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Versatile 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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| Open Access
Heterozygous missense variant in GLI2 impairs human endocrine pancreas development
Mutations in the Hedgehog signaling have not been previously associated to diabetes. Here, authors identify a missense variant of GLI2 in a family with early-onset diabetes and report an essential role of this gene during human iPSC-based pancreatic differentiation.
- Laura M. Mueller
- , Abigail Isaacson
- & Francesca M. Spagnoli
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Complex 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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A 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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High-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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Derivation 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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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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RAAS-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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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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A 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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C9orf72-ALS human iPSC microglia are pro-inflammatory and toxic to co-cultured motor neurons via MMP9
The role of microglia in amyotrophic lateral sclerosis (ALS) is unclear. Here, the authors show that iPSC microglia from C9orf72-ALS patients are toxic to motor neurons and identify microglial MMP9 as a potential therapeutic target.
- Björn F. Vahsen
- , Sumedha Nalluru
- & Kevin Talbot
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| Open Access
Human blood vessel organoids reveal a critical role for CTGF in maintaining microvascular integrity
The microvasculature is critical for delivery of oxygen and metabolites throughout tissues. Here they use human blood vessel organoids to show that CTGF is a critical paracrine regulator of microvascular integrity that can restore pericyte coverage and vessel structure.
- Sara G. Romeo
- , Ilaria Secco
- & Anna Zampetaki
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Modeling and therapeutic targeting of inflammation-induced hepatic insulin resistance using human iPSC-derived hepatocytes and macrophages
Hepatic insulin resistance is an established driver of type 2 diabetes but is difficult to model in vitro. Here researchers use co-culture of hepatocytes and macrophages derived from the same human iPSC line to show how inflammation disrupts insulin-mediated regulation of hepatic glucose metabolism and identify targets for therapy of hepatic insulin resistance.
- Marko Groeger
- , Koji Matsuo
- & Holger Willenbring
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Directed 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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A village in a dish model system for population-scale hiPSC studies
Village cultures, where multiple stem cell lines are cultured in a single dish, provide an elegant solution for population-scale studies. Here, authors show the utility of village models – showing that expression heterogeneity is largely a result of line-specific effects and not village cultures.
- Drew R. Neavin
- , Angela M. Steinmann
- & Joseph E. Powell
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Transcriptomics of Hirschsprung disease patient-derived enteric neural crest cells reveals a role for oxidative phosphorylation
Hirschsprung disease is caused by defects in enteric neural crest cell. Here, using induced pluripotent stem cell-based models of Hirschsprung and single-cell transcriptomic analysis the authors define various factors associated with Hirschsprung pathogenesis.
- Zhixin Li
- , Kathy Nga-Chu Lui
- & Elly Sau-Wai Ngan
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Rewired m6A epitranscriptomic networks link mutant p53 to neoplastic transformation
The dysregulation of the m6A epitranscriptomic networks have been reported to contribute to the development of gliomas. Here, the authors utilize induced pluripotent stem cell-derived astrocytes with a p53 mutation and demonstrate that mutant p53 upregulates the m6A reader YTHDF2, resulting in the initiation of gliomas.
- An Xu
- , Mo Liu
- & Dung-Fang Lee
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Engraftment of allogeneic iPS cell-derived cartilage organoid in a primate model of articular cartilage defect
Allogeneic iPSC-derived cartilage organoids survive and integrate with surrounding native cartilage without immune reactions in a primate model of chondral defects in the knee joints, being remodeled and functioning as articular cartilage.
- Kengo Abe
- , Akihiro Yamashita
- & Noriyuki Tsumaki
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Multimodal monitoring of human cortical organoids implanted in mice reveal functional connection with visual cortex
Neuronal organoids derived from human induced pluripotent stem cells can be transplanted and integrated into the rodent cortex for the study of brain development and function. Here the authors demonstrate use of transparent graphene microelectrodes and two photon imaging for longitudinal, multimodal monitoring of functional connectivity between human iPSC derived neuronal organoids and the mouse cortex.
- Madison N. Wilson
- , Martin Thunemann
- & Duygu Kuzum
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| Open Access
Glucose absorption drives cystogenesis in a human organoid-on-chip model of polycystic kidney disease
In polycystic kidney disease (PKD), fluid-filled cysts arise from tubules. Here the authors show that subjecting organoids to fluid shear stress in a PKD-on-a-chip microphysiological system promotes cyst expansion via an absorptive pathway.
