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| 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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Article
| 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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| 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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| 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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Article
| Open AccessThe Fgf/Erf/NCoR1/2 repressive axis controls trophoblast cell fate
Repression of gene expression contributes to lineage-specific transcriptional signatures. Here Lackner et al. demonstrate that the Erf-NCoR1/2 complex controls trophoblast differentiation by linking signalling with transcriptional repression
- Andreas Lackner
- , Michael Müller
- & Paulina A. Latos
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Article
| Open AccessUSP7 controls NGN3 stability and pancreatic endocrine lineage development
Tightly controlled NGN3 expression is essential for endocrine cell generation in the developing pancreas, with dysregulation leading to hyperglycemia in mice. Here they identify USP7 as a key post-translational regulator of NGN3 stability and show that this axis is required for endocrine development and beta-cell differentiation.
- Teodora Manea
- , Jessica Kristine Nelson
- & Rocio Sancho
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Article
| Open AccessBone marrow endosteal stem cells dictate active osteogenesis and aggressive tumorigenesis
This study identified a new class of skeletal stem cells in the endosteal space of bone marrow, which are abundant in young bone marrow, express Fgfr3 with osteoblast-chondrocyte transitional identities and can turn into bone tumor-making cells.
- Yuki Matsushita
- , Jialin Liu
- & Noriaki Ono
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Article
| Open AccessThe small and large intestine contain related mesenchymal subsets that derive from embryonic Gli1+ precursors
Stromal cells are essential for intestinal homeostasis. Here the authors describe the phenotype, transcriptional profile and location of stromal cell subsets in the adult murine small intestine and colon lamina propria and demonstrate that these cells derive from Gli1+ precursors present in embryonic day 12.5 intestine.
- Simone Isling Pærregaard
- , Line Wulff
- & William W. Agace
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Article
| Open AccessRNA binding protein SYNCRIP maintains proteostasis and self-renewal of hematopoietic stem and progenitor cells
Hematopoietic stem cells (HSCs) are essential for long-term repopulation after secondary transplantation. Here they show that SYNCRIP safeguards HSC self-renewal during regenerative stress by maintaining both proteostasis and CDC42-regulated cell polarity.
- Florisela Herrejon Chavez
- , Hanzhi Luo
- & Michael G. Kharas
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Article
| Open AccessIntegrated transcriptome landscape of ALS identifies genome instability linked to TDP-43 pathology
The causes of ALS remain unclear with many proposed pathomechanisms. Here, the authors integrate iPSC-derived motor neuron and post-mortem datasets and identify a heightened DNA damage response accompanied by accumulation of somatic mutations in ALS.
- Oliver J. Ziff
- , Jacob Neeves
- & Rickie Patani
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Article
| Open AccessExpansion of human megakaryocyte-biased hematopoietic stem cells by biomimetic Microniche
An effective expansion system for therapeutic megakaryocyte-biased hematopoietic stem cells has not been developed. Here the authors present a microniche-based system that supports scalable expansion of human Mk-biased HSCs and identify their immune phenotype.
- Yinghui Li
- , Mei He
- & Yingdai Gao
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Article
| Open AccessDRAG in situ barcoding reveals an increased number of HSPCs contributing to myelopoiesis with age
Using in situ single cell lineage tracing technology DRAG, we show that, unlike emergency myelopoiesis post-transplantation, aged HSPCs do not functionally decline in the number of myeloid cells that they produce.
- Jos Urbanus
- , Jason Cosgrove
- & Leïla Perié
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Article
| Open AccessTranscriptomics of Hirschsprung disease patient-derived enteric neural crest cells reveals a role for oxidative phosphorylation
Hirschsprung disease is caused by defects in enteric neural crest cell. Here, using induced pluripotent stem cell-based models of Hirschsprung and single-cell transcriptomic analysis the authors define various factors associated with Hirschsprung pathogenesis.
- Zhixin Li
- , Kathy Nga-Chu Lui
- & Elly Sau-Wai Ngan
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Article
| Open AccessHigh ploidy large cytoplasmic megakaryocytes are hematopoietic stem cells regulators and essential for platelet production
Not all megakaryocytes are created equal, with sub-populations identified that generate platelets and differentially regulate blood stem cells. These sub-populations, conserved in humans, are important in treating blood and clotting disorders.
- Shen Y. Heazlewood
- , Tanveer Ahmad
- & Susan K. Nilsson
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Article
| Open AccessExcessive serine from the bone marrow microenvironment impairs megakaryopoiesis and thrombopoiesis in Multiple Myeloma
The molecular mechanisms underlying the development of thrombocytopenia in multiple myeloma (MM) remain to be explored. Here, the authors show an association of thrombocytopenia with poor prognosis in MM and identify serine as a key metabolic regulator of thrombocytopenia.
- Chunmei Kuang
- , Meijuan Xia
- & Wen Zhou
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Article
| Open AccessWHIM Syndrome-linked CXCR4 mutations drive osteoporosis
Using a mouse model harboring a WHIM Syndrome-linked gain-of-function CXCR4 mutation and bone marrow samples from WHIM patients, the authors show that proper CXCR4 signaling termination is essential for bone tissue homeostasis.
- Adrienne Anginot
- , Julie Nguyen
- & Karl Balabanian
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Article
| Open AccessRestoring bone marrow niche function rejuvenates aged hematopoietic stem cells by reactivating the DNA Damage Response
Aging is associated with a loss of blood stem cell fitness in part due to defects in stem cell-supportive niches. Here, the authors demonstrate that restoring niche function by treatment with Netrin-1 is able to rejuvenate aged blood stem cells.
- Pradeep Ramalingam
- , Michael C. Gutkin
- & Jason M. Butler
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Article
| Open AccessKIAA1199 deficiency enhances skeletal stem cell differentiation to osteoblasts and promotes bone regeneration
The levels of a factor secreted by bone marrow stromal cells, KIAA1199, associate with osteoporotic fracture risk. Here, the authors show that KIAA1199 deficiency can lead to enhanced bone formation, accelerated bone healing, and protects from ovariectomy-induced bone loss.
- Li Chen
- , Kaikai Shi
- & Moustapha Kassem
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Article
| Open AccessRetinoic acid signaling modulation guides in vitro specification of human heart field-specific progenitor pools
The heart is formed from several spatiotemporally distinct progenitor pools during development. Here they show that modulation of retinoic acid signaling can instruct human pluripotent stems cells into heart progenitors that are useful for studying human development and disease.
- Dorota Zawada
- , Jessica Kornherr
- & Alexander Goedel
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Article
| Open AccessFarrerol directly activates the deubiqutinase UCHL3 to promote DNA repair and reprogramming when mediated by somatic cell nuclear transfer
Here the authors find that farrerol directly binds to UCHL3 and activates its deubiquitinase activity, and that farrerol promotes development of SCNT embryos by enhancing HR repair and restoring epigenetic networks in a UCHL3-dependent manner.
- Weina Zhang
- , Mingzhu Wang
- & Ying Jiang
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Article
| Open AccessAge-dependent Pdgfrβ signaling drives adipocyte progenitor dysfunction to alter the beige adipogenic niche in male mice
Thermogenic beige fat can reduce fat mass and improve metabolic health, yet the ability to form beige fat rapidly declines with age. Here, the authors show that targeting the age-related ramping of Pdgfrβ signalling restores the ageing adipose tissue niche to ignite beige fat development.
- Abigail M. Benvie
- , Derek Lee
- & Daniel C. Berry
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Article
| Open AccessConserved transcription factors promote cell fate stability and restrict reprogramming potential in differentiated cells
Transdifferentiation has been proposed as an approach for regenerative medicine, but the mechanisms that safeguard cell identity are not well established. Here they identify transcription factors that oppose transdifferentiation and show that knockdown of these genes improves recovery after myocardial infarction.
- Maria A. Missinato
- , Sean Murphy
- & Alexandre R. Colas
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Article
| Open AccessRewired m6A epitranscriptomic networks link mutant p53 to neoplastic transformation
The dysregulation of the m6A epitranscriptomic networks have been reported to contribute to the development of gliomas. Here, the authors utilize induced pluripotent stem cell-derived astrocytes with a p53 mutation and demonstrate that mutant p53 upregulates the m6A reader YTHDF2, resulting in the initiation of gliomas.
