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| Open AccessFate specification is spatially intermingled across planarian stem cells
Stem cells can select among a wide array of fates. Here, the authors utilize spatial transcriptomics and three-dimensional neighborhood analysis to uncover that fate choices in planarian stem cells occur in a highly intermingled pattern.
- Chanyoung Park
- , Kwadwo E. Owusu-Boaitey
- & Peter W. Reddien
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Article
| Open AccessPAX3-FOXO1 dictates myogenic reprogramming and rhabdomyosarcoma identity in endothelial progenitors
Histologically, PAX3-FOXO1 (P3F) fusion-positive rhabdomyosarcoma (FP-RMS) resembles muscles cells, however, its cell-of-origin is less clear. Here, the authors demonstrate that P3F expression induces endothelial cells reprogramming into functional myogenic stem cells, driving the formation of FP-RMS in mouse models.
- Madeline B. Searcy
- , Randolph K. Larsen IV
- & Mark E. Hatley
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Article
| Open AccessIntra- and inter-molecular regulation by intrinsically-disordered regions governs PUF protein RNA binding
FBF-2 and LST-1 repress gld-1 mRNA expression to maintain C. elegans germline stem cells. The authors show that an intrinsically-disordered region of FBF-2 autoinhibits its RNA binding. LST-1 antagonizes this interaction to promote RNA binding.
- Chen Qiu
- , Zihan Zhang
- & Traci M. Tanaka Hall
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Article
| Open AccessProenkephalin-A secreted by renal proximal tubules functions as a brake in kidney regeneration
The coordination of pro- and anti-regenerative factors is essential for organ regeneration. The authors show here that proenkephalin-A, secreted by proximal renal tubules in zebrafish, negatively regulates hydrogen peroxide production remodelling H3K4me3 in renal progenitor cells and controlling kidney regeneration strength.
- Chi Liu
- , Xiaoliang Liu
- & Jinghong Zhao
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Article
| Open AccessFunctional dissection of PRC1 subunits RYBP and YAF2 during neural differentiation of embryonic stem cells
RYBP and YAF2 are a pair of paralog subunits of variant PRC1. Here, authors show that RYBP decrease but YAF2 increase during mESC neural differentiation, and that they are not redundant but function differentially in regulating this differentiation.
- Yanjiang Liu
- , Gongcheng Hu
- & Hongjie Yao
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Article
| Open AccessGli1 marks a sentinel muscle stem cell population for muscle regeneration
Adult skeletal muscle regeneration is mainly driven by muscle stem cells (MuSCs), which are highly heterogeneous. Here, the authors found that a population of MuSCs, marked by Gli1 expression, is key contributor to muscle regeneration.
- Jiayin Peng
- , Lili Han
- & Yun Zhao
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Article
| Open AccessOptogenetic control of YAP reveals a dynamic communication code for stem cell fate and proliferation
The transcriptional regulator YAP controls cellular decisions such as proliferation, differentiation, and pluripotency. Here, the authors show a concentration-dependent and temporal communication code for YAP that enables cells to choose between these programs.
- Kirstin Meyer
- , Nicholas C. Lammers
- & Orion D. Weiner
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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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Article
| Open AccessOrganoids transplantation attenuates intestinal ischemia/reperfusion injury in mice through L-Malic acid-mediated M2 macrophage polarization
Intestinal ischemia/reperfusion (I/R) injury is a life-threatening problem in surgeries. Here, authors report that intestinal organoids transplantation attenuates intestinal I/R injury in mice through L-Malic acid-mediated M2 macrophage polarization.
- Fang-Ling Zhang
- , Zhen Hu
- & Ke-Xuan Liu
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Article
| Open AccessMetabolic regulation of proteome stability via N-terminal acetylation controls male germline stem cell differentiation and reproduction
How cellular metabolism is connected to differentiation remains poorly understood. Here the authors report a regulatory cascade in which circulating citrate regulates sperm production by controlling protein stability via a specific protein post-translational modification.
- Charlotte M. François
- , Thomas Pihl
- & Bruno Hudry
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Article
| Open AccessHierarchical assembly of tryptophan zipper peptides into stress-relaxing bioactive hydrogels
Rational design has endowed self-assembling peptides with structural similarities to natural materials, but recreating the dynamic functional properties inherent to natural systems remains challenging. Here the authors report the discovery of a short peptide based on the tryptophan zipper motif, that shows multiscale hierarchical ordering into hydrogels that display emergent dynamic properties.
- Ashley K. Nguyen
- , Thomas G. Molley
- & Kristopher A. Kilian
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Article
| Open AccessPhase separation of BuGZ regulates gut regeneration and aging through interaction with m6A regulators
Phase separation serves to compartmentalize and concentrate cellular components to facilitate essential physiological processes. Here, the authors elucidate the role and mechanism of BuGZ-mediated phase separation in the context of gut regeneration and aging.
