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| 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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| 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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| 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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| 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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| 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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| 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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| 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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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 AccessMulti-omics analysis of human mesenchymal stem cells shows cell aging that alters immunomodulatory activity through the downregulation of PD-L1
Mesenchymal stem cells (MSC) are used for immunosuppressive therapy and a uniform source or heterogeneity characterisation is needed. Here the authors use multi-omics to compare human MSC from different sources and ages of donors and show differences in gene expression and immunosuppressive function.
- Yuchen Gao
- , Ying Chi
- & Xiaomin Zhang
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Article
| Open AccessClearance of defective muscle stem cells by senolytics restores myogenesis in myotonic dystrophy type 1
Muscle stem cells drive muscle regeneration and are affected in myotonic dystrophy type 1. Here, the authors demonstrate that some muscle stem cells show signs of senescence in myotonic dystrophy type 1 and administer senolytics to eliminate these defective cells and restore myogenesis.
- Talita C. Conte
- , Gilberto Duran-Bishop
- & Nicolas A. Dumont
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Article
| Open AccessPorous microneedle patch with sustained delivery of extracellular vesicles mitigates severe spinal cord injury
Efficient delivery of extracellular vesicles to the injured spinal cord, with minimal damage, remains challenging. Here, the authors fabricate a minimally invasive microneedle device, which provides efficient and sustained extracellular vesicle delivery for spinal cord injury treatment.
- Ao Fang
- , Yifan Wang
- & Xuhua Wang
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Article
| Open AccessPlakoglobin is a mechanoresponsive regulator of naive pluripotency
The mechanical microenvironment influences stem cell pluripotency. Here, the authors culture stem cells in microgels with controlled volumetric confinement and identify Plakoglobin as a mechanoresponsive regulator of pluripotency in mouse and human.
- Timo N. Kohler
- , Joachim De Jonghe
- & Florian Hollfelder
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| Open AccessGenome-wide screening in pluripotent cells identifies Mtf1 as a suppressor of mutant huntingtin toxicity
Huntington’s disease is caused by mutation in the HTT gene. Here, the authors screen for suppressors of mutant HTT-induced toxicity, identifying Mtf1. Mtf1 reduced oxidative stress and cell death in stem cells, and motor defects and protein aggregates in mouse models.
- Giorgia Maria Ferlazzo
- , Anna Maria Gambetta
- & Graziano Martello
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Article
| Open AccessModeling and therapeutic targeting of inflammation-induced hepatic insulin resistance using human iPSC-derived hepatocytes and macrophages
Hepatic insulin resistance is an established driver of type 2 diabetes but is difficult to model in vitro. Here researchers use co-culture of hepatocytes and macrophages derived from the same human iPSC line to show how inflammation disrupts insulin-mediated regulation of hepatic glucose metabolism and identify targets for therapy of hepatic insulin resistance.
- Marko Groeger
- , Koji Matsuo
- & Holger Willenbring
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Article
| Open AccessSingle-cell transcriptomics uncovers EGFR signaling-mediated gastric progenitor cell differentiation in stomach homeostasis
Gastric progenitor cells are essential for tissue homeostasis of the stomach. Here, using single-cell RNA sequencing and gastric organoid experiments, the authors demonstrate that EGFR signaling promotes gastric progenitor cell differentiation.
- Hitomi Takada
- , Yohei Sasagawa
- & Akira Kurisaki
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Article
| Open AccessDissecting the roles of MBD2 isoforms and domains in regulating NuRD complex function during cellular differentiation
MBD proteins are integral subunits of the NuRD complex, a crucial regulator of cellular differentiation. Here the authors systematically dissect which MBD protein domains and isoforms are essential for neuronal differentiation.
- Nina Schmolka
- , Ino D. Karemaker
- & Tuncay Baubec
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Article
| Open AccessHedgehog signaling via its ligand DHH acts as cell fate determinant during skeletal muscle regeneration
Successful skeletal muscle regeneration relies on the interplay of multiple cell populations. Here, the authors describe how ciliary Hedgehog signaling coordinates the intercellular crosstalk required to balance wound healing and fatty fibrosis.
- Alessandra M. Norris
- , Ambili Bai Appu
- & Daniel Kopinke
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Article
| Open AccessIntracellular pH dynamics regulates intestinal stem cell lineage specification
Myriad extracellular and intracellular cues regulate stem cell fate choice. Here, Liu et al. report intracellular pH dynamics as a previously unrecognized regulator to selectively mediate the secretory cell fate decision of the intestinal stem cell.
- Yi Liu
- , Efren Reyes
- & Diane L. Barber
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Article
| Open AccessSelective binding of retrotransposons by ZFP352 facilitates the timely dissolution of totipotency network
During zygotic genome activation the embryo must re-wire the regulatory network that sustains totipotency earlier during development. Here they identify ZFP352 as an essential factor that targets retrotransposon families to facilitate dissolution of the totipotency network and enable ZGA.
