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| Open AccessEnhancing genome editing in hPSCs through dual inhibition of DNA damage response and repair pathways
Precise genome editing is crucial. Here the authors demonstrate that dual inhibition of p53-mediated cell death and distinct activation of the DNA damage repair system upon DNA damage by cytosine base editor (CBE) or prime editor (PE) additively enhanced editing efficiency in hPSCs.
- Ju-Chan Park
- , Yun-Jeong Kim
- & Hyuk-Jin Cha
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Article
| Open AccessMultiplexed bulk and single-cell RNA-seq hybrid enables cost-efficient disease modeling with chimeric organoids
IPSC-derived organoids model diseases. Multiplexed coculture and demultiplexing natural genetic barcodes aid in studying genetic effects. Here, authors introduce Vireo-bulk to deconvolve bulk RNA-seq data, quantify donor abundance and identify differentially expressed genes.
- Chen Cheng
- , Gang Wang
- & Jin Zhang
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Article
| Open AccessPRPF8-mediated dysregulation of hBrr2 helicase disrupts human spliceosome kinetics and 5´-splice-site selection causing tissue-specific defects
PRPF8 is a hotspot for mutations causing retinitis pigmentosa-type 13. Here the authors generated PRPF8 patient-specific retinal cells, demonstrating an important role for this splicing factor in spliceosome kinetics and 5’ splice site selection.
- Robert Atkinson
- , Maria Georgiou
- & Majlinda Lako
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Article
| Open AccessA let-7 microRNA-RALB axis links the immune properties of iPSC-derived megakaryocytes with platelet producibility
The authors pioneered the iPSC-derived platelet transfusion in human. Here they employ miRNA switches, identifying RALB as a determinant of immune megakaryocytes and a marker for quality control, advancing standardization of iPSC-platelet production.
- Si Jing Chen
- , Kazuya Hashimoto
- & Koji Eto
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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 AccessHeterozygous 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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Article
| 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 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 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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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 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 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 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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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 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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| 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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| 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 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 AccessOptogenetic control of YAP reveals a dynamic communication code for stem cell fate and proliferation
The transcriptional regulator YAP controls cellular decisions such as proliferation, differentiation, and pluripotency. Here, the authors show a concentration-dependent and temporal communication code for YAP that enables cells to choose between these programs.
- Kirstin Meyer
- , Nicholas C. Lammers
- & Orion D. Weiner
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Article
| Open AccessC9orf72-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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Article
| Open AccessMonolayer platform to generate and purify primordial germ-like cells in vitro provides insights into human germline specification
Generation of primordial germ cell-like cells (PGCLCs) from human pluripotent cells (hPSCs) offers insight into the mechanisms underlying human reproduction, but often requires complex methods. Here they describe a simplified monolayer protocol to differentiate and purify PGCLCs for further analysis.
- Sivakamasundari Vijayakumar
- , Roberta Sala
- & Vittorio Sebastiano
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Article
| Open AccessHuman 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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Article
| Open AccessGenome-wide screening in pluripotent cells identifies Mtf1 as a suppressor of mutant huntingtin toxicity
Huntington’s disease is caused by mutation in the HTT gene. Here, the authors screen for suppressors of mutant HTT-induced toxicity, identifying Mtf1. Mtf1 reduced oxidative stress and cell death in stem cells, and motor defects and protein aggregates in mouse models.
- Giorgia Maria Ferlazzo
- , Anna Maria Gambetta
- & Graziano Martello
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Article
| Open AccessModeling 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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| 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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Article
| Open AccessA 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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Article
| Open AccessApicobasal RNA asymmetries regulate cell fate in the early mouse embryo
How do cells of the preimplantation mouse embryo make decisions? Here the authors discovered that the spatial sorting of mRNAs, tRNA, rRNAs and organelles lead to localized translation, conducive for cell fate allocation and embryonic development.
- Azelle Hawdon
- , