Featured
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| Open AccessLimb reduction in an Esco2 cohesinopathy mouse model is mediated by p53-dependent apoptosis and vascular disruption
Roberts syndrome (RBS) is an autosomal recessive disorder with profound growth deficiency and limb reduction caused by ESCO2 loss-of-function variants. Here, the authors show that the pathogenesis of limb reduction in an Esco2 cohesinopathy mouse model of Roberts syndrome has an underlying vascular etiology that is mediated by p53-signaling, sharing commonality with thalidomide embryopathy.
- Arielle S. Strasser
- , Ana Silvia Gonzalez-Reiche
- & Ethylin Wang Jabs
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Article
| Open AccessA male mouse model for metabolic dysfunction-associated steatotic liver disease and hepatocellular carcinoma
Metabolic dysfunction-associated steatotic liver disease (MASLD) characterizes a spectrum of liver disorders initiated by hepatic lipid accumulation associated with metabolic syndrome. Here, the authors generate a mouse model that recapitulates the main histopathologic, transcriptomics, and metabolic alterations observed in MASLD patients.
- Byung-Kwan Jeong
- , Won-Il Choi
- & Hail Kim
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Article
| Open AccessTherapeutic strategy for spinal muscular atrophy by combining gene supplementation and genome editing
Spinal muscular atrophy (SMA) is caused by a defect in the SMN1 gene, leading to muscle weakness and motor neuron loss. Here, the authors show that combining CRISPR-Cas9 genome editing with gene supplementation improves survival and motor function in SMA mice, highlighting a potential new treatment avenue.
- Fumiyuki Hatanaka
- , Keiichiro Suzuki
- & Juan Carlos Izpisua Belmonte
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| Open AccessEfficient and reproducible generation of human iPSC-derived cardiomyocytes and cardiac organoids in stirred suspension systems
Human iPSC-CMs are invaluable for cardiac disease modeling and regeneration. Here, authors developed an optimized suspension culture protocol to efficiently and reproducibly differentiate hiPSCs into cardiomyocytes and cardiac organoids.
- Maksymilian Prondzynski
- , Paul Berkson
- & William T. Pu
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Article
| Open AccessGenetic diversity of 1,845 rhesus macaques improves genetic variation interpretation and identifies disease models
This study on the genetic diversity of 1,845 rhesus macaques improves genetic variation interpretation and identifies macaque models for inherited human retinal and neurodevelopment diseases.
- Jun Wang
- , Meng Wang
- & Rui Chen
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Article
| Open AccessRecreating the biological steps of viral infection on a cell-free bioelectronic platform to profile viral variants of concern
Screening platforms for rapid detection of infectious viruses are needed for diagnostic and therapeutic development. Here, authors present a bioelectronic platform that detects the entry processes of infectious viruses within minutes and differentiates the relative fusogenicities of viral variants.
- Zhongmou Chao
- , Ekaterina Selivanovitch
- & Susan Daniel
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| Open AccessTracking single hiPSC-derived cardiomyocyte contractile function using CONTRAX an efficient pipeline for traction force measurement
Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) are powerful in vitro models. Here the authors report CONTRAX, an open-access, versatile, and streamlined pipeline for quantitative tracking of the contractile dynamics of single hiPSC-CMs over time at increased throughput.
- Gaspard Pardon
- , Alison S. Vander Roest
- & Beth L. Pruitt
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Article
| Open AccessRed2Flpe-SCON: a versatile, multicolor strategy for generating mosaic conditional knockout mice
Inducible genetic mosaics can provide information about cellular lineages that are otherwise difficult to obtain. Here the authors report a mosaic knockout system called Red2Flpe-SCON, which allows lineage tracing of wild-type and mutant cells using a multicolour fluorescent reporter in mice.
- Szu-Hsien Sam Wu
- , Somi Kim
- & Bon-Kyoung Koo
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Article
| Open AccessEvolution of connectivity architecture in the Drosophila mushroom body
Brain evolution at the cellular level is understudied. Here, the authors compare olfactory circuits from three Drosophila species, finding species-specific connectivity patterns associated with food odours and suggesting that more connectivity may be related to learning performance.