- Qiaoqiao Zhang
- , Kai Deng
- & Hao Jiang
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Article
| Open AccessA DEAD-box helicase drives the partitioning of a pro-differentiation NAB protein into nuclear foci
The mechanism of spatiotemporal gene regulation during animal development is a fundamental question in biology. Here the authors show that the DEAD-box helicase DDX-23 controls stem cell fate by driving the formation of NAB repressive transcriptional condensates.
- Akiko Doi
- , Gianmarco D. Suarez
- & H. Robert Horvitz
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Article
| Open AccessSpecies-specific metabolic reprogramming in human and mouse microglia during inflammatory pathway induction
The innate immune cells undergo metabolic reprogramming upon inflammation. Here, the authors report that both mouse and human microglia display a metabolic reprogramming in the presence of a TLR4 activation, however species-specific enzymes are responsible for this process.
- Angélica María Sabogal-Guáqueta
- , Alejandro Marmolejo-Garza
- & Amalia Dolga
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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 AccessHMGA2 directly mediates chromatin condensation in association with neuronal fate regulation
High-mobility group AT-hook (HMGA) proteins 1 and 2 are nonhistone chromatin proteins involved in different biological processes. Here the authors reveal that HMGA2 is a bona fide chromatin condensation factor that undergoes liquid–liquid phase separation, and that its chromatin condensation activity is important for the maintenance of mouse neural progenitor cells.
- Naohiro Kuwayama
- , Tomoya Kujirai
- & Yukiko Gotoh
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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 AccessMulti-species atlas resolves an axolotl limb development and regeneration paradox
Single-cell transcriptomic cross-species comparison identifies critical limb developmental cell type apical-ectodermal ridge in the prime limb regeneration model axolotl, and its differential usage during amphibian limb regeneration.
- Jixing Zhong
- , Rita Aires
- & Can Aztekin
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Article
| Open AccessSubventricular zone cytogenesis provides trophic support for neural repair in a mouse model of stroke
The functions of newborn cells arising from the subventricular zone in response to stroke have been unclear. Here, the authors show that cells migrating from the subventricular zone after stroke promote brain repair and functional recovery in mice.
- Michael R. Williamson
- , Stephanie P. Le
- & Michael R. Drew
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Article
| Open AccessLuminal Rank loss decreases cell fitness leading to basal cell bipotency in parous mammary glands
Rocha and co-authors show that loss of luminal Rank signaling causes abnormal alveolar differentiation and lactation failure. Subsequent pregnancies activate bipotency in basal cells, replacing unfit luminal cells, and restoring lactation.
- Ana Sofia Rocha
- , Alejandro Collado-Solé
- & Eva González-Suárez
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Article
| Open AccessMechanically induced pyroptosis enhances cardiosphere oxidative stress resistance and metabolism for myocardial infarction therapy
Therapeutic options for myocardial infarction therapy remain limited. Here the authors report the application of an optimized liquid crystal substrate in the mass production and effective preconditioning of cardiospheres, which could generate cardiospheres with improved cell bioactivity and resistance to oxidative stress for myocardial infarction therapy.
- Yingwei Wang
- , Qi Li
- & Zheng Wu
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Article
| Open AccessIFNγ-Stat1 axis drives aging-associated loss of intestinal tissue homeostasis and regeneration
Omrani, Krepelova et al. report that aging-induced proinflammatory IFNγ/Stat1 signalling primes intestinal stem cells to a secretory fate and to antigen presenting cells impairing the regenerative capacity of the aging gut epithelium.
- Omid Omrani
- , Anna Krepelova
- & Francesco Neri
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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 AccessC9orf72-ALS human iPSC microglia are pro-inflammatory and toxic to co-cultured motor neurons via MMP9
The role of microglia in amyotrophic lateral sclerosis (ALS) is unclear. Here, the authors show that iPSC microglia from C9orf72-ALS patients are toxic to motor neurons and identify microglial MMP9 as a potential therapeutic target.
- Björn F. Vahsen
- , Sumedha Nalluru
- & Kevin Talbot
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Article
| Open AccessGenetic reversal of the globin switch concurrently modulates both fetal and sickle hemoglobin and reduces red cell sickling
The authors report in full the primary endpoint data of a pilot clinical trial (NCT 03282656) that used post-transcriptional gene silencing of BCL11A expression to reverse the fetal to adult hemoglobin switch in sickle cell disease. They develop new single-cell flow cytometry and microfluidic techniques to predict the efficacy of HbF induction and show that red blood cells from these patients exhibit greater resistance to deoxygenation-induced polymerization than red blood cells from hydroxyurea-responsive patients.
- Daniel C. De Souza
- , Nicolas Hebert
- & John M. Higgins
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Article
| Open AccessA CCL2+DPP4+ subset of mesenchymal stem cells expedites aberrant formation of creeping fat in humans
Extra-intestinal “creeping fat” is a hallmark of Crohn’s disease. Here, using single-cell transcriptomics and lipid metabolomics, the authors identify a subset of mesenchymal stem cells that promote adipogenesis in creeping fat formation.
- Fengfei Wu
- , Fangting Wu
- & Lan Bai
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Article
| Open AccessMetabolic Reprogramming via ACOD1 depletion enhances function of human induced pluripotent stem cell-derived CAR-macrophages in solid tumors
The functional-metabolic state of macrophages fundamentally influences the tumour microenvironment, making adoptive cell therapy with pro-inflammatory macrophages an attractive anti-tumour approach. Here authors introduce pluripotent stem cell-derived CAR-macrophage that are depleted of ACOD1, an essential gene in itaconate metabolism, which reprograms them to a pro-inflammatory state enabling enhanced anti-tumour function.
- Xudong Wang
- , Siyu Su
- & Jin Zhang
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Article
| Open AccessEfficient intervention for pulmonary fibrosis via mitochondrial transfer promoted by mitochondrial biogenesis
Using healthy mitochondria to restore impaired mitochondrial homeostasis is a promising therapy for pulmonary fibrosis. Here the authors use joint-engineered mesenchymal stem cells for efficient mitochondrial delivery to injured lung cells, showing a successful mitigation of the disease.
- Ting Huang
- , Ruyi Lin
- & Jianqing Gao
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Article
| Open AccessMonolayer platform to generate and purify primordial germ-like cells in vitro provides insights into human germline specification
Generation of primordial germ cell-like cells (PGCLCs) from human pluripotent cells (hPSCs) offers insight into the mechanisms underlying human reproduction, but often requires complex methods. Here they describe a simplified monolayer protocol to differentiate and purify PGCLCs for further analysis.
- Sivakamasundari Vijayakumar
- , Roberta Sala
- & Vittorio Sebastiano
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Article
| Open AccessHuman blood vessel organoids reveal a critical role for CTGF in maintaining microvascular integrity
The microvasculature is critical for delivery of oxygen and metabolites throughout tissues. Here they use human blood vessel organoids to show that CTGF is a critical paracrine regulator of microvascular integrity that can restore pericyte coverage and vessel structure.
- Sara G. Romeo
- , Ilaria Secco
- & Anna Zampetaki
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Article
| Open AccessZika virus targets human trophoblast stem cells and prevents syncytialization in placental trophoblast organoids
The pathological effects of Zika virus (ZIKV) infection on placental trophoblast progenitor cells in early human embryos are not well understood. In this study, using human trophoblast stem cells (hTSCs), Wu et al. show that hTSCs are readily infected by ZIKV, but that there is increasing resistance to the virus as differentiation towards mature lineages proceeds.
- Hao Wu
- , Xing-Yao Huang
- & Cheng-Feng Qin
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Article
| Open AccessPlacental growth factor exerts a dual function for cardiomyogenesis and vasculogenesis during heart development
Growth factors play key roles during heart development. Here they show that PLGF has both autocrine and paracrine roles during cardiomyogenesis and vasculogenesis, suggesting it may have therapeutic potential for heart disease.
- Nevin Witman
- , Chikai Zhou
- & Makoto Sahara
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Article
| Open AccessA tissue-intrinsic IL-33/EGF circuit promotes epithelial regeneration after intestinal injury
Mechanisms promoting epithelial regeneration after intestinal injury are poorly understood. Here, authors report that intestinal stem cells produce IL-33 after radiation injury, which induces Paneth cells to produce EGF and promote regeneration.
- Marco Calafiore
- , Ya-Yuan Fu
- & Alan M. Hanash
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Article
| Open AccessAscl1 and Ngn2 convert mouse embryonic stem cells to neurons via functionally distinct paths
Expression of transcription factors can convert one cell type to another beyond developmental paths. Here, the authors show that cells can take two mechanistically distinct paths in the same transition paradigm when driven by the similar proneural factors Ascl1 and Ngn2.
- Gintautas Vainorius
- , Maria Novatchkova
- & Ulrich Elling
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Article
| Open AccessAutocrine TGF-β-positive feedback in profibrotic AT2-lineage cells plays a crucial role in non-inflammatory lung fibrogenesis
IPF is a progressive disease with few inflammatory pathology. Here, using alveolar organoid technology, the authors identified autocrine TGF-β-positive feedback in AT2-lineage cells as a core mechanism of inflammation-independent lung fibrogenesis.
- Yasunori Enomoto
- , Hiroaki Katsura
- & Mitsuru Morimoto
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Article
| Open AccessTargeted mechanical stimulation via magnetic nanoparticles guides in vitro tissue development
Highly localized mechanical forces that shape in vivo tissue development remain challenging to recapitulate in vitro. Here the authors use magnetically actuated nanoparticles to generate spatially defined forces within organoids, which guide the spatial organization of tissue patterning and growth.
