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| Open AccessOrgo-Seq integrates single-cell and bulk transcriptomic data to identify cell type specific-driver genes associated with autism spectrum disorder
Cerebral organoids can be used to gain insights into neuropsychiatric disorders. Here the authors carry out RNAseq characterization from organoids derived from donors with autism spectrum disorder to identify associated cell type specific driver genes.
- Elaine T. Lim
- , Yingleong Chan
- & George M. Church
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Article
| Open AccessSMYD5 catalyzes histone H3 lysine 36 trimethylation at promoters
SETD2 methylates histone H3K36me3 in gene bodies in mammalian cells. Here the authors show H3K36me3 is also enriched at the promoter regions, and that this methylation is carried out by SMYD5, which is recruited by RNA polymerase II. They furthermore show SMYD5 is elevated in liver cancer and is correlated with changes in gene expression.
- Yanjun Zhang
- , Yuan Fang
- & Dong Fang
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Article
| Open AccessSalivary gland organoid culture maintains distinct glandular properties of murine and human major salivary glands
The long-term maintenance of diverse salivary gland cells remains challenging. Here the authors establish a protocol for long-term maintenance of murine and human salivary gland organoids exhibiting gland-specific gene expression, gland functions, and cellular diversity confirmed by scRNA-seq.
- Yeo-Jun Yoon
- , Donghyun Kim
- & Jae-Yol Lim
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Article
| Open AccessCell fate roadmap of human primed-to-naive transition reveals preimplantation cell lineage signatures
Cell fate dynamics during human naïve pluripotency establishment remain poorly understood. Here, Bi et al. depict a high-resolution cell roadmap of the primed-to-naïve pluripotency transition, providing hints for embryo modeling-related studies.
- Yan Bi
- , Zhifen Tu
- & Yixuan Wang
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Article
| Open AccessIntegrative epigenomic and transcriptomic analysis reveals the requirement of JUNB for hematopoietic fate induction
Here they perform an integrative analysis of the epigenetic landscape of human pluripotent stem cell hematopoietic differentiation and show that JUNB is an indispensable transcription factor for hemogenic endothelium development.
- Xia Chen
- , Peiliang Wang
- & Jie Na
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Article
| Open AccessAdaptive liquid interfaces induce neuronal differentiation of mesenchymal stem cells through lipid raft assembly
In this work the authors report how human mesenchymal stem cells rapidly adapt to dynamic microenvironment through lipid raft in membrane microdomains that direct neurogenesis.
- Xiaofang Jia
- , Jingwen Song
- & Katsuhiko Ariga
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Article
| Open AccessCCN1 interacts with integrins to regulate intestinal stem cell proliferation and differentiation
Intestinal stem cells contribute to homeostasis through a balance between self-renewal and differentiation. Here the authors show that CCN1 is an intestinal stem cell niche factor that activates integrin αvβ3/αvβ5 signaling to regulate proliferation and differentiation through distinct downstream pathways.
- Jong Hoon Won
- , Jacob S. Choi
- & Joon-Il Jun
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Article
| Open AccessThe microRNA cluster C19MC confers differentiation potential into trophoblast lineages upon human pluripotent stem cells
Little is known about the epigenetic mechanisms of the first cell fate commitment in humans. Here, the authors show that activation of the miRNA cluster C19MC confers differentiation potential into trophoblast lineages on human embryonic stem cells.
- Norio Kobayashi
- , Hiroaki Okae
- & Takahiro Arima
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Article
| Open AccessRobust derivation of transplantable dopamine neurons from human pluripotent stem cells by timed retinoic acid delivery
Stem cell based replacement therapies could provide a treatment for Parkinson’s disease. Here the authors outline a retinoic acid-based approach for robust derivation of dopamine neurons from stem cells that restore motor deficits in parkinsonian rats.
- Zhanna Alekseenko
- , José M. Dias
- & Johan Ericson
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Article
| Open AccessActivation of Nkx2.5 transcriptional program is required for adult myocardial repair
Cardiac developmental genes have been associated with regenerative potential. Here the authors identify a Nkx2.5-dependent gene regulatory network operating through ect2, psmb3, and psmd7 to orchestrate cell cycle re-entry, proteolysis, and mitochondrial metabolism during myocardial repair.
- Carmen de Sena-Tomás
- , Angelika G. Aleman
- & Kimara L. Targoff
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Article
| Open AccessSignal requirement for cortical potential of transplantable human neuroepithelial stem cells
The regulatory pathways that control the human neural progenitor cell pool are not well understood. Here, Varga et al. identify signals that control the division of human pluripotent stem cell derived neural stem cells and their ability to make cortical neurons and glia.
