
- , Clay Smyth
- & Simon Little
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Article
| Open AccessExosomal circEZH2_005, an intestinal injury biomarker, alleviates intestinal ischemia/reperfusion injury by mediating Gprc5a signaling
Currently, intestinal ischemia/reperfusion injury lacks ideal diagnostic markers and effective therapeutic targets. Here, the authors show exosomal circEZH2_005 is an intestinal injury biomarker and protects the intestine from ischemia/reperfusion injury by promoting crypt cell proliferation via affecting hnRNPA1- mediated Gprc5a stability.
- Wenjuan Zhang
- , Bowei Zhou
- & Ke-Xuan Liu
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| Open AccessExtravillous trophoblast cell lineage development is associated with active remodeling of the chromatin landscape
Invasive extravillous trophoblast cells are a key feature of placentation and successful pregnancy. Here, the authors identify transcription factors and regulatory mechanisms critical for extravillous trophoblast cell lineage development.
- Kaela M. Varberg
- , Esteban M. Dominguez
- & Elin Grundberg
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Article
| Open AccessDirect correction of haemoglobin E β-thalassaemia using base editors
The authors demonstrate efficient and direct correction of the DNA mutation causing Haemoglobin E β-thalassaemia with CRISPR Cas9 base editors. The work includes profiling of off-target effects using deep neural networks.
- Mohsin Badat
- , Ayesha Ejaz
- & James O. J. Davies
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Article
| Open AccessRedox-dependent Igfbp2 signaling controls Brca1 DNA damage response to govern neural stem cell fate
How reactive oxygen species regulate neuronal stem cell (NSC) behavior is poorly understood. Here, the authors report that Ncf1-dependent oxidation of Igfbp2 cystines represses DNA repair networks to regulate NSC self-renewal and cell fate decisions.
- Weam S. Shahin
- , Shima O. Ebed
- & John F. Engelhardt
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Article
| Open AccessHBEGF-TNF induce a complex outer retinal pathology with photoreceptor cell extrusion in human organoids
Complex neuropathologies, like macular degeneration, are common but incompletely understood. Here the authors report a complex human retina pathology organoid model induced by HBEGF-TNF, causing PIEZO1-mediated photoreceptor degeneration by cell extrusion.
- Manuela Völkner
- , Felix Wagner
- & Mike O. Karl
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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 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
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Article
| Open AccessTranslational control by DHX36 binding to 5′UTR G-quadruplex is essential for muscle stem-cell regenerative functions
Skeletal muscle stem cells (or satellite cells, SCs) are normally quiescent but activate and expand in response to injury. Here the authors show that induction of DHX36 helicase during SC activation promotes mRNA translation by binding to 5′UTR mRNA G-quadruplexes (rG4) in targets including Gnai2 and unwinding them.
- Xiaona Chen
- , Jie Yuan
- & Huating Wang
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Article
| Open AccessSingle-cell transcriptomic analysis reveals disparate effector differentiation pathways in human Treg compartment
Human Treg cells are central to immune tolerance, yet their heterogeneity and differentiation remain incompletely understood. Here the authors perform single-cell RNA and T cell receptor sequencing to resolve Treg cells from healthy individuals and patients with or without acute graft-versus-host disease revealing Treg complexity in health and disease.
- Yuechen Luo
- , Changlu Xu
- & Xiaoming Feng
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Article
| Open AccessIn vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche
Short term systemic expression of the reprogramming factors Oct-3/4, Sox2, Klf4, c-Myc (OSKM) rejuvenates aging cells and promotes tissue regeneration. Here the authors show that myofiber-specific expression of OSKM accelerates muscle regeneration by reducing secretion of muscle stem cell quiescence promoting Wnt4.
- Chao Wang
- , Ruben Rabadan Ros
- & Juan Carlos Izpisua Belmonte
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Article
| Open AccessSox9 and Rbpj differentially regulate endothelial to mesenchymal transition and wound scarring in murine endovascular progenitors
How endothelial to mesenchymal transition is regulated in endovascular progenitors is unclear. Here, the authors show that blocking Sox9 expression in murine endovascular progenitors regulates this transition on skin wounding, affecting the size of scarring, with changes in Rbpj having the opposite effect.
- Jilai Zhao
- , Jatin Patel
- & Kiarash Khosrotehrani
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Article
| Open AccessHOXBLINC long non-coding RNA activation promotes leukemogenesis in NPM1-mutant acute myeloid leukemia
Nucleophosmin (NPM1) gene mutation induces a specific gene expression program leading to acute myeloid leukaemia. Here, the authors show that mutant NPM1 activates a HOXB locus-associated long non-coding RNA which is essential for its associated oncogenic transcriptional program and leukaemia development.
- Ganqian Zhu
- , Huacheng Luo
- & Mingjiang Xu
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| Open AccessLoss of NARS1 impairs progenitor proliferation in cortical brain organoids and leads to microcephaly
Asparaginyl-tRNA synthetase1 (NARS1) is required for protein synthesis. Here, the authors identify biallelic NARS1 mutations in individuals with microcephaly and neurodevelopmental delay. Cortical brain organoid modeling recapitulates microcephaly characteristics and scRNA-seq reveals a role for NARS1 in radial glial cell proliferation.
- Lu Wang
- , Zhen Li
- & Joseph G. Gleeson
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Article
| Open AccessEnhancing myocardial repair with CardioClusters
Despite recent progress to advance cardiac cell-based therapy for patients, heart failure mortality rivals most cancers. Here, the authors describe an approach to control and pattern 3 distinct human cardiac cell populations to promote superior repair and regeneration after myocardial infarction.
- Megan M. Monsanto
- , Bingyan J. Wang
- & Mark A. Sussman
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| Open AccessIdentification of cell surface markers and establishment of monolayer differentiation to retinal pigment epithelial cells
Whilst pigmentation has been used to identify retinal pigment epithelial (RPE) cells, surface markers for these cells remain unclear. Here, the authors define surface markers for the RPE including CD140b, which help produce hPSC-derived RPE cells at a large scale following a robust, direct and scalable monolayer differentiation protocol.
- Alvaro Plaza Reyes
- , Sandra Petrus-Reurer
- & Fredrik Lanner
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Article
| Open AccessTargeting specificity of APOBEC-based cytosine base editor in human iPSCs determined by whole genome sequencing
Cytidine base editors are powerful tools for making subtle genome alterations. Here the authors analyse edited human iPSCs with whole genome sequencing and reveal the spectrum of off-target effects.
- Erica McGrath
- , Hyunsu Shin
- & Zhaohui Ye
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Article
| Open AccessDual stem cell therapy synergistically improves cardiac function and vascular regeneration following myocardial infarction
Myocardial infarction causes damage to the myocardium and vasculature. Here the authors show in a rat model of myocardial infarction that cardiomyocytes derived from human induced pluripotent stem cells combined with a human mesenchymal stem cell-loaded patch lead to improved cardiac function and promote vessel formation.
- Soon-Jung Park
- , Ri Youn Kim
- & Hun-Jun Park
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| Open AccessOrganoid-derived C-Kit+/SSEA4− human retinal progenitor cells promote a protective retinal microenvironment during transplantation in rodents
Stem cell transplantation to treat retinal degeneration could be limited by the degenerative microenvironment. Here, the authors show that C-Kit+/SSEA4– progenitor cells enriched from human embryonic stem cell derived retinal organoids protect retinal structure, suppress microglial activation, gliosis and inflammation.
- Ting Zou
- , Lixiong Gao
- & Zheng Qin Yin
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Article
| Open AccessBiologically relevant laminin as chemically defined and fully human platform for human epidermal keratinocyte culture
In vitro expansion of human epidermal keratinocytes to resurface severe wound defects still relies on a human/mouse xenograft culture system. Here the authors develop a fully human, xeno-free culture system using skin-associated laminins, normally present in vivo, to replace mouse feeder cells.
- Monica Suryana Tjin
- , Alvin Wen Choong Chua
- & Karl Tryggvason
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| 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 AccessSelf-patterning of rostral-caudal neuroectoderm requires dual role of Fgf signaling for localized Wnt antagonism
The neuroectoderm is patterned in a rostral-caudal axis in the embryo but how positional information is interpreted, is unclear. Here, the authors show that in mouse 3D embryonic stem cell cultures, there is self-patterning that depends on sequential activation of localised Fgf then Wnt signalling.
- Nozomu Takata
- , Eriko Sakakura
- & Yoshiki Sasai
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| Open AccessOCT4 impedes cell fate redirection by the melanocyte lineage master regulator MITF in mouse ESCs
Lineage master regulators induce differentiation and how the melanocyte master regulator Microphthalmia-associated transcription factor (MITF) is regulated is unclear. Here, the authors show that the pluripotency master regulator, OCT4, counteracts differentiation induced by MITF in mouse embryonic stem cells.
- Danna Sheinboim
- , Itay Maza
- & Carmit Levy
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Article
| Open AccessMHC matching improves engraftment of iPSC-derived neurons in non-human primates
Major histocompatibility complex (MHC) matching improves graft survival rates after organ transplantation. Here the authors show that in macaques, MHC-matched iPSC-derived neurons provide better engraftment in the brain, with a lower immune response and higher survival of the transplanted neurons.
- Asuka Morizane
- , Tetsuhiro Kikuchi
- & Jun Takahashi
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| Open AccessTransplantation of enteric nervous system stem cells rescues nitric oxide synthase deficient mouse colon
Isolated human and mouse enteric nervous system stem cells (ENSCs) are capable of integrating and promoting innervation of the mouse colon. Here the authors show that transplantation of mouse ENSCs into a mouse model of human enteric neuropathy restores colon motility.
- Conor J. McCann
- , Julie E. Cooper
- & Nikhil Thapar
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Article
| Open AccessJoint morphogenetic cells in the adult mammalian synovium
The stem cells that maintain and repair adult joint tissues in mammals, including articular cartilage, remain incompletely defined. Here the authors perform lineage tracing studies in adult mice and find an ontogenetically defined progenitor cell population that is functional in the synovial joint and distinct from previously reported mesenchymal stem cell populations.
- Anke J. Roelofs
- , Janja Zupan
- & Cosimo De Bari
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| Open AccessAn immortalized adult human erythroid line facilitates sustainable and scalable generation of functional red cells
The generation of a sustainable supply of erythroid progenitors is essential for the reliable production of anin vitroderived red blood cell clinical product. Here the authors immortalize early human erythroblasts to generate the first cell line capable of differentiation into functional adult reticulocytes.
- Kongtana Trakarnsanga
- , Rebecca E. Griffiths
- & Jan Frayne
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| Open AccessPurification of functional human ES and iPSC-derived midbrain dopaminergic progenitors using LRTM1
Midbrain dopaminergic neurons generated from stem cells show promise for the treatment of Parkinson’s disease. Here, the authors use the cell surface marker, LRTM1, to enrich the midbrain dopaminergic progenitors and show improved motor function/cell survival when grafted into rat/monkey brains, respectively.
- Bumpei Samata
- , Daisuke Doi
- & Jun Takahashi
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| Open AccessExploiting endogenous fibrocartilage stem cells to regenerate cartilage and repair joint injury
A potentially superior tissue regenerative strategy to stem cell transplantation is modulation of endogenous stem cells. Here the authors show fibrocartilage stem cells exist in the temporomandibular joint that contribute to cartilage regeneration and can be manipulated to enhance regeneration through canonical Wnt signalling.
- Mildred C. Embree
- , Mo Chen
- & Jeremy J. Mao
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Article
| Open AccessGeneration of mice with longer and better preserved telomeres in the absence of genetic manipulations
Telomere shortening has been linked to some aspects of organismal ageing. Here the authors create chimaeric mice that contain a mix of cells with normal or unnaturally long telomeres, and show chimaeric mice are protected from some forms of ageing-associated cellular damage and have accelerated wound-healing.
- Elisa Varela
- , Miguel A. Muñoz-Lorente
- & Maria A. Blasco
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Article
| Open AccessTumour resistance in induced pluripotent stem cells derived from naked mole-rats
The naked mole-rat exhibits an exceptional resistance to cancer. Here, the authors show that induced pluripotent stem cells derived from the naked mole-rat lack teratoma-forming tumorigenicity due to a naked mole-rat-specific ARF-dependent tumour-suppression mechanism.
- Shingo Miyawaki
- , Yoshimi Kawamura
- & Kyoko Miura
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| Open AccessGeneration of stem cell-derived β-cells from patients with type 1 diabetes
Pancreatic β cells can be generated from pluripotent stem cells. Here, the authors show that human induced pluripotent stem cells from patients with type 1 diabetes can be differentiated into β-like cells that have no detectable differences compared with cells from non-diabetic individuals.
- Jeffrey R. Millman
- , Chunhui Xie
- & Douglas A. Melton
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| Open AccessSepsis induces long-term metabolic and mitochondrial muscle stem cell dysfunction amenable by mesenchymal stem cell therapy
Sepsis patients often develop muscle atrophy that can last for years. Here the authors show in a mouse model that sepsis causes long-term impairment of the satellite cells, affecting mitochondrial function and energy metabolism, and that injection of mesenchymal stem cells restores satellite cell metabolism and muscle regeneration.
- P. Rocheteau
- , L. Chatre
- & F. Chrétien
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Article
| Open AccessTAK1 modulates satellite stem cell homeostasis and skeletal muscle repair
TAK1 is a MEK kinase family member that activates pro-survival NF-kB signalling but also pro-apoptotic caspase signalling in various cell types. Here the authors show that satellite-cell specific deletion of TAK1 in mice depletes the muscle stem cell pool and thus limits myofibre regeneration after injury.
- Yuji Ogura
- , Sajedah M. Hindi
- & Ashok Kumar
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Article
| Open AccessOsteoclasts control reactivation of dormant myeloma cells by remodelling the endosteal niche
Therapy resistant dormant myeloma cells contribute to disease relapse. Here, the authors use intravital microscopy to track the location of these cells and demonstrate that they hone to the endosteal niche within the bone.
- Michelle A. Lawson
- , Michelle M. McDonald
- & Peter I. Croucher
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Article
| Open AccessDipeptide species regulate p38MAPK–Smad3 signalling to maintain chronic myelogenous leukaemia stem cells
Chronic myelogenous leukaemia contains a stem cell fraction and targeting this population of cells is an attractive therapeutic strategy. Here, the authors demonstrate that the stem cells take up dipeptides and that inhibiting the dipeptide transporter could reduce the number of these stem cells in mice.
- Kazuhito Naka
- , Yoshie Jomen
- & Seong-Jin Kim
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Article
| Open AccessDirecting cell therapy to anatomic target sites in vivo with magnetic resonance targeting
Cell therapy requires the targeting of cells to specific sites in the body. Here Muthana et al.use a standard MRI scanner to direct oncolytic macrophages, labelled with magnetic nanoparticles, to primary and metastatic tumour sites in mice, and demonstrate that this leads to reduced tumour growth.
- Munitta Muthana
- , Aneurin J. Kennerley
- & Claire Lewis
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Article
| Open AccessNon-autonomous DAF-16/FOXO activity antagonizes age-related loss of C. elegans germline stem/progenitor cells
The number of germline stem/progenitor cells in C. elegansdeclines with age. Here the authors show this cell loss is mediated by the transcription factor DAF-16/FOXO acting in specific somatic gonad cells, demonstrating that stem cell aging can be anatomically uncoupled from organismal aging.
- Zhao Qin
- & E. Jane Albert Hubbard
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TRF1 is a stem cell marker and is essential for the generation of induced pluripotent stem cells
TRF-1 is a telomere-binding protein that protects chromosome ends from degradation. Schneider and colleagues show that TRF1 is a marker of adult stem cell compartments and of induced pluripotent stem cells, and that TRF1 is essential for the induction and maintenance of pluripotency.
- Ralph P. Schneider
- , Ianire Garrobo
- & Maria A. Blasco
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Skeletal muscle stem cells adopt a dormant cell state post mortem and retain regenerative capacity
Stem cells hold great potential for therapeutic use but their supply is limited. Latilet al.isolate muscle stem cells from human and mouse cadavers after 17 and 14 days, respectively, and show that when transplanted into mice the cells can regenerate tissues.
- Mathilde Latil
- , Pierre Rocheteau
- & Fabrice Chrétien
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In vitro production of fertile sperm from murine spermatogonial stem cell lines
Recent technological advances have allowed the expansion of spermatogonial stem cellsin vitro; however, in vivo conditions are required for the full differentiation of the cells. In this study, an in vitroorgan culture system is developed that allows the differentiation of the germ cells in the laboratory.
- Takuya Sato
- , Kumiko Katagiri
- & Takehiko Ogawa
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Article
| Open AccessParkinson's disease induced pluripotent stem cells with triplication of the α-synuclein locus
Pluripotent stem cells can be generated from the somatic cells of humans and are a useful model to study disease. Here, pluripotent stem cells are made from a patient with familial Parkinson's disease, and the resulting neurons exhibit elevated levels of α-synuclein, recapitulating the molecular features of the patient's disease.
- Michael J. Devine
- , Mina Ryten
- & Tilo Kunath