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Development of pathophysiologically relevant models of sickle cell disease and β-thalassemia for therapeutic studies
Sickle cell disease (SCD) and β-thalassemia (BT) are globally prevalent inherited blood disorders but, despite extensive research, no ex vivo system exists for SCD and BT. Here, the authors generate pathophysiologically relevant erythroid progenitor models of SCD and BT.
- Pragya Gupta
- , Sangam Giri Goswami
- & Sivaprakash Ramalingam
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Article
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In vitro induction of patterned branchial arch-like aggregate from human pluripotent stem cells
Early patterning of neural crest cells in the craniofacial primordium is important for its subsequent development. Here, authors establish in vitro model of branchial arch from human pluripotent stem cells for determining underlying mechanisms.
- Yusuke Seto
- , Ryoma Ogihara
- & Mototsugu Eiraku
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Article
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The transcriptional regulatory network modulating human trophoblast stem cells to extravillous trophoblast differentiation
Extravillous trophoblasts are pivotal in placental invasion and artery remodeling. Here the authors report stage-specific transcriptional regulators and their sequential roles in guiding proper trophoblast differentiation.
- Mijeong Kim
- , Yu Jin Jang
- & Jonghwan Kim
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Article
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Trophoblast stem cell-based organoid models of the human placental barrier
The placenta is a transient organ that regulates the fetal environment, but our understanding of placental barrier function has been hampered by the lack of in vitro models. Here they develop human placental organoids that resemble the placental villus and form an intact syncytiotrophoblast barrier when cultured in a column model.
- Takeshi Hori
- , Hiroaki Okae
- & Hirokazu Kaji
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Article
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Increased iron uptake by splenic hematopoietic stem cells promotes TET2-dependent erythroid regeneration
The cues guiding hematopoietic stem cells (HSCs) to regenerate specific cell types lost due to injury remain elusive. This study shows that iron instructs erythroid differentiation of HSCs during anemia in a Tet2-dependent manner.
- Yu-Jung Tseng
- , Yuki Kageyama
- & Daisuke Nakada
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Article
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Cultured meat with enriched organoleptic properties by regulating cell differentiation
Achieving organoleptic properties of conventional meat is important for cultured meat production. Here, the authors demonstrate that the texture, flavor, and nutritional content of cultured meat can be significantly enhanced by regulating cell differentiation inside hydrogel scaffolds.
- Milae Lee
- , Sohyeon Park
- & Jinkee Hong
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Article
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Efficient generation of a self-organizing neuromuscular junction model from human pluripotent stem cells
Here, Urzi et al. pioneered a 2D self-organizing neuromuscular junction (soNMJ) model from human pluripotent stem cells, with implications for neuromuscular disease modeling and drug screening approaches.
- Alessia Urzi
- , Ines Lahmann
- & Mina Gouti
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Article
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Essential transcription factors for induced neuron differentiation
Using integrative multi-omics and CRISPR knock-out of all ~1,900 transcription factors, the authors identify essential transcription factors required for Neurogenin-driven differentiation of human cortical neurons.
- Congyi Lu
- , Görkem Garipler
- & Neville E. Sanjana
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Article
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Enhanced production of mesencephalic dopaminergic neurons from lineage-restricted human undifferentiated stem cells
The differentiation of human pluripotent stem cells into dopaminergic neurons is challenging. Here, the authors developed lineage-restricted undifferentiated stem cells, which have an enhanced ability for differentiating into dopaminergic neurons.
- Muyesier Maimaitili
- , Muwan Chen
- & Mark Denham
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Article
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Metabolic regulation of proteome stability via N-terminal acetylation controls male germline stem cell differentiation and reproduction
How cellular metabolism is connected to differentiation remains poorly understood. Here the authors report a regulatory cascade in which circulating citrate regulates sperm production by controlling protein stability via a specific protein post-translational modification.
- Charlotte M. François
- , Thomas Pihl
- & Bruno Hudry
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Article
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A DEAD-box helicase drives the partitioning of a pro-differentiation NAB protein into nuclear foci
The mechanism of spatiotemporal gene regulation during animal development is a fundamental question in biology. Here the authors show that the DEAD-box helicase DDX-23 controls stem cell fate by driving the formation of NAB repressive transcriptional condensates.