- Balazs V. Varga
- , Maryam Faiz
- & Andras Nagy
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Article
| Open AccessCell cycle gene regulation dynamics revealed by RNA velocity and deep-learning
Single-cell RNA-sequencing technology gives access to cell cycle dynamics without externally perturbing the cell. Here the authors present DeepCycle,a robust deep learning method to infer the cell cycle state in single cells from scRNA-seq data.
- Andrea Riba
- , Attila Oravecz
- & Nacho Molina
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Article
| Open AccessBMP4 drives primed to naïve transition through PGC-like state
Multiple pluripotent states have been described in mouse and human stem cells. Here the authors describe trajectories during BMP4 induced primed to naïve transition, which bifurcates into naïve and trophoblast-like branches with a PGC-like intermediate at the naïve branch.
- Shengyong Yu
- , Chunhua Zhou
- & Jing Liu
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Article
| Open AccessThe planarian wound epidermis gene equinox is required for blastema formation in regeneration
Many regenerative animals form an outgrowth at wound sites called a blastema. Here the authors identify equinox, which is expressed in the planarian wound epidermis and essential to initiate positional information regeneration and blastema formation.
- M. Lucila Scimone
- , Jennifer K. Cloutier
- & Peter W. Reddien
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Article
| Open AccessEpigenetic traits inscribed in chromatin accessibility in aged hematopoietic stem cells
Haematopoietic stem cells (HSCs) exhibit considerable cell-intrinsic changes with age. Here the authors demonstrate that differentially accessible regions in aged HSC chromatin are enriched for stress-responsive enhancers and act as an epigenetic hub to augment transcriptional responses of aged HSCs to external stimuli.
- Naoki Itokawa
- , Motohiko Oshima
- & Atsushi Iwama
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Article
| Open AccessA conserved YAP/Notch/REST network controls the neuroendocrine cell fate in the lungs
Notch signaling is known to control neuroendocrine fate in the lungs. Shue and colleagues further identify the REST and YAP transcriptional regulators as key components of the Notch signaling pathway in the control of the neuroendocrine cell fate in lung development, lung injury response, and small-cell lung cancer.
- Yan Ting Shue
- , Alexandros P. Drainas
- & Julien Sage
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Article
| Open AccessRunx1 and Runx2 inhibit fibrotic conversion of cellular niches for hematopoietic stem cells
The transcription factors, Runx1 and Runx2 are critical embryonically for generation of HSCs and osteoblasts, respectively. Here the authors show that adult mice lacking Runx1 and Runx2 in HSC-supporting CAR cells displayed an increase in fibrosis with reduced HSCs in bone marrow.
- Yoshiki Omatsu
- , Shota Aiba
- & Takashi Nagasawa
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Article
| Open AccessA genome-wide CRISPR-Cas9 knockout screen identifies essential and growth-restricting genes in human trophoblast stem cells
Here the authors perform a genome-wide CRISPR-Cas9 knockout screen to systematically identify and characterize essential and growth-restricting genes in human trophoblast cells. They identify TEAD1 as a key regulator that plays an important role in the specification, maintenance, and differentiation of the human trophoblast lineage by modulating chromatin architecture and gene expression.
- Chen Dong
- , Shuhua Fu
- & Thorold W. Theunissen
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Article
| Open AccessDistinctive molecular features of regenerative stem cells in the damaged male germline
Male germline regeneration after damage is dependent on spermatogonial stem cells (SSCs) but pathways mediating the regenerative response are unclear. Here the authors define roles for growth factor signalling and mTORC1 in SSC-driven regeneration.
- Hue M. La
- , Jinyue Liao
- & Robin M. Hobbs
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Article
| Open AccessA FoxA2+ long-term stem cell population is necessary for growth plate cartilage regeneration after injury
The growth plate cartilage supports long bone growth. Here the authors identify FoxA2+ long term stem cells in the growth plate that are stratified with short term PTHrP+ cells, participate in production of hyaline cartilage, expand in response to trauma, and whose ablation impairs cartilage regeneration.
- Shanmugam Muruganandan
- , Rachel Pierce
- & Andreia M. Ionescu
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Article
| Open AccessPreventing erosion of X-chromosome inactivation in human embryonic stem cells
Cloutier et al. discover that human embryonic stem cells (hESCs) cultured with media containing inhibitors of GSK3 proteins undergo erosion of X-chromosome inactivation, which equalizes X-linked gene expression between females and males. The findings inform the faithful culture of hESCs.
