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| Open AccessVariant PCGF1-PRC1 links PRC2 recruitment with differentiation-associated transcriptional inactivation at target genes
Polycomb repressive complexes (PRC1 and PRC2) repress genes that are crucial for development via epigenetic modifications; however, their role in differentiation is not well known. Here the authors reveal that a PCGF1-containing PRC1 variant facilitates exit from pluripotency by downregulating target genes and recruiting PRC2.
- Hiroki Sugishita
- , Takashi Kondo
- & Haruhiko Koseki
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Article
| Open AccessDisrupting biological sensors of force promotes tissue regeneration in large organisms
Humans and other large mammals heal wounds by forming fibrotic scar tissue with diminished function. Here, the authors show that disrupting mechanotransduction through the focal adhesion kinase pathway in large animals accelerates healing, prevents fibrosis, and enhances skin regeneration.
- Kellen Chen
- , Sun Hyung Kwon
- & Geoffrey C. Gurtner
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Article
| Open AccessCortical overgrowth in a preclinical forebrain organoid model of CNTNAP2-associated autism spectrum disorder
Mutations in CNTNAP2 have been associated with a syndromic form of Autism Spectrum Disorder. Here the authors show that forebrain organoids generated from induced pluripotent stem cells of patients with a syndromic form of ASD with a homozygous truncating mutation in CNTNAP2 displayed an increase in volume and total cell number, which is driven by abnormal cellular proliferation and neurogenesis.
- Job O. de Jong
- , Ceyda Llapashtica
- & Sander Markx
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Article
| Open AccessBioengineered embryoids mimic post-implantation development in vitro
Previous approaches to derive embryoids either lack physiological morphology and signaling interactions, or are unconducive to model post-gastrulation development. Here the authors use a high-throughput approach to induce mouse embryonic stem cells into epiblast-like aggregates, which are then co-cultured with mouse trophoblast stem cell aggregates, to yield embryoids with axial morphogenesis and anterior development.
- Mehmet U. Girgin
- , Nicolas Broguiere
- & Matthias P. Lutolf
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Article
| Open AccessOCT4 cooperates with distinct ATP-dependent chromatin remodelers in naïve and primed pluripotent states in human
Although the interactors of pluripotency factors have been identified in mouse embryonic stem cells (ESCs), their interactors in human ESCs remain unexplored. Here the authors map OCT4 protein interactions in naïve and primed human ESCs to find specific interactions with BAF subunits that promote an open chromatin architecture at blastocyst-associated genes and ectodermal genes, respectively.
- Xin Huang
- , Kyoung-mi Park
- & Thorold W. Theunissen
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Article
| Open AccessSelf-assembling human heart organoids for the modeling of cardiac development and congenital heart disease
There is a pressing need to develop representative organ-like platforms recapitulating complex in vivo phenotypes to study human development and disease in vitro. Here the authors present a method to generate human heart organoids by self-assembly using pluripotent stem cells, compare these to age-matched fetal cardiac tissues and recreate a model of pregestational diabetes.
- Yonatan R. Lewis-Israeli
- , Aaron H. Wasserman
- & Aitor Aguirre
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Article
| Open AccessAmnion signals are essential for mesoderm formation in primates
Human and murine embryonic development has disparities, highlighting the need for primate systems. Here, the authors construct a post-implantation transcriptional atlas from non-human primate embryos and show ISL1 controls a gene regulatory network in the amnion required for mesoderm formation.
- Ran Yang
- , Alexander Goedel
- & Kenneth R. Chien
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Article
| Open AccessA TALE/HOX code unlocks WNT signalling response towards paraxial mesoderm
Cells in the developing embryo interpret WNT signalling with context-dependence, but the mechanism decoding these cues is unclear. Here, the authors show that combinatorial TALE/HOX activity destabilizes nucleosomes at WNT-responsive regions to activate paraxial mesodermal genes.
- Luca Mariani
- , Xiaogang Guo
- & Elisabetta Ferretti
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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 AccessGrafting of iPS cell-derived tenocytes promotes motor function recovery after Achilles tendon rupture
Tendon self-renewal occurs rarely and reconstructive surgery comes with significant limitations. Here the authors present an induced pluripotent stem cell-based method to generate tenocytes, analyze their developmental trajectory using scRNA-seq, and demonstrate their contribution to motor function recovery after Achilles tendon injury via engraftment and paracrine effects.