- Zhengyi Li
- , Haiyan Xu
- & Hongqing Liang
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Article
| Open AccessDirected differentiation of mouse pluripotent stem cells into functional lung-specific mesenchyme
Mesenchymal lineages play critical roles during development, though these cells are frequently overlooked in directed differentiation models. Here they derive lung-specific mesenchyme from mouse iPSCs and generate organoids consisting of both mesenchymal and epithelial progenitors, observing functional epithelial-mesenchymal crosstalk.
- Andrea B. Alber
- , Hector A. Marquez
- & Darrell N. Kotton
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Article
| Open AccessA village in a dish model system for population-scale hiPSC studies
Village cultures, where multiple stem cell lines are cultured in a single dish, provide an elegant solution for population-scale studies. Here, authors show the utility of village models – showing that expression heterogeneity is largely a result of line-specific effects and not village cultures.
- Drew R. Neavin
- , Angela M. Steinmann
- & Joseph E. Powell
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Article
| Open AccessPluripotency-independent induction of human trophoblast stem cells from fibroblasts
In this work Naama et al. describe and deeply characterize a direct approach to produce human induced trophoblast stem cells from fibroblasts and show that it produces superior hiTSCs when compared to OSKM-hiTSCs.
- Moriyah Naama
- , Moran Rahamim
- & Yosef Buganim
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Article
| Open AccessLIS1 RNA-binding orchestrates the mechanosensitive properties of embryonic stem cells in AGO2-dependent and independent ways
LIS1 protein is important for brain development and stem cells’ survival. Here the authors show that LIS1 binds RNA and interact with RNA-binding proteins regulating the physical properties of mouse embryonic stem cells.
- Aditya Kshirsagar
- , Svetlana Maslov Doroshev
- & Orly Reiner
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Article
| Open AccessSpatiotemporal transcriptomic atlas reveals the dynamic characteristics and key regulators of planarian regeneration
Cui et al. present a comprehensive three-dimensional spatiotemporal transcriptome landscape of planarian regeneration. They identified a novel pluripotent neoblast subtype and new spatially specific genes essential to tissue regeneration.
- Guanshen Cui
- , Kangning Dong
- & Yun-Gui Yang
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Article
| Open AccessApicobasal RNA asymmetries regulate cell fate in the early mouse embryo
How do cells of the preimplantation mouse embryo make decisions? Here the authors discovered that the spatial sorting of mRNAs, tRNA, rRNAs and organelles lead to localized translation, conducive for cell fate allocation and embryonic development.
- Azelle Hawdon
- , Niall D. Geoghegan
- & Jennifer Zenker
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Article
| Open AccessHematopoietic reconstitution dynamics of mobilized- and bone marrow-derived human hematopoietic stem cells after gene therapy
Scala et al. show that mobilized peripheral blood hematopoietic stem/progenitor cells are more enriched in repopulating stem cells than bone marrow. Moreover, the quantity and type of infused subsets correlated with gene therapy outcome in humans.
- Serena Scala
- , Francesca Ferrua
- & Alessandro Aiuti
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Article
| Open AccessmacroH2A2 antagonizes epigenetic programs of stemness in glioblastoma
Self-renewing cells play an important role in initiation, progression, and therapy resistance in glioblastoma. Here, the authors identify histone variant macroH2A2 as a regulator of chromatin organisation resulting in the suppression of transcriptional programs of self-renewal in glioblastoma.
- Ana Nikolic
- , Francesca Maule
- & Marco Gallo
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Article
| Open AccessEstablishment of gastrointestinal assembloids to study the interplay between epithelial crypts and their mesenchymal niche
Most intestinal organoid models do not accurately model the interactions between epithelial and stromal cells. Here they establish a colon assembloid system with epithelial and stromal cells and demonstrate that BMP signals from differentiating epithelial cells promote mesenchymal niche organization.
- Manqiang Lin
- , Kimberly Hartl
- & Michael Sigal
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Article
| Open AccessThe NuRD complex cooperates with SALL4 to orchestrate reprogramming
Somatic reprogramming involves both transcriptional and epigenetic resetting, but we don’t yet fully understand this process. Here they show that Jdp2, Glis1, Esrrb, and Sall4 can mediate reprogramming by recruiting the NuRD complex to close chromatin, highlighting a potential role in cell fate control.
- Bo Wang
- , Chen Li
- & Duanqing Pei
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Article
| Open AccessCellular population dynamics shape the route to human pluripotency
The contribution of cell-extrinsic factors during cellular reprogramming to human induced pluripotent stem cells has long been overlooked. Here, the authors show functional protein communication between reprogramming intermediates and the re-shaping of a permissive extracellular environment.
- Francesco Panariello
- , Onelia Gagliano
- & Nicola Elvassore
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Article
| Open AccessAcoel single-cell atlas reveals expression dynamics and heterogeneity of adult pluripotent stem cells
Multiple species can achieve whole-body regeneration through the action of adult stem cells, though little is known about how these cells compare across species. Here they investigated the stem cells of a marine worm, the acoel Hofstenia miamia, and identified heterogeneity of these cells during development and regeneration.
- Ryan E. Hulett
- , Julian O. Kimura
- & Mansi Srivastava
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