- Marissa Cloutier
- , Surinder Kumar
- & Sundeep Kalantry
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Article
| Open AccessAn instantly fixable and self-adaptive scaffold for skull regeneration by autologous stem cell recruitment and angiogenesis
Limited stem cells and mismatched interface fusion have plagued biomaterial-mediated cranial reconstruction. Here, the authors engineer an instantly fixable and self-adaptive scaffold to promote calcium chelation and interface integration, regulate macrophage M2 polarization, and recruit endogenous stem cells.
- Gonggong Lu
- , Yang Xu
- & Xingdong Zhang
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Article
| Open AccessTranscription Factor 4 loss-of-function is associated with deficits in progenitor proliferation and cortical neuron content
Transcription Factor 4 (TCF4) has been associated with autism and schizophrenia. Here, the authors demonstrate aberrant proliferation and differentiation in neural cells and organoids carrying mutations in TCF4.
- Fabio Papes
- , Antonio P. Camargo
- & Alysson R. Muotri
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Article
| Open AccessRegulation of chromatin accessibility by the histone chaperone CAF-1 sustains lineage fidelity
Cell fate commitment involves transcription factor activity and changes in chromatin architecture. Here the authors show that CAF-1 maintains lineage fidelity by controlling chromatin accessibility at specific sites; suppressing CAF-1 triggers differentiation of myeloid stem and progenitor cells into a mixed lineage state.
- Reuben Franklin
- , Yiming Guo
- & Sihem Cheloufi
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Article
| Open AccessPeriodic formation of epithelial somites from human pluripotent stem cells
Somitogenesis has been well characterized in model organisms, resulting in detailed description of the somite segmentation clock. Here they generate somitogenic organoids from human pluripotent stem cells that recapitulate somitogenesis, periodic segmentation, and proper polarity.
- Marina Sanaki-Matsumiya
- , Mitsuhiro Matsuda
- & Miki Ebisuya
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Article
| Open AccessCell-lineage controlled epigenetic regulation in glioblastoma stem cells determines functionally distinct subgroups and predicts patient survival
The epigenetic regulation of glioblastoma stem cell (GSC) function remains poorly understood. Here, the authors compare the chromatin accessibility landscape of GSC cultures from mice and patients and suggest that the epigenome of GSCs is cell lineage-regulated and could predict patient survival.
- Xi Lu
- , Naga Prathyusha Maturi
- & Xingqi Chen
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Article
| Open AccessSingle cell analyses identify a highly regenerative and homogenous human CD34+ hematopoietic stem cell population
The trajectories of hematopoietic stem cells (HSCs) during lineage commitment are complex. Here, the authors use single cell RNA-sequencing and xenotransplantation to uncover CD34 + EPCR + (CD38/CD45RA)- HSCs, which high repopulating and self-renewal properties.
- Fernando Anjos-Afonso
- , Florian Buettner
- & Dominique Bonnet
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Article
| Open AccessDifferential effects of macrophage subtypes on SARS-CoV-2 infection in a human pluripotent stem cell-derived model
Model systems to study SARS-CoV-2 infection are required to better understand the immune response. Here the authors use a lung and macrophage co-culture system by differentiation of human pluripotent stem cells to better understand the phenotype and gene expression changes in host lung cells and macrophages after SARS-CoV-2 infection in vitro.
- Qizhou Lian
- , Kui Zhang
- & Huanhuan Joyce Chen
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Article
| Open AccessCHD7 regulates bone-fat balance by suppressing PPAR-γ signaling
CHD7 is chromatin remodeler and mutations of CHD7 are the main cause of CHARGE syndrome. Here the authors show that conditional knockout of Chd7 in bone marrow mesenchymal stem cells (MSCs) and pre-osteoblasts leads to a skeletal system development disorder in mice and upregulated PPAR signaling, disrupting the balance between osteogenic and adipogenic differentiation.
- Caojie Liu
- , Qiuchan Xiong
- & Ning Kang
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Article
| Open AccessThe nuclear receptor ERR cooperates with the cardiogenic factor GATA4 to orchestrate cardiomyocyte maturation
Mature cardiac muscle requires high mitochondrial ATP production and specialized contractile proteins. Here the authors demonstrate that cardiomyocyte-specific contractile maturation involves cooperation between the nuclear receptor ERRγ and cardiogenic transcription factor GATA4, but ERRγ controls metabolic genes independently.