- Taiki Nakajima
- , Akihiro Nakahata
- & Makoto Ikeya
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Article
| Open AccessDL4-μbeads induce T cell lineage differentiation from stem cells in a stromal cell-free system
T cells derived from stem cells can be harnessed for regenerative medicine and cancer immunotherapy, but current technologies limit production and translation. Here, the authors present a serum-free, stromal-cell free DLL4-coated microbead method for the scalable production of T-lineage cells from multiple sources of stem cells.
- Ashton C. Trotman-Grant
- , Mahmood Mohtashami
- & Juan Carlos Zúñiga-Pflücker
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Article
| Open AccessHuman iPS-derived pre-epicardial cells direct cardiomyocyte aggregation expansion and organization in vitro
The authors form pre-epicardial cells (PECs) from hiPSC-derived lateral plate mesoderm on treating with BMP4, RA and VEGF, and co-culture these PECs with cardiomyocytes, inducing cardiomyocyte aggregation, proliferation and network formation with more mature structures and improved beating/contractility.
- Jun Jie Tan
- , Jacques P. Guyette
- & Harald C. Ott
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Article
| Open AccessCTCF is a barrier for 2C-like reprogramming
Embryos at the 2-cell (2C) stage are totipotent, and overexpression of Dux transcription factor convert embryonic stem cells (ESCs) to a 2C-like state. Here the authors show that DUX-mediated 2C-like reprogramming is associated with DNA damage at CTCF sites and CTCF depletion promotes 2Clike conversion.
- Teresa Olbrich
- , Maria Vega-Sendino
- & Sergio Ruiz
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Article
| Open AccessThe HSP90/R2TP assembly chaperone promotes cell proliferation in the intestinal epithelium
RPAP3 is a subunit of the R2TP complex, a co-chaperone of HSP90, with substrate proteins involved in transcription, ribosome biogenesis, DNA repair and cell growth. Here the authors report that deletion of Rpap3 abrogates cell proliferation and homeostasis in mouse intestine, partly through destabilization of PI3K-like kinases, while elevated RPAP3 levels in colorectal tumors are associated with poor prognosis.
- Chloé Maurizy
- , Claire Abeza
- & Bérengère Pradet-Balade
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Article
| Open AccessHuman sensorimotor organoids derived from healthy and amyotrophic lateral sclerosis stem cells form neuromuscular junctions
Organoids have improved disease modeling. Here, the authors generate human sensorimotor organoids derived from hiPSCs of individuals with ALS. These organoids contain skeletal muscle, sensory and motor neurons as well as astrocytes, microglia, and vasculature and form neuromuscular junctions.
- João D. Pereira
- , Daniel M. DuBreuil
- & Brian J. Wainger
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Article
| Open AccessSkeletal stem and progenitor cells maintain cranial suture patency and prevent craniosynostosis
Cranial sutures are major growth centers for the skull vault and premature fusion leads to pathological fusion, craniosynostosis. Here the authors isolate Wnt responsive skeletal stem and progenitor cells from sutures, that can be transplanted together with Wnt3a protein to repair craniosynostosis in a mouse model.
- Siddharth Menon
- , Ankit Salhotra
- & Natalina Quarto
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| Open AccessLabel-free imaging for quality control of cardiomyocyte differentiation
Differentiation of hPSCs to cardiomyocytes suffers from high variability. Here the authors report a label-free live cell imaging platform based on autofluorescence imaging to enable the prediction of cardiomyocyte differentiation efficiency from hPSCs.
- Tongcheng Qian
- , Tiffany M. Heaster
- & Melissa C. Skala
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| Open AccessRetinoblastoma from human stem cell-derived retinal organoids
Retinoblastoma is a heritable pediatric cancer driven by mutations in RB1. Here, the authors demonstrate the first patient derived model of retinoblastoma using iPSCs from patients with germline mutations in RB1.
- Jackie L. Norrie
- , Anjana Nityanandam
- & Michael A. Dyer
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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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| Open AccessDevelopment of a quantitative prediction algorithm for target organ-specific similarity of human pluripotent stem cell-derived organoids and cells
Quantitative methods to assess the quality of hPSC-derived organoids have not been developed. Here they present a prediction algorithm to assess the transcriptomic similarity between hPSC-derived organoids and the corresponding human target organs and perform validation on lung bud organoids, antral gastric organoids, and cardiomyocytes.