- Kaitlyn Elizabeth Ellis
- , Sven Bervoets
- & Sophie Jeanne Cécile Caron
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Article
| Open AccessOrthogonal proteogenomic analysis identifies the druggable PA2G4-MYC axis in 3q26 AML
The overexpression of the ecotropic viral integration site-1 gene (EVI1/MECOM) marks the most lethal acute myeloid leukemia subgroup carrying 3q26 abnormalities. Here, pan-histone deacetylase inhibitors are identified as potent repressors of EVI1 and PA2G4 as a druggable target.
- Matteo Marchesini
- , Andrea Gherli
- & Giovanni Roti
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Article
| Open AccessLSD1 drives intestinal epithelial maturation and controls small intestinal immune cell composition independent of microbiota in a murine model
Post birth the gastrointestinal tract undergoes development including the establishment of the microbiome, establishment of tolerance and maturation of the epithelium. Here the authors show a histone demethylase LSD1 is required for postnatal intestinal epithelium maturation and how this impacts local immune cell composition and gut homeostasis.
- Alberto Díez-Sánchez
- , Håvard T. Lindholm
- & Menno J. Oudhoff
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Article
| Open AccessProjective light-sheet microscopy with flexible parameter selection
Projection imaging for multi-cellular samples can be hindered by several factors, including low contrast. Here, the authors propose projective light-sheet imaging with parameter selection (props) of imaging depth, position and viewing angle.
- Bingying Chen
- , Bo-Jui Chang
- & Reto Fiolka
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Article
| Open AccessVersatile human cardiac tissues engineered with perfusable heart extracellular microenvironment for biomedical applications
The application of engineered cardiac tissues is limited due to their immaturity and lack of functionality. Here, the authors develop an integrated culture platform featuring heart extracellular matrix cultured in a microfluidic chip to facilitate cardiac tissue development for versatile biomedical applications.
- Sungjin Min
- , Suran Kim
- & Seung-Woo Cho
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Article
| Open AccessTissue engineered vascular grafts are resistant to the formation of dystrophic calcification
Advancements in congenital heart surgery stress the need for durable biomaterials. Here, the authors compare tissue-engineered vascular grafts (TEVGs) with traditional polytetrafluoroethylene grafts, revealing TEVGs’ superior durability and reduced calcification, promising improved long-term success for surgeries.
- Mackenzie E. Turner
- , Kevin M. Blum
- & Christopher K. Breuer
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Article
| Open AccessArticular surface interactions distinguish dinosaurian locomotor joint poses
Criteria for evaluating joint articulation in vertebrates are lacking. Here, the authors propose an approach for combining measurements of 3D articular overlap, symmetry, and congruence into a single metric, and apply this to examine the walking stride of Deinonychus antirrhopus.
- Armita R. Manafzadeh
- , Stephen M. Gatesy
- & Bhart-Anjan S. Bhullar
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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 AccessHuman apical-out nasal organoids reveal an essential role of matrix metalloproteinases in airway epithelial differentiation
Airway organoids made in Matrigel are in basal-out orientation. Here, authors present apical-out nasal organoids using a biochemically defined hydrogel system, revealing that matrix metalloproteinases are required for normal epithelial development.
- Liyue Li
- , Linyi Jiao
- & Chunwei Li
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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 AccessIdentification of gene function based on models capturing natural variability of Arabidopsis thaliana lipid metabolism
The use of automated tools to reconstruct lipid metabolic pathways is not warranted in plants. Here, the authors construct Plant Lipid Module for Arabidopsis rosette using constraint-based modeling, demonstrate its integration in other plant metabolic models, and use it to dissect the genetic architecture of lipid metabolism.
- Sandra Correa Córdoba
- , Hao Tong
- & Zoran Nikoloski
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Article
| Open AccessA synthetic metastatic niche reveals antitumor neutrophils drive breast cancer metastatic dormancy in the lungs
3D scaffolds can be used to recapitulate key aspects of the microenvironment of primary tumors and metastatic organs. Here the authors use subcutaneous porous 3D scaffold implants as a tool to study the immune signals in the lungs of metastatic breast cancer, revealing multifaceted roles of neutrophils in regulating lung metastasis.