- An Xu
- , Mo Liu
- & Dung-Fang Lee
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Article
| Open AccessRecapitulating thyroid cancer histotypes through engineering embryonic stem cells
Thyroid carcinoma (TC) is the most common malignancy of endocrine organs. Here, the authors show the ability of human embryonic stem cells (hESCs) to recapitulate the different TC histotypes upon specific genomic alterations delivered by CRISPR-Cas9 and identify KISS1R and TIMP1 targeting as a therapeutic adjuvant option for undifferentiated TCs.
- Veronica Veschi
- , Alice Turdo
- & Giorgio Stassi
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Article
| Open AccessLongitudinal single-cell profiling of chemotherapy response in acute myeloid leukemia
Relapse within acute myeloid leukaemia may be driven by the presence of leukaemia stem cells. Here, the authors use single cell RNA-seq seq to characterise leukemia stem cells, and show miR-126 as a potential marker of resistance.
- Matteo Maria Naldini
- , Gabriele Casirati
- & Bernhard Gentner
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Article
| Open AccessZebrafish pigment cells develop directly from persistent highly multipotent progenitors
Neural crest cells are highly multipotent stem cells, but it remains unclear how their fate restriction to specific fates occurs. Here, the authors show in zebrafish that broad multipotency is retained even after migration, suggesting that fate restriction occurs directly, but dynamically.
- Tatiana Subkhankulova
- , Karen Camargo Sosa
- & Robert N. Kelsh
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Article
| Open AccessThe Wnt/TCF7L1 transcriptional repressor axis drives primitive endoderm formation by antagonizing naive and formative pluripotency
Signal transduction and gene expression regulation via downstream transcription factors shape the early mammalian embryo. Here the authors show that Wnt/TCF7L1 transcriptional repressive activity is required for primitive endoderm lineage formation.
- Paraskevi Athanasouli
- , Martina Balli
- & Frederic Lluis
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Article
| Open AccessAlcam-a and Pdgfr-α are essential for the development of sclerotome-derived stromal cells that support hematopoiesis
The early ontogeny of hematopoietic niches is largely unknown. This article shows that the sclerotome compartment of somites provides Alcam and Pdgfr-α dependent mesenchymal cells that are essential at every step of the development of hematopoiesis.
- Emi Murayama
- , Catherine Vivier
- & Philippe Herbomel
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Article
| Open AccessPostnatal oogenesis leads to an exceptionally large ovarian reserve in naked mole-rats
Female naked mole rats are long lived and show little or no decline in fertility over their lifespan. Here Brieño-Enríquez et al., demonstrate that naked mole-rats establish an exceptionally large ovarian reserve and undergo postnatal oogenesis.
- Miguel Angel Brieño-Enríquez
- , Mariela Faykoo-Martinez
- & Ned J. Place
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Article
| Open AccessEngraftment of allogeneic iPS cell-derived cartilage organoid in a primate model of articular cartilage defect
Allogeneic iPSC-derived cartilage organoids survive and integrate with surrounding native cartilage without immune reactions in a primate model of chondral defects in the knee joints, being remodeled and functioning as articular cartilage.
- Kengo Abe
- , Akihiro Yamashita
- & Noriyuki Tsumaki
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Article
| Open AccessMethionine adenosyltransferase2A inhibition restores metabolism to improve regenerative capacity and strength of aged skeletal muscle
Aged myoblasts suffer from impaired glycolysis and insulin resistance, but increase methionine catabolism, possibly to meet energetic demands. Here, authors show that inhibiting methionine metabolism via NANOG reprogramming or MAT2A inhibition restores the function and regeneration capacity of aged muscle.
- Nika Rajabian
- , Izuagie Ikhapoh
- & Stelios T. Andreadis
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Article
| Open AccessA single-cell transcriptional atlas reveals resident progenitor cell niche functions in TMJ disc development and injury
The transcriptional network in TMJ disc development and injury remains poorly characterized. Here they generate a scRNA-seq atlas of mouse TMJ disc, and identify the resident progenitor population and how its transcriptional reprogramming contributes to disc repair.
- Ruiye Bi
- , Qing Yin
- & Songsong Zhu
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