- Mi-Ok Lee
- , Su-gi Lee
- & Hyun-Soo Cho
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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 AccessMassively parallel in vivo CRISPR screening identifies RNF20/40 as epigenetic regulators of cardiomyocyte maturation
Throughput of in vivo genetic screens is a barrier to efficient application. Here the authors use a high-throughput CRISPR-based in vivo forward genetic screen in mice to identify transcriptional regulators of cardiomyocyte maturation, including the epigenetic modifiers RNF20 and RNF40.
- Nathan J. VanDusen
- , Julianna Y. Lee
- & William T. Pu
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Article
| Open AccessTEM8 marks neovasculogenic tumor-initiating cells in triple-negative breast cancer
Vasculogenic mimicry (VM) contributes to the development of triple-negative breast cancer. In this study, the authors show that TEM8 is expressed in VM-forming breast cancer stem cells and it promotes stemness and VM differentiation capacity through a RhoC/ROCK1/SMAD5 axis
- Jiahui Xu
- , Xiaoli Yang
- & Suling Liu
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Article
| Open AccessTargeting local lymphatics to ameliorate heterotopic ossification via FGFR3-BMPR1a pathway
Different types of mesenchymal progenitors participate in ectopic bone formation. Here, the authors show Col2+ lineage cells adopt a lymphatic endothelium cell fate, which regulates local inflammatory microenvironment after trauma, thus influencing heterotopic ossification (HO) development via a FGFR3-BMPR1a pathway.
- Dali Zhang
- , Junlan Huang
- & Yangli Xie
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Article
| Open AccessTranscriptional profiling of mESC-derived tendon and fibrocartilage cell fate switch
The transcriptional regulators underlying the induction and differentiation of dense connective tissues remain largely unknown. Here the authors generate tendon and fibrocartilage cells from mouse embryonic stem cells and apply scRNA-seq to identify molecular regulation of the cell fate switch between these lineages.
- Deepak A. Kaji
- , Angela M. Montero
- & Alice H. Huang
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Article
| Open AccessChromatin states shaped by an epigenetic code confer regenerative potential to the mouse liver
Few studies have provided functional analysis of the epigenetic landscape in the regenerating liver. Here the authors define chromatin states in the quiescent vs. regenerating mouse liver through integration of genome wide profiles of DNA methylation, histone modifications, and chromatin accessibility, identifying H3K27me3 as an epigenetic mark conferring regenerative potential.
- Chi Zhang
- , Filippo Macchi
- & Kirsten C. Sadler
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Article
| Open AccessSS18 regulates pluripotent-somatic transition through phase separation
Emerging evidence suggests that exit from pluripotency is a regulated, rather than passive process. Here the authors identify a requirement for SS18-mediated Brg/Brahma-associated factors (BAF) chromatin remodeling complex assembly during exit from pluripotency, and that SS18 promotes BAF assembly through liquidliquid phase separation.
- Junqi Kuang
- , Ziwei Zhai
- & Duanqing Pei
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Article
| Open AccessTCF21+ mesenchymal cells contribute to testis somatic cell development, homeostasis, and regeneration in mice
Whether the adult testis harbours a somatic progenitor population is unknown. Here, the authors provide evidence that the testis interstitial cells expressing the transcription factor Tcf21 maintain adult testis homeostasis during aging, and act as potential reserve somatic progenitors following injury.
- Yu-chi Shen
- , Adrienne Niederriter Shami
- & Saher Sue Hammoud
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Article
| Open AccessUnexpected contribution of fibroblasts to muscle lineage as a mechanism for limb muscle patterning
The dogma is that limb muscle cells originate from somite, while connective tissue fibroblasts derive from lateral plate mesoderm. Here the authors identify a fibroblast population that undergoes myoblast conversion in response to BMP and contributes nuclei to myotubes at the myotendinous junction.