- Tomoya Sakamoto
- , Kirill Batmanov
- & Daniel P. Kelly
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Article
| Open AccessHuman pancreatic microenvironment promotes β-cell differentiation via non-canonical WNT5A/JNK and BMP signaling
In vitro differentiation of pancreatic beta cells offers a potential therapeutic approach for diabetes. Here they show human pluripotent stem cell derived pancreatic progenitors differentiate into insulin-secreting cells by crosstalk of WNT5A and BMP signaling.
- Jolanta Chmielowiec
- , Wojciech J. Szlachcic
- & Malgorzata Borowiak
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Article
| Open AccessElastic dosage compensation by X-chromosome upregulation
The concerted dynamics of X-chromosome upregulation and X-chromosome inactivation, which collectively balance X-chromosome expression, are not well understood. Using allelic single-cell genomics, the authors characterize the dynamics of X-chromosome upregulation and inactivation along mouse embryonic and stem cell development, calling to question keys aspects of the established model of mammalian dosage compensation.
- Antonio Lentini
- , Huaitao Cheng
- & Björn Reinius
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Article
| Open AccessCell-intrinsic Aryl Hydrocarbon Receptor signalling is required for the resolution of injury-induced colonic stem cells
Rapid intestinal regeneration after injury is critical to maintain barrier integrity and homeostasis, but must be tightly controlled to prevent tumorigenesis. Here they show that the aryl hydrocarbon receptor is required to terminate the regenerative response after wound healing.
- Kathleen Shah
- , Muralidhara Rao Maradana
- & Brigitta Stockinger
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Article
| Open AccessTissue extracellular matrix hydrogels as alternatives to Matrigel for culturing gastrointestinal organoids
The culture of gastrointestinal organoids relies on Matrigel that has several drawbacks for clinical application. Here, the authors report the feasibility of gastrointestinal tissue-mimetic matrices as effective alternatives to Matrigel for organoid culture and transplantation.
- Suran Kim
- , Sungjin Min
- & Seung-Woo Cho
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Article
| Open AccessBAF complex-mediated chromatin relaxation is required for establishment of X chromosome inactivation
Female embryonic stem cells (ESCs) are the ideal model to study X chromosome inactivation (XCI) establishment; however, these cells are challenging to keep in culture. Here the authors create fluorescent ‘Xmas’ reporter mice as a renewable source of ESCs and show nucleosome remodelers Smarcc1 and Smarca4 create a nucleosome-free promoter region prior to the establishment of silencing.
- Andrew Keniry
- , Natasha Jansz
- & Marnie E. Blewitt
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Article
| Open AccessFunctional antagonism between ΔNp63α and GCM1 regulates human trophoblast stemness and differentiation
Trophoblast stem cells can be derived from human blastocysts and first-trimester, but not term, cytotrophoblasts. Here the authors show that induction efficiency of cytotrophoblast is determined by antagonism between GCM1 and ΔNp63α and manipulating this antagonism facilitates derivation of TS cells from term placenta.
- Liang-Jie Wang
- , Chie-Pein Chen
- & Hungwen Chen
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Article
| Open AccessEngineering a niche supporting hematopoietic stem cell development using integrated single-cell transcriptomics
Here, the authors use single cell RNA-sequencing to generate an atlas of signaling interactions regulating embryonic hematopoietic stem cell (HSC) development and apply this knowledge to engineer a niche sufficient to support HSC maturation in vitro.
- Brandon Hadland
- , Barbara Varnum-Finney
- & Irwin D. Bernstein
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Article
| Open AccessBMP feed-forward loop promotes terminal differentiation in gastric glands and is interrupted by H. pylori-driven inflammation
Helicobacter pylori causes gastric inflammation, gland hyperplasia and is linked to gastric cancer. Here the authors identify a BMP feedback loop between the stomach epithelium and surrounding stroma that controls gland homeostasis and demonstrate its interruption upon infection with H. pylori.
- Marta Kapalczynska
- , Manqiang Lin
- & Michael Sigal
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Article
| Open AccessSpatiotemporal reprogramming of differentiated cells underlies regeneration and neoplasia in the intestinal epithelium
Rapid turnover and regeneration of intestinal epithelium requires distinct intestinal stem cell (ISC) populations. Here the authors show p57 marks quiescent ISCs, and that differentiated cells revert to stem cell state after injury, through dynamic reprogramming characterized by fetal- and metaplastic-like changes.