- Abdel Rahman Abdel Fattah
- , Niko Kolaitis
- & Adrian Ranga
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Article
| Open AccessCritical dynamics arise during structured information presentation within embodied in vitro neuronal networks
The conditions under which networks of neurons exhibit critical dynamics remains unclear. Here, the authors investigate how simple neural cultures reorganize activity when embodied in a gameplay environment and find that network wide neural criticality arises in nuanced ways.
- Forough Habibollahi
- , Brett J. Kagan
- & Chris French
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Article
| Open AccessDemethylase-independent roles of LSD1 in regulating enhancers and cell fate transition
Here the authors describe the catalytic-independent role of LSD1 in regulating gene expression and cellular differentiation and a mechanism by which the LSD1-P300 axis contributes to the regulation of enhancers and cell fate.
- Cheng Zeng
- , Jiwei Chen
- & Kaixiang Cao
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Article
| Open AccessATF3 induction prevents precocious activation of skeletal muscle stem cell by regulating H2B expression
Muscle regeneration relies on activation and expansion of skeletal muscle stem cells. Here, authors show that ATF3 induction prevents precocious activation of skeletal muscle stem cells by binding and promoting the transcription of Histone2B.
- Suyang Zhang
- , Feng Yang
- & Huating Wang
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Article
| Open AccessPyruvate anaplerosis is a targetable vulnerability in persistent leukaemic stem cells
The persistence of leukemic stem cells (LSCs) is known to limit the success of imatinib in patients with chronic myeloid leukaemia (CML). Here, the authors identify a reliance of these persisting LSCs on pyruvate carboxylase mediated pyruvate anaplerosis for survival after imatinib and demonstrate the therapeutic efficacy of targeting this using an inhibitor of mitochondrial pyruvate carrier.
- Kevin M. Rattigan
- , Zuzana Brabcova
- & G. Vignir Helgason
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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 AccessFluorescent protein lifetimes report densities and phases of nuclear condensates during embryonic stem-cell differentiation
Fluorescent proteins can report on many cellular variables. Here, authors develop a method for reporting high local densities, and use it to show that density distribution of heterochromatin in mouse embryonic stem cells are not in a liquid phase.
- Khalil Joron
- , Juliane Oliveira Viegas
- & Eitan Lerner
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Article
| Open AccessSpinal cord repair is modulated by the neurogenic factor Hb-egf under direction of a regeneration-associated enhancer
Zebrafish can regenerate after paralyzing spine injuries and regain locomotor ability, unlike mammals. Here authors show that the neurogenic factor Hb-egf promotes spinal cord regeneration in zebrafish and is regulated by an enhancer that can similarly direct expression in the pro-regenerative setting of neonatal mice.
- Valentina Cigliola
- , Adam Shoffner
- & Kenneth D. Poss
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Article
| Open AccessSingle-cell analysis of lizard blastema fibroblasts reveals phagocyte-dependent activation of Hedgehog-responsive chondrogenesis
Lizards are the closest known relatives of mammals capable of epimorphic tail regrowth. Here, single-cell analysis of regenerating lizard tails reveals a phagocyte-induced fibroblast population contributing to blastema formation and chondrogenesis.
- Ariel C. Vonk
- , Xiaofan Zhao
- & Thomas P. Lozito
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Article
| 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 AccessHdac1 and Hdac2 regulate the quiescent state and survival of hair-follicle mesenchymal niche
Cell division and stem cell maintenance are tightly linked. Here they show that in the hair follicle an epigenetic mechanism maintains mesenchymal niche dormancy in a highly proliferative microenvironment while repurposing mitogenic signaling to orchestrate the hair cycle clock.
- Hadas Sibony-Benyamini
- , Emil Aamar
- & David Enshell-Seijffers
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Article
| Open AccessSNIP1 and PRC2 coordinate cell fates of neural progenitors during brain development
The balance of stem cell maintenance, differentiation, and programmed death is critical for proper development. Here they show that SNIP1 is critical for stem cell survival and differentiation in the developing brain where it acts downstream of TGFb and NFkB and regulates PRC2 activities for governing cell fates.
- Yurika Matsui
- , Mohamed Nadhir Djekidel
- & Jamy C. Peng
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Article
| Open AccessCyclical dermal micro-niche switching governs the morphological infradian rhythm of mouse zigzag hair
Biological rhythms influence physiology and morphogenesis, though how these influence periodic pattern formation remains unclear. Here the authors show that the infradian rhythm observed in zigzag hairs is regulated by hair progenitors and their micro-niche and influences hair shaft bending.
- Makoto Takeo
- , Koh-ei Toyoshima
- & Takashi Tsuji
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