- Joana Esteves de Lima
- , Cédrine Blavet
- & Delphine Duprez
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Article
| Open AccessERRγ enhances cardiac maturation with T-tubule formation in human iPSC-derived cardiomyocytes
Cardiomyocytes (CMs) derived from human induced pluripotent stem cells (hiPSCs) suffer from limited maturation. Here the authors identify ERRγ agonist as a factor that enhances cardiac morphological, metabolic, contractile and electrical maturation of hiPSC-derived CMs with T-tubule formation.
- Kenji Miki
- , Kohei Deguchi
- & Yoshinori Yoshida
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Article
| Open AccessArginine methylation of METTL14 promotes RNA N6-methyladenosine modification and endoderm differentiation of mouse embryonic stem cells
The methyltransferase complex of METTL3-METTL14-WTAP is responsible for m6A modification on RNA. Here the authors report that METTL14 arginine 255 (R255) is methylated by PRMT1 and this modification increases interaction of METTL3/METTL14 interaction with WTAP and substrate RNA, promoting m6A methylation activity of the complex.
- Xiaona Liu
- , Hailong Wang
- & Shan Xiao
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Article
| Open AccessA single cell characterisation of human embryogenesis identifies pluripotency transitions and putative anterior hypoblast centre
Single cell analysis of early human embryos identifies key changes in pluripotency, the requirement of FGF signalling for embryo survival, and defines a putative anterior-like region of hypoblast cells, providing insights into how early human development is regulated.
- Matteo A. Molè
- , Tim H. H. Coorens
- & Magdalena Zernicka-Goetz
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Article
| Open AccessGeneration of patterned kidney organoids that recapitulate the adult kidney collecting duct system from expandable ureteric bud progenitors
Here, the authors model the collecting duct system in kidneys by taking ureteric bud (UB) progenitor cells from both mouse and human primary tissues, as well as from hESC and hiPSC to generate organoids, which can model congenital anomalies of the kidney and urinary tract.
- Zipeng Zeng
- , Biao Huang
- & Zhongwei Li
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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 AccessChromosome compartments on the inactive X guide TAD formation independently of transcription during X-reactivation
Both A/B compartments and TADs are thought to be absent from the inactive X chromosome, but to be re-established with transcriptional reactivation and chromatin opening during X-reactivation. Here, the authors characterise gene reactivation, chromatin opening and chromosome topology during X-reactivation, observe A/B-like compartments on the inactive X that guide TAD formation independently of transcription during X-reactivation.
- Moritz Bauer
- , Enrique Vidal
- & Bernhard Payer
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Article
| Open AccessHIRA stabilizes skeletal muscle lineage identity
The epigenetic mechanisms coordinating the maintenance of adult cellular lineages remain poorly understood. Here the authors demonstrate that HIRA, a H3.3 histone chaperone, establishes the chromatin landscape required for skeletal muscle cell identity.
- Joana Esteves de Lima
- , Reem Bou Akar
- & Frédéric Relaix
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Article
| Open AccessChemical combinations potentiate human pluripotent stem cell-derived 3D pancreatic progenitor clusters toward functional β cells
Human pluripotent stem cell (hPSC) derived pancreatic beta cells are a promising and potentially limitless source for cell replacement therapy. Here the authors perform stage-wise chemical screening to develop an improved protocol for hPSC differentiation to functional pancreatic beta cells at high efficiency.
- Haisong Liu
- , Ronghui Li
- & Juan Carlos Izpisua Belmonte
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Article
| Open AccessHOXA13 in etiology and oncogenic potential of Barrett’s esophagus
Barrett’s esophagus is a pro-oncogenic lesion in the proximal gastrointestinal tract, but with a distal colon-like morphology. Here the authors report that the distal HOX gene HOXA13 is expressed in Barrett’s esophagus and in single cells of the physiological esophagus, and may underlie the phenotypic aspects of metaplasia and increase proliferation.
- Vincent T. Janmaat
- , Kateryna Nesteruk
- & Maikel P. Peppelenbosch
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Article
| Open AccessReinforcing one-carbon metabolism via folic acid/Folr1 promotes β-cell differentiation
Regeneration of insulin-producing beta-cells may become a future alternative treatment of diabetes. Here the authors report a genetic screen in a zebrafish model that mimics the loss of beta-cells in diabetes, and identified that the folate receptor Folr1 or folinic acid treatment can stimulate beta-cell regeneration.
