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| Open AccessComplex regulatory networks influence pluripotent cell state transitions in human iPSCs
Stem cells exist in vitro in a spectrum of interconvertible pluripotent states. Here, authors show that pluripotency and self-renewal processes have a high level of regulatory complexity and suggest that genetic factors contribute to cell state transitions in human iPSC lines.
- Timothy D. Arthur
- , Jennifer P. Nguyen
- & Kelly A. Frazer
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Article
| Open AccessCis inhibition of NOTCH1 through JAGGED1 sustains embryonic hematopoietic stem cell fate
Notch signaling is critical for HSC emergence. Here, the authors identify a sub-set of hemogenic endothelial cells with high Notch activity that it is gradually shut down through cis inhibition of NOTCH1 by JAG1, and report that this process sustains HSC.
- Roshana Thambyrajah
- , Maria Maqueda
- & Anna Bigas
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| Open AccessTime-integrated BMP signaling determines fate in a stem cell model for early human development
The interpretation of the key developmental signal BMP remains poorly understood. Here, the authors show that the total time-integrated signaling controls differentiation in a stem cell embryo model and provide a possible mechanism.
- Seth Teague
- , Gillian Primavera
- & Idse Heemskerk
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Article
| Open AccessA microfluidic platform integrating functional vascularized organoids-on-chip
Vascularization remains a significant challenge in organoid technology. Here, the authors develop a microfluidic platform that enhances organoid growth, function and maturation, by establishing functional perfusable vascular networks.
- Clément Quintard
- , Emily Tubbs
- & Xavier Gidrol
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Article
| Open AccessMosquito midgut stem cell cellular defense response limits Plasmodium parasite infection
Here, the authors study the cellular response of midgut progenitors in Anopheles stephensi to Plasmodium berghei infection. They show that midgut stem cells are able to detect Plasmodium oocysts and eliminate them in a Jak/STAT pathway dependent manner.
- Ana-Beatriz F. Barletta
- , Jamie C. Smith
- & Carolina Barillas-Mury
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Article
| Open AccessNeurofibromin 1 controls metabolic balance and Notch-dependent quiescence of murine juvenile myogenic progenitors
The establishment of the postnatal skeletal muscle stem cell pool is not well understood. Here the authors show a requirement for Nf1 to coordinate muscle fiber growth and stem cell quiescence induction, and to prevent detrimental metabolic reprogramming with life-long consequences.
- Xiaoyan Wei
- , Angelos Rigopoulos
- & Sigmar Stricker
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Article
| Open AccessIn 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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| Open AccessThe 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
| Open AccessDynamic nucleolar phase separation influenced by non-canonical function of LIN28A instructs pluripotent stem cell fate decisions
The role of nucleolar phase separation in stem cell fate decision is not well understood. Here, the authors show that the nucleolus-localized LIN28A protein undergoes LLPS in mESCs and in vitro, and that pluripotency state conversion depends on this phase separation capacity.
- Tianyu Tan
- , Bo Gao
- & Jin Zhang
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Article
| Open AccessTrophoblast 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
| Open AccessDiffusible fraction of niche BMP ligand safeguards stem-cell differentiation
The activity of Drosophila male germline stem cells is tightly regulated by a cluster of somatic niche cells. Here they find that Dpp induces opposed cellular responses in stem cells versus in differentiating descendants, thereby ensuring spatial control of the niche with a single factor.
- Sharif M. Ridwan
- , Autumn Twillie
- & Mayu Inaba
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Article
| Open AccessChemically-defined and scalable culture system for intestinal stem cells derived from human intestinal organoids
Challenges in reproducibility and large-scale expansion limit the current applicability of human intestinal organoids. Here, the authors present a feeder-free, chemically-defined culture method for enrichment of intestinal stem cells isolated from 3D human intestinal organoids.
- Ohman Kwon
- , Hana Lee
- & Mi-Young Son
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Article
| Open AccessSexual dimorphism in melanocyte stem cell behavior reveals combinational therapeutic strategies for cutaneous repigmentation
Vitiligo is an autoimmune condition that results in skin depigmentation due to melanocyte loss, but the root causes are not well understood. Here they identify sexual dimorphism in melanocyte stem cells behavior arising from distinct skin inflammatory responses, and propose Prostaglandin E2 as a potential therapy for depigmentation conditions.
- Luye An
- , Dahihm Kim
- & Andrew C. White
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Article
| Open AccessLNP-RNA-engineered adipose stem cells for accelerated diabetic wound healing
Adipose stem cells are promising therapeutic agents in tissue regeneration. Here the authors develop a lipid nanoparticle/RNA engineering platform to enhance the protein production of these cells, which demonstrate superior healing efficacy in a mouse model of diabetic cutaneous wounds.