- Jing Wang
- , Ramon Ocadiz-Ruiz
- & Lonnie D. Shea
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| Open AccessSpatially controlled construction of assembloids using bioprinting
Bioprinting has potential in the biofabrication of three dimensional tissues, but is poorly suited to the manipulation of neural organoids. Here, the authors develop a bioprinting platform to allow the arrangement of organoids to form assembloids.
- Julien G. Roth
- , Lucia G. Brunel
- & Sarah C. Heilshorn
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| Open AccessProfiling of basal and ligand-dependent GPCR activities by means of a polyvalent cell-based high-throughput platform
Interrogating the dynamic and functionally diverse signaling of GPCRs requires comprehensive cellular tools. Here Zeghal et al. develop Tango-Trio, a screening platform capable of profiling basal and drug-activated activities at hundreds of GPCRs.
- Manel Zeghal
- , Geneviève Laroche
- & Patrick M. Giguère
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| Open AccessThe long non-coding RNA NEAT1 is a ΔNp63 target gene modulating epidermal differentiation
The transcription factor ΔNp63 is a master regulator of epithelial development and integrity of stratified epithelial tissues. Here, the authors unveiled the lncRNA NEAT1 as an additional player of the highly complex regulatory network by which ΔNp63 controls epidermal homeostasis.
- Claudia Fierro
- , Veronica Gatti
- & Angelo Peschiaroli
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Article
| Open AccessTargeted viral adaptation generates a simian-tropic hepatitis B virus that infects marmoset cells
Hepatitis B virus is an almost uniquely human-tropic pathogen for which model systems are scarce. Here, the authors determine key residues within the HBV receptor that form a barrier in the HBV life cycle in primates and identify marmosets as a model candidate for infection with simian-tropic HBV.
- Yongzhen Liu
- , Thomas R. Cafiero
- & Alexander Ploss
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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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| Open AccessA previously uncharacterized Factor Associated with Metabolism and Energy (FAME/C14orf105/CCDC198/1700011H14Rik) is related to evolutionary adaptation, energy balance, and kidney physiology
The human genome still contains numerous uncharacterized genes. Here, the authors identify a fast evolving Factor associated with Metabolism and Energy (FAME) that is associated with altered body weight, energy expenditure, and metabolism and study its function in knockout mouse models.
- Julian Petersen
- , Lukas Englmaier
- & Igor Adameyko
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Article
| Open AccessMuscle cell-type diversification is driven by bHLH transcription factor expansion and extensive effector gene duplications
Different muscle cell types account for specific abilities in animals, yet how their diversification arose remains unclear. Here, the authors show that gene duplications of bHLH transcription factors and effector genes contributed to the diversification of muscle cell types in the sea anemone Nematostella.
- Alison G. Cole
- , Stefan M. Jahnel
- & Ulrich Technau
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Article
| Open AccessReproducing extracellular matrix adverse remodelling of non-ST myocardial infarction in a large animal model
The study of the pathophysiology and possible interventions for non-ST-segment elevation myocardial infarction is hindered by the lack of a reproducible pre-clinical model. Here, authors develop an ovine model to reproduce post-ischemic remodeling in non-ST myocardial infarction and reveal distinct complex sugar moieties in cellular membranes and extracellular matrix patterns in infarcted tissue.
- Paolo Contessotto
- , Renza Spelat
- & Mark Da Costa
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Article
| Open AccessHBEGF-TNF induce a complex outer retinal pathology with photoreceptor cell extrusion in human organoids
Complex neuropathologies, like macular degeneration, are common but incompletely understood. Here the authors report a complex human retina pathology organoid model induced by HBEGF-TNF, causing PIEZO1-mediated photoreceptor degeneration by cell extrusion.
- Manuela Völkner
- , Felix Wagner
- & Mike O. Karl
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Article
| Open AccessLysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs
Tuberculosis is a major cause of mortality, and the rise of drug-resistant strains of Mycobacterium tuberculosis requires the urgent development of safe and effective treatments. In this work, the authors develop a compound against lysyl-tRNA synthetase, demonstrating on-target mechanism of action and efficacy in vivo.
- Simon R. Green
- , Susan H. Davis
- & Laura A. T. Cleghorn
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Article
| Open AccessTopical application of an irreversible small molecule inhibitor of lysyl oxidases ameliorates skin scarring and fibrosis
Scars are a significant problem caused by excess collagen in the skin. Here the authors develop a topical drug that reduces collagen stability and leads to improved scar appearance and stiffness in preclinical models.
- Nutan Chaudhari
- , Alison D. Findlay
- & Mark W. Fear
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| Open AccessFunctional neuronal circuitry and oscillatory dynamics in human brain organoids
Brain organoids replicate cellular organization found in the developing human brain. Here, the authors utilize microelectronics to map activity in brain organoids and assemble functional circuits that mirror complexity found in brain networks in vivo.
- Tal Sharf
- , Tjitse van der Molen
- & Kenneth S. Kosik
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Article
| Open AccessCell landscape of larval and adult Xenopus laevis at single-cell resolution
Single-cell RNA sequencing technology offers a unique opportunity to dissect cell heterogeneity of animals. Here, the authors construct a Xenopus cell landscape including larval and adult organs to dissect cell heterogeneity of the amphibian.
- Yuan Liao
- , Lifeng Ma
- & Xiaoping Han
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| Open AccessConstruction of the axolotl cell landscape using combinatorial hybridization sequencing at single-cell resolution
The Mexican axolotl is a well-established tetrapod model for regeneration and development. Here the authors report a scRNA-seq method to profile neotenic, metamorphic and limb development stages, highlighting unique perturbation patterns of cell type-related gene expression throughout metamorphosis.
- Fang Ye
- , Guodong Zhang
- & Guoji Guo
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| Open AccessA reference single-cell regulomic and transcriptomic map of cynomolgus monkeys
Non-human primates are attractive laboratory animal models that can accurately reflect some developmental and pathological features of humans. Here the authors chart a reference cell map of cynomolgus monkeys using both scATAC-seq and scRNA-seq data across multiple organs, providing insights into the molecular dynamics and cellular heterogeneity of this organism.
- Jiao Qu
- , Fa Yang
- & Dijun Chen
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| Open AccessCyclic microchip assay for measurement of hundreds of functional proteins in single neurons
Current single-cell tools are limited by the number of proteins they can analyse. Here the authors report a single-cell cyclic multiplex in situ tagging (CycMIST) method for functional proteome profiling of single cells, allowing multiple rounds of multiplexing of the same single cells on a microchip.
- Liwei Yang
- , Avery Ball
- & Jun Wang
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Article
| Open AccessEnhanced BRAF engagement by NRAS mutants capable of promoting melanoma initiation
The factors that determine the distinct profiles of NRAS mutants across different tumor types remain unclear. Here, the authors use an allelic series of conditional mouse models to investigate the molecular mechanisms underlying the enrichment of specific NRAS mutants in human melanoma
- Brandon M. Murphy
- , Elizabeth M. Terrell
- & Christin E. Burd
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Article
| Open AccessNeuroligin-mediated neurodevelopmental defects are induced by mitochondrial dysfunction and prevented by lutein in C. elegans
Mitochondrial deficiency causes rare incurable disorders. Here, the authors use C. elegans to study these diseases and find that the natural compound lutein prevents neurodevelopmental deficits, thus pointing to a possible therapeutic target for the human diseases.
- Silvia Maglioni
- , Alfonso Schiavi
- & Natascia Ventura
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Article
| Open AccessProtective effect of platinum nano-antioxidant and nitric oxide against hepatic ischemia-reperfusion injury
Pharmacological interventions against hepatic ischemia-reperfusion injury remain limited. Here, the authors provide a nanotherapeutics-based solution combining reactive oxygen species scavenging and nitric oxide modulation.
- Jing Mu
- , Chunxiao Li
- & Xiaoyuan Chen
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Article
| Open AccessMultidimensional chromatin profiling of zebrafish pancreas to uncover and investigate disease-relevant enhancers
Alterations in cis-regulatory elements (CREs) can contribute to pancreatic diseases. Here the authors combine chromatin profiling and interaction points with in vivo reporter assays in zebrafish to uncover functionally equivalent human CREs, helping to predict disease-relevant enhancers.
- Renata Bordeira-Carriço
- , Joana Teixeira
- & José Bessa
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Article
| Open AccessA microphysiological model of human trophoblast invasion during implantation
Normal and abnormal pregnancy is challenging to study and involves complex interactions between maternal and fetal cells. Here the authors present an implantation-on-a-chip device capable of modeling trophoblast invasion, a process critical to the establishment of pregnancy.