- Sienna R. Li
- , Ramila E. Gulieva
- & Benjamin S. Freedman
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Retrotransposon instability dominates the acquired mutation landscape of mouse induced pluripotent stem cells
Retrotransposons are mobile genetic elements normally repressed by DNA methylation in differentiated cells. Here, the authors show that DNA hypomethylation in mouse induced pluripotent stem cells allows retrotransposons to jump, but this can be blocked with a reverse transcriptase inhibitor.
- Patricia Gerdes
- , Sue Mei Lim
- & Geoffrey J. Faulkner
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A soft and ultrasensitive force sensing diaphragm for probing cardiac organoids instantaneously and wirelessly
It is challenging to directly characterize mechanical properties of soft 3D cardiac organoids with current sensors. Here the authors report an electronic skin-based all-soft organoid-sensing system which can wirelessly monitor minute force profiles of cardiac organoids in real-time in-situ.
- Quanxia Lyu
- , Shu Gong
- & Wenlong Cheng
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Norepinephrine transporter defects lead to sympathetic hyperactivity in Familial Dysautonomia models
Sympathetic neurons are affected in familial dysautonomia, a rare disease associated with a mutation in ELP1, but the mechanisms are not fully understood. Here the authors show, using neurons derived from participants with familial dysauotnomia, that spontaneous sympathetic neuron hyperactivity is observed and is associated with norepinephrine transporter deficits.
- Hsueh-Fu Wu
- , Wenxin Yu
- & Nadja Zeltner
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Human multilineage pro-epicardium/foregut organoids support the development of an epicardium/myocardium organoid
Stem cell models of organogenesis are a valuable tool for the study of human development, but often lack the context of tissue-tissue interaction. Here they generate human multi-lineage organoids comprising pro-epicardium, septum transversum, and liver bud, which they co-culture with heart organoids to generate a physiologically relevant model of organogenesis.
- Mariana A. Branco
- , Tiago P. Dias
- & Maria Margarida Diogo
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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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Imprinting fidelity in mouse iPSCs depends on sex of donor cell and medium formulation
Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) is associated with epigenetic alterations. Here the authors assess DNA methylation in detail in multiple female and male mouse iPSC lines generated with different protocols and find that defects depend on the sex of donor cells and can be partially mitigated by Vitamin C.
- Maria Arez
- , Melanie Eckersley-Maslin
- & Simão Teixeira da Rocha
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A multimodal iPSC platform for cystic fibrosis drug testing
Hundreds of mutations in the gene CFTR lead to cystic fibrosis and represent a challenge to developing therapeutics. Here, authors demonstrate the ability of airway cells derived from human iPSCs to model genotype-specific CFTR function as well as pharmacologic rescue of disease causing mutations.
- Andrew Berical
- , Rhianna E. Lee
- & Finn J. Hawkins
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Transcriptomic and proteomic retinal pigment epithelium signatures of age-related macular degeneration
Age-related macular degeneration (AMD) is a leading cause of vision loss, and there is no approved treatment for AMD with geographic atrophy. Here, the authors used transcriptomic and proteomic analyses of patient induced pluripotent stem cell-derived retinal pigment epithelium to better understand disease mechanisms.
- Anne Senabouth
- , Maciej Daniszewski
- & Alice Pébay
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Transcription 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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Epithelial phenotype restoring drugs suppress macular degeneration phenotypes in an iPSC model
Age-related macular degeneration is characterized by lipid-rich drusen deposits underneath the retinal pigment epithelium (RPE). Here the authors report an in vitro iPSC-RPE model for AMD that recapitulates drusen and RPE atrophy, and identify two drugs that reduce drusen deposits and restore RPE epithelial phenotype.
- Ruchi Sharma
- , Aman George
- & Kapil Bharti
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A 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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Cortical overgrowth in a preclinical forebrain organoid model of CNTNAP2-associated autism spectrum disorder
Mutations in CNTNAP2 have been associated with a syndromic form of Autism Spectrum Disorder. Here the authors show that forebrain organoids generated from induced pluripotent stem cells of patients with a syndromic form of ASD with a homozygous truncating mutation in CNTNAP2 displayed an increase in volume and total cell number, which is driven by abnormal cellular proliferation and neurogenesis.
- Job O. de Jong
- , Ceyda Llapashtica
- & Sander Markx
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Grafting of iPS cell-derived tenocytes promotes motor function recovery after Achilles tendon rupture
Tendon self-renewal occurs rarely and reconstructive surgery comes with significant limitations. Here the authors present an induced pluripotent stem cell-based method to generate tenocytes, analyze their developmental trajectory using scRNA-seq, and demonstrate their contribution to motor function recovery after Achilles tendon injury via engraftment and paracrine effects.
- Taiki Nakajima
- , Akihiro Nakahata
- & Makoto Ikeya
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| Open Access
Human sensorimotor organoids derived from healthy and amyotrophic lateral sclerosis stem cells form neuromuscular junctions
Organoids have improved disease modeling. Here, the authors generate human sensorimotor organoids derived from hiPSCs of individuals with ALS. These organoids contain skeletal muscle, sensory and motor neurons as well as astrocytes, microglia, and vasculature and form neuromuscular junctions.
- João D. Pereira
- , Daniel M. DuBreuil
- & Brian J. Wainger
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| Open Access
Retinoblastoma from human stem cell-derived retinal organoids
Retinoblastoma is a heritable pediatric cancer driven by mutations in RB1. Here, the authors demonstrate the first patient derived model of retinoblastoma using iPSCs from patients with germline mutations in RB1.
- Jackie L. Norrie
- , Anjana Nityanandam
- & Michael A. Dyer
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Decreased GLUT2 and glucose uptake contribute to insulin secretion defects in MODY3/HNF1A hiPSC-derived mutant β cells
Heterozygous HNF1A mutations can give rise to maturity onset diabetes of the young 3 (MODY3), characterized by insulin secretion defects. Here the authors show that MODY3-related HNF1A mutation in patient hiPSCderived pancreatic cells decreases glucose transporter GLUT2 expression due to compromised DNA binding.
- Blaise Su Jun Low
- , Chang Siang Lim
- & Adrian Kee Keong Teo
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| Open Access
Defective metabolic programming impairs early neuronal morphogenesis in neural cultures and an organoid model of Leigh syndrome
Leigh syndrome (LS) is a severe neurometabolic disorder which lacks effective models. Here, the authors developed human neuronal models of LS carrying mutations in SURF1 which show impaired neuronal morphogenesis due to metabolic deficiencies.
- Gizem Inak
- , Agnieszka Rybak-Wolf
- & Alessandro Prigione
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| Open Access
Pharmacological rescue in patient iPSC and mouse models with a rare DISC1 mutation
Previous work has shown in iPSC derived neurons that synaptic impairments are associated with a 4bp DISC1 deletion. Here the authors demonstrate a role for the PDE4 signalling pathway in these synaptic impairments.
- Nam-Shik Kim
- , Zhexing Wen
- & Guo-li Ming
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| Open Access
Single cell transcriptomic analysis of human pluripotent stem cell chondrogenesis
Application of human induced pluripotent stem cells (hiPSCs) for tissue regeneration is hindered by off-target cell differentiation. Here, the authors use bulk and single cell RNA-sequencing to identify WNT and MITF as off-target hubs during chondrogenic differentiation; inhibiting these pathways enhanced homogeneity and yield.
- Chia-Lung Wu
- , Amanda Dicks
- & Farshid Guilak
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| Open Access
BrainPhys neuronal medium optimized for imaging and optogenetics in vitro
Current media for neuronal cell and organoid cultures are suboptimal for functional imaging and optogenetics experiments, owing to phototoxicity and unphysiological performance. Here the authors formulate an optimised neuronal medium to support live cell imaging and electrophysiological activity.
- Michael Zabolocki
- , Kasandra McCormack
- & Cedric Bardy
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Article
| Open Access
Versatile live-cell activity analysis platform for characterization of neuronal dynamics at single-cell and network level
Current methods of neuronal network imaging cannot be used for continuous, long-term functional recordings. Here, the authors present a dual-mode high-density microelectrode array, which can simultaneously record in full-frame and high-signal-to-noise modes for label-free electrophysiological measurements.
- Xinyue Yuan
- , Manuel Schröter
- & Urs Frey
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Article
| Open Access
Frataxin gene editing rescues Friedreich’s ataxia pathology in dorsal root ganglia organoid-derived sensory neurons
Friedreich’s ataxia (FRDA) is an autosomal-recessive disorder. Here the authors describe a DRG organoid from patient derived-neurons and co-culture with muscle cells to mimic the disorder in vitro and demonstrate potential correction of the phenotype by CRISPR based editing.
- Pietro Giuseppe Mazzara
- , Sharon Muggeo
- & Vania Broccoli
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| Open Access
Targeting QKI-7 in vivo restores endothelial cell function in diabetes
Vascular endothelial cell (EC) dysfunction contributes to the occurrence of diabetic complications. Here the authors report that in diabetic conditions, upregulation of the RNA binding protein QKI-7 in ECs due to the imbalance of RNA splicing factors CUG-BP and hnRNPM contributes to EC dysfunction, and that in vivo QKI-7 silencing improves blood flow recovery in diabetic mice with limb ischemia.
- Chunbo Yang
- , Magdalini Eleftheriadou
- & Andriana Margariti
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| Open Access
Pre-clinical study of induced pluripotent stem cell-derived dopaminergic progenitor cells for Parkinson’s disease
Induced pluripotent stem cell (iPSC) derived dopaminergic neurons are a promising source for cell-based Parkinson’s disease (PD) therapy. Here the authors report a comprehensive pre-clinical evaluation of the safety and efficacy of dopaminergic progenitors derived from a clinical-grade human iPSC line.
- Daisuke Doi
- , Hiroaki Magotani
- & Jun Takahashi
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| Open Access
Characterization of a pluripotent stem cell-derived matrix with powerful osteoregenerative capabilities
Production of a safe and manufacturable material to mimic anabolic bone for tissue engineering has been hard to achieve to date. Here the authors use a mesenchymal stem cell line generated from induced pluripotent stem cells to produce osteogenic cell-matrix, displaying significant healing properties in mice.
- Eoin P. McNeill
- , Suzanne Zeitouni
- & Carl A. Gregory
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| Open Access
Synergistic gene editing in human iPS cells via cell cycle and DNA repair modulation
Precision editing with CRISPR-Cas9 often suffers from poor efficiency. Here the authors identify culture conditions and small molecules that synergize to promote homology-directed repair (HDR) in induced pluripotent stem (iPS) cells.
- Thomas L. Maurissen
- & Knut Woltjen
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| Open Access
Single-cell RNA-sequencing of differentiating iPS cells reveals dynamic genetic effects on gene expression
Studying the genetic effects on early stages of human development is challenging due to a scarcity of biological material. Here, the authors utilise induced pluripotent stem cells from 125 donors to track gene expression changes and expression quantitative trait loci at single cell resolution during in vitro endoderm differentiation.
- Anna S. E. Cuomo
- , Daniel D. Seaton
- & Oliver Stegle
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| Open Access
Generation of mesenchyme free intestinal organoids from human induced pluripotent stem cells
Human induced pluripotent stem cell-derived intestinal organoids (HIOs) are powerful tools to study development and diseases of the gastrointestinal tract. Here, the authors develop a directed differentiation protocol to generate mesenchyme-free HIOs that can be patterned towards proximal small intestine or colonic epithelium, and demonstrated their utility in modeling CFTR function.
- Aditya Mithal
- , Amalia Capilla
- & Gustavo Mostoslavsky
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| Open Access
Genetic aberrations in iPSCs are introduced by a transient G1/S cell cycle checkpoint deficiency
Point mutations have been found in induced pluripotent stem cells (iPSCs) but when they arise is unclear. Here, the authors show that a G1/S cell cycle checkpoint deficiency transiently occurs early in genome reprogramming, suggesting a common developmental pathway between iPSC and tumorigenesis, and generate genetic burden-free human iPSCs.
- Ryoko Araki
- , Yuko Hoki
- & Masumi Abe
PRPF8-mediated dysregulation of hBrr2 helicase disrupts human spliceosome kinetics and 5´-splice-site selection causing tissue-specific defects