- Tsunaki Higa
- , Yasutaka Okita
- & Keiichi I. Nakayama
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Article
| Open AccessA non-dividing cell population with high pyruvate dehydrogenase kinase activity regulates metabolic heterogeneity and tumorigenesis in the intestine
Metabolic reprogramming upon SIRT6 loss induces tumour formation in the intestine but the mechanism is unclear. Here, the authors show that loss of SIRT6 leads to the expansion of epithelial cells with high pyruvate dehydrogenase kinase activity resulting in enhanced stem cell activity and tumour-initiating potential
- Carlos Sebastian
- , Christina Ferrer
- & Raul Mostoslavsky
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Article
| Open AccessMassively parallel reporter perturbation assays uncover temporal regulatory architecture during neural differentiation
How gene regulatory elements regulate gene expression during cellular differentiation remains largely unknown. Here the authors use perturbation-based massively parallel reporter assays at early time points of neural differentiation to systematically characterize how regulatory elements and motifs within them guide different transcriptional patterns.
- Anat Kreimer
- , Tal Ashuach
- & Nadav Ahituv
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Article
| Open AccessPrimary cilia on muscle stem cells are critical to maintain regenerative capacity and are lost during aging
Repair of muscle damage requires muscle stem cells, which lose regenerative capacity with aging. Here, the authors show that a sensory organelle, the primary cilium, is critical for muscle stem cell proliferation during regeneration and lost with aging.
- Adelaida R. Palla
- , Keren I. Hilgendorf
- & Helen M. Blau
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Article
| Open AccessGpr125 is a unifying hallmark of multiple mammary progenitors coupled to tumor latency
Gpr125 has emerged as a specific marker of mammary stem cells and basal progenitors. Here they show that Gpr125 cells congregate at ductal tips during morphogenesis and amass at tumor margins, and that high Gpr125 predicts early tumor onset and poor outcome in basal breast cancer.
- Elena Spina
- , Julia Simundza
- & Pamela Cowin
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Article
| Open AccessElectrical modulation of transplanted stem cells improves functional recovery in a rodent model of stroke
Paul George and colleagues developed a conductive polymer system to enable stem cell delivery and electrical modulation in vivo. Employing this system improved functional stroke recovery in rodents and identified important repair pathways.
- Byeongtaek Oh
- , Sruthi Santhanam
- & Paul M. George
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Article
| Open AccessMalfunction of airway basal stem cells plays a crucial role in pathophysiology of tracheobronchopathia osteoplastica
Tracheobronchopathia osteoplastica (TO), is an underreported affliction characterized by squamous metaplasia and heterotopic bone formation in trachea and bronchi. Here the authors apply functional, as well as genome-wide transcriptional and epigenetic profiling to identify airway basal cells dysfunction underlying TO.
- Yue Hong
- , Shan Shan
- & Tao Ren
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Article
| Open AccessA specialized bone marrow microenvironment for fetal haematopoiesis
The colonization of bone marrow by haematopoietic stem and progenitor cells is critical for lifelong blood cell formation. Here the authors report distinct features of fetal bone marrow and show that artery-derived signals promote haematopoietic colonization.
- Yang Liu
- , Qi Chen
- & Ralf H. Adams
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Article
| Open AccessA systematic review and meta-analysis of gene therapy with hematopoietic stem and progenitor cells for monogenic disorders
Ex-vivo gene therapy with hematopoietic stem and progenitor cells (HSPCs) is a promising treatment for monogenic diseases. Here the authors report a systematic review and meta-analysis of available evidence assessing clinical outcomes of HSPC gene therapy from clinical trials.
- Francesca Tucci
- , Stefania Galimberti
- & Alessandro Aiuti
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Article
| Open AccessComprehensive 3D epigenomic maps define limbal stem/progenitor cell function and identity
Genome topology provides a structural basis for epigenome-mediated transcriptional regulation in eukaryotes. Here the authors characterized the 3D genome of stratified squamous epithelia. They generated a Hi-C map of human limbal stem/progenitor cells (LSCs) and integrated these data with epigenomics, transcription factor binding maps, and transcriptome data.
- Mingsen Li
- , Huaxing Huang
- & Hong Ouyang
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Article
| Open AccessA comprehensive temporal patterning gene network in Drosophila medulla neuroblasts revealed by single-cell RNA sequencing
During development, neural progenitors generate a variety of neural types sequentially. Here the authors examine gene expression patterns in Drosophila neural progenitors at single-cell level, and identify a gene regulatory network controlling the sequential generation of different neural types.
- Hailun Zhu
- , Sihai Dave Zhao
- & Xin Li
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