- Ju Young Park
- , Sneha Mani
- & Dan Dongeun Huh
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Article
| Open AccessCell-specific alterations in Pitx1 regulatory landscape activation caused by the loss of a single enhancer
Developmental genes are frequently controlled by multiple enhancers sharing similar specificities, so deletions of such regulatory elements often fail to reveal their full function. Here the authors use the Pitx1 testbed locus to characterize the regulatory and cellular identity alterations following the deletion in vivo of one of its enhancers.
- Raquel Rouco
- , Olimpia Bompadre
- & Guillaume Andrey
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Article
| Open AccessA tissue-bioengineering strategy for modeling rare human kidney diseases in vivo
The lack of animal models for some human diseases precludes our understanding of disease mechanisms and our ability to test new therapies in vivo. Here the authors present a tissue bioengineering strategy for the study of a rare kidney tumor called angiomyolipoma, in vitro and in vivo, using patient-derived hiPSCs.
- J. O. R. Hernandez
- , X. Wang
- & D. R. Lemos
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Article
| Open AccessEngineered osteoclasts as living treatment materials for heterotopic ossification therapy
Heterotopic ossification (HO) is the formation of pathological mature bone within extraskeletal soft tissues, and there are currently no reliable methods for removing these calcified plaques. Here, the authors demonstrate that chemically engineered osteoclasts coated with tetracycline can improve their targeting capacity to ectopic calcifications, which extends their bone resorption functions for the treatment of HO.
- Wenjing Jin
- , Xianfeng Lin
- & Ruikang Tang
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Article
| Open AccessSpatially resolved transcriptomics reveals the architecture of the tumor-microenvironment interface
During tumor progression, cancer cells contact different neighboring cell types, but it is unclear how these interactions affect cancer cell behavior. Here, the authors use spatially resolved transcriptomics and single-cell RNA-seq to study the role of cilia at the tumormicroenvironment interface.
- Miranda V. Hunter
- , Reuben Moncada
- & Richard M. White
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Article
| Open AccessPhysiologic biomechanics enhance reproducible contractile development in a stem cell derived cardiac muscle platform
Investigations of human cardiac disease involving human pluripotent stem cell-derived cardiomyocytes are limited by the disorganized presentation of biomechanical cues resulting in cell immaturity. Here the authors develop a platform of micron-scale 2D cardiac muscle bundles to precisely deliver physiologic cues, improving reproducibility and throughput.
- Yao-Chang Tsan
- , Samuel J. DePalma
- & Adam S. Helms
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Article
| Open AccessMeasuring kinetics and metastatic propensity of CTCs by blood exchange between mice
Current methods for acquiring dissemination kinetics of rare circulating tumor cells (CTCs) that form metastases have several limitations. Here, the authors show an approach for measuring endogenous CTC kinetics by continuously exchanging CTC-containing blood between un-anesthetized, tumor-bearing mice and healthy, tumor-free counterparts.
- Bashar Hamza
- , Alex B. Miller
- & Scott R. Manalis
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Article
| Open AccessSelf-assembling human heart organoids for the modeling of cardiac development and congenital heart disease
There is a pressing need to develop representative organ-like platforms recapitulating complex in vivo phenotypes to study human development and disease in vitro. Here the authors present a method to generate human heart organoids by self-assembly using pluripotent stem cells, compare these to age-matched fetal cardiac tissues and recreate a model of pregestational diabetes.
- Yonatan R. Lewis-Israeli
- , Aaron H. Wasserman
- & Aitor Aguirre
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Article
| Open AccessBioengineered embryoids mimic post-implantation development in vitro
Previous approaches to derive embryoids either lack physiological morphology and signaling interactions, or are unconducive to model post-gastrulation development. Here the authors use a high-throughput approach to induce mouse embryonic stem cells into epiblast-like aggregates, which are then co-cultured with mouse trophoblast stem cell aggregates, to yield embryoids with axial morphogenesis and anterior development.
- Mehmet U. Girgin
- , Nicolas Broguiere
- & Matthias P. Lutolf