- Akiko Doi
- , Gianmarco D. Suarez
- & H. Robert Horvitz
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Article
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Metabolic 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
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Placental 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
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Single-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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Dissecting 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
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Pluripotency-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
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Spatiotemporal 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
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The 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
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USP7 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
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The 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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Excessive 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
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Retinoic 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
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Zebrafish 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
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ZBTB12 is a molecular barrier to dedifferentiation in human pluripotent stem cells
The metastability of stem cells requires a mechanism for actively blocking dedifferentiation to achieve successful differentiation. Here the authors show that ZBTB12 serves as a molecular barrier to dedifferentiation by repressing a primate-specific retrotransposon, HERVH.
- Dasol Han
- , Guojing Liu
- & Jiwon Jang
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Article
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Epigenetic and transcriptional regulations prime cell fate before division during human pluripotent stem cell differentiation
Many stem cells exhibit cell division coupled to differentiation, though the changes occurring between consecutive cell divisions have been difficult to study. Here they use synchronized hPSC culture to show that production of transcription factors and epigenetic changes are linked with cell division timing.
- Pedro Madrigal
- , Siwei Deng
- & Siim Pauklin
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Epithelial disruption drives mesendoderm differentiation in human pluripotent stem cells by enabling TGF-β protein sensing
Fate specification in the mammalian epiblast rely on complex interactions between morphogens and tissue organization. Here, the authors highlight epithelial integrity as a key determinant of TGF-β activity and a mechanism guiding morphogen sensing and spatial cell fate change.
- Thomas Legier
- , Diane Rattier
- & Rosanna Dono
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Article
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Large-scale perfused tissues via synthetic 3D soft microfluidics
Bioengineering live tissues has remained challenging due to limited nutrient exchange in the growing tissues. Here, the authors have developed micro-perfused 2-photon printing of 3D microfluidics, to engineer large-scale, viable and functional neural and hepatic 3D tissues.
- Sergei Grebenyuk
- , Abdel Rahman Abdel Fattah
- & Adrian Ranga
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Perspective
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Molecular versatility during pluripotency progression
During development the embryo must balance lineage specification against the preservation of plasticity using a limited molecular toolkit. In this Perspective, the authors propose Molecular Versatility as a paradigm for grouping molecular mechanisms that are repurposed through development to exert distinct functions.
- Giacomo Furlan
- , Aurélia Huyghe
- & Fabrice Lavial
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Lamin A/C-dependent chromatin architecture safeguards naïve pluripotency to prevent aberrant cardiovascular cell fate and function
LMNA mutations cause severe heart dysfunction. Here the authors show that Lamin A/C plays a key role in 3D chromatin architecture in naïve pluripotent stem cells, which ensures proper cardiovascular cell fate and function, and shed light on the mechanisms involved in LMNA cardiomyopathies.
- Yinuo Wang
- , Adel Elsherbiny
- & Gergana Dobreva
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The type 1 diabetes gene TYK2 regulates β-cell development and its responses to interferon-α
The TYK2 gene is associated with development of type 1 diabetes. Here the authors show that TYK2 regulates β-cell development, but at the same time TYK2 inhibition in the islets prevents IFNα responses and enhances their survival against CD8+ T-cell cytotoxicity; representing a potent therapeutic target to halt T1D progression.
- Vikash Chandra
- , Hazem Ibrahim
- & Timo Otonkoski
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Article
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Enhanced metanephric specification to functional proximal tubule enables toxicity screening and infectious disease modelling in kidney organoids
Proximal nephron in pluripotent stem cell derived kidney organoids are immature with limited support for functional solute channels. Vanslambrouck et al report improved metanephric specification, generating enhanced kidney organoids with superior proximal tubules, spatially arranged nephrons, and applications for disease research, and drug screening.
- Jessica M. Vanslambrouck
- , Sean B. Wilson
- & Melissa H. Little
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Endothelial cell cycle state determines propensity for arterial-venous fate
During blood vessel development, endothelial cells become specified toward arterial or venous fates. Chavkin et al find that distinct endothelial cell cycle states provide windows of opportunity for the molecular induction of arterial or venous fate.
- Nicholas W. Chavkin
- , Gael Genet
- & Karen K. Hirschi
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A stem cell roadmap of ribosome heterogeneity reveals a function for RPL10A in mesoderm production
How ribosomes differ in composition and function to regulate gene expression is poorly understood. Here, the authors show that ribosome composition changes during stem cell differentiation and identify a ribosomal protein that regulates production of the mesoderm lineage.
- Naomi R. Genuth
- , Zhen Shi
- & Maria Barna
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Article
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devCellPy is a machine learning-enabled pipeline for automated annotation of complex multilayered single-cell transcriptomic data
A major informatic challenge in single cell RNA-sequencing analysis is the precise annotation of datasets where cells exhibit complex multilayered identities or transitory states. Here the authors present devCellPy, a Python-based package that enables the automated prediction of cell types across complex cellular hierarchies, species, and experimental systems with high accuracy, particularly for developmental scRNA-seq datasets.