- Yonger Xue
- , Yuebao Zhang
- & Yizhou Dong
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Article
| Open AccessSelf-renewing human naïve pluripotent stem cells dedifferentiate in 3D culture and form blastoids spontaneously
Blastoids are emerging models for early embryo development exploration in vitro. Here, authors found self-renewing human naïve PSCs spontaneously and efficiently give rise to blastoids upon three-dimensional suspension culture.
- Mingyue Guo
- , Jinyi Wu
- & José C. R. Silva
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Article
| Open AccessSox9 regulates alternative splicing and pancreatic beta cell function
Sox9 is a well-known transcriptional regulator of embryonic pancreas and endocrine cell development. Here, the authors show that loss of Sox9 in mature beta cells disrupts alternative splicing patterns and impairs insulin secretion, with significant implications for cellular function.
- Sapna Puri
- , Hasna Maachi
- & Matthias Hebrok
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Article
| Open AccessVGLL1 cooperates with TEAD4 to control human trophectoderm lineage specification
Authors report that VGLL1 regulates cell fate determination and self-renewal of human pluripotent stem cell-derived trophectoderm-like cells and trophoblast stem cells via modulation of chromatin accessibility in cooperation with TEAD4.
- Yueli Yang
- , Wenqi Jia
- & Wenjuan Li
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Article
| Open AccessNAD+ dependent UPRmt activation underlies intestinal aging caused by mitochondrial DNA mutations
How age-accumulated mtDNA mutations in the small intestine modulate intestinal homeostasis is unclear. Here, the authors show that increased mtDNA mutation burden triggers an ATF5 dependent UPRmt by NAD+ depletion, and thus regulates intestinal aging through impaired Wnt/β-catenin signaling.
- Liang Yang
- , Zifeng Ruan
- & Xingguo Liu
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Article
| Open AccessIncreased 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
| Open AccessHigh-dimensional phenotyping to define the genetic basis of cellular morphology
Characterizing how genetic variation impacts cell morphology can provide an important links between disease association and cellular function. Here the authors identified the morphological impacts of genomic variants by generating high-throughput morphological profiling and whole genome sequencing data on iPSCs from 297 donors.
- Matthew Tegtmeyer
- , Jatin Arora
- & Soumya Raychaudhuri
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| Open AccessDrosophila activins adapt gut size to food intake and promote regenerative growth
While activins are critical regulators of early development, their role in maintaining adult tissue homeostasis remains obscure. Here the authors explore the role of activins in promoting intestinal regeneration and nutrient-dependent gut resizing in Drosophila.
- Christian F. Christensen
- , Quentin Laurichesse
- & Ditte S. Andersen
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| Open AccessThe single-cell transcriptomic atlas and RORA-mediated 3D epigenomic remodeling in driving corneal epithelial differentiation
Ocular homeostasis and vision depend on the differentiation of limbal stem/progenitor cells into corneal epithelial cells. Here, the authors report transcriptional dynamics and RORA-mediated epigenetic remodeling underlying the differentiation of human corneal epithelium.
- Mingsen Li
- , Huizhen Guo
- & Hong Ouyang
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Article
| Open AccessNlrc3 signaling is indispensable for hematopoietic stem cell emergence via Notch signaling in vertebrates
The emergence of hematopoietic stem and progenitor cells is finely tuned by a variety of signaling pathways. Here, the authors find that Nlrc3 is highly expressed during hematopoietic differentiation in vivo and in vitro, activates the Notch pathway, and acts downstream of NF-kB signaling.
- Shuyang Cai
- , Honghu Li
- & He Huang
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Article
| Open AccessDerivation of human primordial germ cell-like cells in an embryonic-like culture
Derivation of human primordial germ cell-like cells (hPGCLCs) is critical for reproductive medicine. Here, authors report the induction of hPGCLCs in a bioengineered human pluripotent stem cell culture that mimics peri-implantation human development.
- Sajedeh Nasr Esfahani
- , Yi Zheng
- & Jianping Fu
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Article
| Open AccessMcam inhibits macrophage-mediated development of mammary gland through non-canonical Wnt signaling
Mammary epithelial cells act to continuously renew the mammary tissue and must balance differentiation and self-renewal. Here they show that Mcam, a non-canonical Wnt pathway member, regulates communication between macrophages and mammary epithelial cells, thereby maintaining self-renewal and subsequently promoting mammary ductal morphogenesis.
- Xing Yang
- , Haibo Xu
- & Baowei Jiao
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Article
| Open AccessCultured 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
| Open Accessp53 suppresses MHC class II presentation by intestinal epithelium to protect against radiation-induced gastrointestinal syndrome
Radiation induced gastrointestinal syndrome is a complication of radiotherapy and the tumor suppressor p53 is implicated in protection from gastrointestinal toxicity. Here Wang and colleagues show that p53 protection against radiation-induced gastrointestinal syndrome involves intestinal stem cell function and inhibition of inflammation triggered by radiation via the IL12- p40/MHC-II axis.
- Jianming Wang
- , Chun-Yuan Chang
- & Wenwei Hu
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Article
| Open AccessRole of UPF1-LIN28A interaction during early differentiation of pluripotent stem cells
UPF1 and LIN28A are RNA-binding proteins involved in post-transcriptional regulation and cell differentiation. Here, authors report that they interact with each other via specific domains and regulate ectodermal specialization of human pluripotent stem cells.
- Seungwon Jung
- , Seung Hwan Ko
- & Jungwook Hwang
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Article
| Open AccessUnique adipose tissue invariant natural killer T cell subpopulations control adipocyte turnover in mice
Invariant natural killer T (iNKT) cells have recently been reported to play a key role in adipose tissue homeostasis. Here, the authors show that adipose tissue iNKT cells mediate immune responses that control adipocyte turnover in mice.
- Sang Mun Han
- , Eun Seo Park
- & Jae Bum Kim
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Article
| Open AccessReassessing endothelial-to-mesenchymal transition in mouse bone marrow: insights from lineage tracing models
Endothelial cells (ECs) and bone marrow stromal cells (BMSCs) support hematopoiesis and hematopoietic regeneration. Whether ECs are a source of BMSCs remains unclear. Here, using lineage tracing models the authors show that ECs are not a source of BMSCs during homeostasis and regeneration.
- Jia Cao
- , Ling Jin
- & Hui Xie
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Article
| Open AccessAdult stem cell activity in naked mole rats for long-term tissue maintenance
Authors report that long-term intestinal tissue maintenance in naked mole rats is achieved by having an expanded pool of slow-dividing adult stem cells while a higher proportion of differentiated cells confer enhanced function and protection to the intestinal mucosa.
- Shamir Montazid
- , Sheila Bandyopadhyay
- & Shazia Irshad
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Article
| Open AccessCommon and divergent gene regulatory networks control injury-induced and developmental neurogenesis in zebrafish retina
The molecular mechanisms controlling injury-dependent neuronal regeneration are largely unknown. Here, the authors use integrated multiomic analysis to characterize gene regulatory networks controlling injury-induced neurogenesis in zebrafish retina
- Pin Lyu
- , Maria Iribarne
- & Seth Blackshaw
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Article
| Open AccessEfficient 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
| Open AccessAlveolar epithelial progenitor cells require Nkx2-1 to maintain progenitor-specific epigenomic state during lung homeostasis and regeneration
Alveolar epithelial progenitors in the lungs can regenerate the epithelial surface after acute injury. Here they generate lung organoids that can be used to study lung regeneration after injury and identify Nkx2-1 as a key regulator of alveolar progenitor activation.
- Andrea Toth
- , Paranthaman Kannan
- & William J. Zacharias
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Article
| Open AccessEssential 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
| Open AccessDPPIV+ fibro-adipogenic progenitors form the niche of adult skeletal muscle self-renewing resident macrophages
Although macrophages infiltrating the skeletal muscles are known to be important in muscle growth and repair, much less is known about muscle-resident macrophages. Here, the authors identify a fibro-adipogenic progenitor niche involved in the maintenance of skeletal muscle-resident macrophages.
- Farshad Babaeijandaghi
- , Nasim Kajabadi
- & Fabio M. V. Rossi
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Article
| Open AccessA patterned human primitive heart organoid model generated by pluripotent stem cell self-organization
Pluripotent stem cell-derived organoids can recapitulate significant hallmarks of human organ development and are becoming critical tools for human research. Here, the authors report significant technical steps for generating sophisticated synthetic human primitive heart organoids.
- Brett Volmert
- , Artem Kiselev
- & Aitor Aguirre
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| Open AccessModeling cardiac fibroblast heterogeneity from human pluripotent stem cell-derived epicardial cells
Cardiac fibroblasts play an essential role in heart development. Here Fernandes et al. describe a human pluripotent stem cell-derived epicardial organoid system to investigate the role of fibroblasts in cardiovascular development and disease.
- Ian Fernandes
- , Shunsuke Funakoshi
- & Gordon Keller
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Article
| Open AccessRAAS-deficient organoids indicate delayed angiogenesis as a possible cause for autosomal recessive renal tubular dysgenesis
Autosomal Recessive Renal Tubular Dysgenesis (AR-RTD) arises from mutations in Angiotensin II sensing genes, but how they impact the kidney was unclear. This study reveals that delayed angiogenesis at a critical developmental window underlies AR-RTD.