- Christos Karampelias
- , Habib Rezanejad
- & Olov Andersson
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Article
| Open AccessEstablishment of a fluorescent reporter of RNA-polymerase II activity to identify dormant cells
The identification and characterisation of dormant cells is currently difficult. Here the authors report Optical Stem Cell Activity Reporter (OSCAR) to assess RNA polymerase II activity and identify dormant cell populations in intestinal epithelial cells in vivo.
- Rasmus Freter
- , Paola Falletta
- & Francesco Neri
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Article
| Open AccessConstruction of a mammalian embryo model from stem cells organized by a morphogen signalling centre
Following instruction by a morphogen secreting centre, aggregates of mouse embryonic stem cells develop into embryo-like structures organized around an axial mesoderm, which show extensive characteristics of a neurula-stage mouse embryo, with antero-posterior and dorso-ventral patterning of germ layer derivatives.
- Peng-Fei Xu
- , Ricardo Moraes Borges
- & Christine Thisse
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Article
| Open AccessAcetylation of PAX7 controls muscle stem cell self-renewal and differentiation potential in mice
The acetyltransferase MYST1 stimulated by acetyl-CoA, and the deacetylase SIRT2 stimulated by NAD+, regulate PAX7 acetylation in muscle stem cells, which in turn, regulates stem cell self-renewal and regeneration following injury in mouse skeletal muscle.
- Marie-Claude Sincennes
- , Caroline E. Brun
- & Michael A. Rudnicki
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Article
| Open AccessHuman stem cells harboring a suicide gene improve the safety and standardisation of neural transplants in Parkinsonian rats
Stem cell grafts present a risk of tissue overgrowth/tumors. Here, the authors utilise a human pluripotent stem cell line carrying a FailSafe suicide gene to not only ablate proliferative cells, but through timely gene activation, improve the purity of neural grafts in Parkinsonian rats.
- Isabelle R. de Luzy
- , Kevin C. L. Law
- & Clare L. Parish
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Article
| Open AccessGeneration of mature compact ventricular cardiomyocytes from human pluripotent stem cells
Cardiomyocytes of heart ventricles consist of subpopulations of trabecular and compact subtypes. Here the authors describe the generation of structurally, metabolically and functionally mature compact ventricular cardiomyocytes as well as mature atrial cardiomyocytes from human pluripotent stem cells.
- Shunsuke Funakoshi
- , Ian Fernandes
- & Gordon Keller
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Article
| Open AccessDecreased GLUT2 and glucose uptake contribute to insulin secretion defects in MODY3/HNF1A hiPSC-derived mutant β cells
Heterozygous HNF1A mutations can give rise to maturity onset diabetes of the young 3 (MODY3), characterized by insulin secretion defects. Here the authors show that MODY3-related HNF1A mutation in patient hiPSCderived pancreatic cells decreases glucose transporter GLUT2 expression due to compromised DNA binding.
- Blaise Su Jun Low
- , Chang Siang Lim
- & Adrian Kee Keong Teo
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Article
| Open AccessSmall-molecule inhibition of Lats kinases may promote Yap-dependent proliferation in postmitotic mammalian tissues
Although Hippo signaling restricts regeneration in many mammalian organs, the pharmaceutical tools available to modulate the pathway have been limited. Here, the authors report a small molecule that may inhibit a key element in the Hippo cascade and may activate regenerative responses in several mammalian tissues.
- Nathaniel Kastan
- , Ksenia Gnedeva
- & A. J. Hudspeth
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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 AccessA 3D system to model human pancreas development and its reference single-cell transcriptome atlas identify signaling pathways required for progenitor expansion
From single-cell transcriptome analyses to defining culture media for spheroids, the authors provide a census of information to understand the development of human pancreatic progenitors. This approach identifies signalling pathways (EGF and FGF) regulating progenitor proliferation.
- Carla A. Gonçalves
- , Michael Larsen
- & Anne Grapin-Botton
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Article
| Open AccessChemically defined and xeno-free culture condition for human extended pluripotent stem cells
The applications of human extended pluripotent stem cells (which can form both embryonic and extraembryonic lineages) demand a xeno-free culture condition; here, the authors provide a chemically defined and xeno-free culture system to do so.
- Bei Liu
- , Shi Chen
- & Hongkui Deng
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