- Francisco X. Galdos
- , Sidra Xu
- & Sean M. Wu
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Article
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Spatiotemporal single-cell regulatory atlas reveals neural crest lineage diversification and cellular function during tooth morphogenesis
The mechanisms that govern cell fate decisions of postmigratory cranial neural crest cells remain largely unknown. Here the authors present a spatiotemporal single-cell regulatory atlas tracking these cells’ dental lineage diversification.
- Junjun Jing
- , Jifan Feng
- & Yang Chai
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Article
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PCGF6 controls neuroectoderm specification of human pluripotent stem cells by activating SOX2 expression
Variant Polycomb complexes can have tissue-specific roles during development. Here they show that PCGF6 controls lineage-specification in human PSCs by promoting neuroectoderm differentiation and repressing mesendoderm differentiation via distinct downstream targets.
- Xianchun Lan
- , Song Ding
- & Wei Jiang
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Article
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CDK9 activity switch associated with AFF1 and HEXIM1 controls differentiation initiation from epidermal progenitors
Epidermal progenitors are poised for differentiation, which allows for continual balance of self-renewal and differentiation. Here they show that the Super Elongation Complex regulates this process through direct regulation of a set of rapid response genes that involves a CDK9 activity switch.
- Sarah M. Lloyd
- , Daniel B. Leon
- & Xiaomin Bao
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Article
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N6-methyladenosine modification-mediated mRNA metabolism is essential for human pancreatic lineage specification and islet organogenesis
Ma et al. profile the dynamic landscape of m6A during pancreatic differentiation, and identify ALKBH5 as an essential m6A regulator supporting pancreatic differentiation, indicating a role for m6A-mediated mRNA metabolism in cell-fate specification.
- Xiaojie Ma
- , Jie Cao
- & Saiyong Zhu
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Article
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Interchromosomal interaction of homologous Stat92E alleles regulates transcriptional switch during stem-cell differentiation
Asymmetric inheritance of organelles, proteins and RNAs occurs during stem cell division. Here the authors show the strength of pairing of homologous Stat92E loci, a stem cell-specific gene, changes immediately after the asymmetric division due to asymmetric inheritance of new histones to one of the daughter cells and is important for turning off gene expression in this cell as it differentiates.
- Matthew Antel
- , Romir Raj
- & Mayu Inaba
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Article
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TET1 dioxygenase is required for FOXA2-associated chromatin remodeling in pancreatic beta-cell differentiation
Here the authors show that TET1 is required for the generation of functional insulin-producing cells, FOXA2 physically interacts with TET1 and contributes to specific recruitment of TET1 to mediate chromatin opening at the regulatory elements of pancreatic lineage determinants.
- Jianfang Li
- , Xinwei Wu
- & Ruiyu Xie
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Article
| Open Access
Intestine-enriched apolipoprotein b orthologs are required for stem cell progeny differentiation and regeneration in planarians
Lipid metabolism regulates stem cell states and differentiation. Here, the authors demonstrate a requirement in planarians for Apolipoprotein B-mediated neutral lipid transport from intestinal stores to stem cells and their progeny during differentiation and whole-body regeneration.
- Lily L. Wong
- , Christina G. Bruxvoort
- & David J. Forsthoefel
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Article
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Transcription factor-driven coordination of cell cycle exit and lineage-specification in vivo during granulocytic differentiation
Here the authors show that differentiation of haematopoietic stem cells into mature blood cells is primed by cell type-specific transcription factors at the enhancer level during early differentiation, before they confere promoter-driven growth arrest, and activate post-mitotic terminal differentiation.
- Kim Theilgaard-Mönch
- , Sachin Pundhir
- & Bo T. Porse
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Article
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NANOG initiates epiblast fate through the coordination of pluripotency genes expression
Pluripotent epiblast cells segregate from primitive endoderm in the blastocyst inner cell mass (ICM). Here the authors show that mosaic epiblast differentiation during mouse and human preimplantation development initiates stochastically in ICM progenitors, independently of the FGF pathway, and requires NANOG activity
- Nicolas Allègre
- , Sabine Chauveau
- & Claire Chazaud
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Article
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Integrative 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 Access
Robust 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 Access
Regulation 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 Access
Periodic 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
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CHD7 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
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Human 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
Charting cellular differentiation trajectories with Ricci flow