- Naomi Pode-Shakked
- , Megan Slack
- & Raphael Kopan
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Article
| Open AccessGeneration of three-dimensional meat-like tissue from stable pig epiblast stem cells
Cultured meat technology promises to alleviate protein shortages, but still faces many challenges. Here, the authors achieve serum-free myogenic differentiation of porcine pre-gastrulation epiblast stem cells and generate meat-like tissue via edible plant-based scaffolds without any animal compounds.
- Gaoxiang Zhu
- , Dengfeng Gao
- & Jianyong Han
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Article
| Open AccessClonal hematopoiesis related TET2 loss-of-function impedes IL1β-mediated epigenetic reprogramming in hematopoietic stem and progenitor cells
The expansion of cells with TET2 mutations within the blood is associated with increased risk for all-cause mortality, development of leukemia and cardiovascular disease. Here authors show IL1 promotes the clonal expansion TET2 knockout cells, enhancing their self-renewal, promoting their myeloid bias and impairing an IL1 driven loss of methylation at lymphoid and erythroid regulatory elements.
- J. McClatchy
- , R. Strogantsev
- & A. Agarwal
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Article
| Open AccessEnhanced 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
| Open AccessRole of PDGFRA+ cells and a CD55+ PDGFRALo fraction in the gastric mesenchymal niche
Digestive epithelia self-renew or differentiate in response to mesenchymal cues. Manieri et al. characterize gastric corpus and antral mesenchyme separately and identify PDGFRALo CD55+ cells as those selectively supporting epithelial growth in vitro.
- Elisa Manieri
- , Guodong Tie
- & Ramesh A. Shivdasani
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Article
| Open AccessThe SPOC proteins DIDO3 and PHF3 co-regulate gene expression and neuronal differentiation
Death-inducer obliterator 3 (DIDO3) and PHD finger protein 3 (PHF3) are paralogue proteins that regulate transcription elongation by docking onto phosphorylated serine-2 in the C-terminal domain (CTD) of Pol II through their SPOC domains. Here the authors characterize the interplay of these proteins and show that they coregulate neuronal target genes.
- Johannes Benedum
- , Vedran Franke
- & Dea Slade
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Article
| Open AccessSPINK1-induced tumor plasticity provides a therapeutic window for chemotherapy in hepatocellular carcinoma
In liver cancer, the presence of tumour-initiating cell subsets are associated with poorer prognosis and chemotherapy resistance in liver cancer. Here, the authors show that upon treatment with 5-FU or cisplatin, this subset releases SPINK1 which binds EGFR, activating the ERK-CDK4/6-E2F2 signaling cascade and resulting in chemoresistance.
- Ki-Fong Man
- , Lei Zhou
- & Stephanie Ma
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Article
| Open AccessTemporal morphogen gradient-driven neural induction shapes single expanded neuroepithelium brain organoids with enhanced cortical identity
PSC-brain organoids are typically formed by static medium switches. Here, authors show that a temporal morphogen gradient during neural induction allows the formation of well-specified cortical organoids with a self-organized single neuroepithelium.
- Anna Pagliaro
- , Roxy Finger
- & Benedetta Artegiani
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Article
| Open AccessAutophagy drives the conversion of developmental neural stem cells to the adult quiescent state
Neural stem cells in the adult mammalian brain derive from proliferating precursors that are spared as dormant reservoirs during development. Here, the authors show that autophagy is required for neural stem cells to transition to the adult quiescent state.
- Isabel Calatayud-Baselga
- , Lucía Casares-Crespo
- & Helena Mira
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Article
| Open AccessA reversible state of hypometabolism in a human cellular model of sporadic Parkinson’s disease
Mitochondrial dysfunction is a contributing factor in Parkinson’s disease. Here the authors carry out a multilayered omics analysis of Parkinson’s disease patient-derived neuronal cells, which reveals a reversible hypometabolism mediated by α-ketoglutarate dehydrogenase deficiency, which is correlated with disease progression in the donating patients.
- Sebastian Schmidt
- , Constantin Stautner
- & Wolfgang Wurst
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Article
| Open AccessNod1-dependent NF-kB activation initiates hematopoietic stem cell specification in response to small Rho GTPases
The signals that enable endothelial cells to switch to hemogenic to generate hematopoietic stem cells are poorly understood. Here, the authors identify an intracellular sensor of pathogens as an inductive developmental cue that primes this switch.
- Xiaoyi Cheng
- , Radwa Barakat
- & Raquel Espin-Palazon
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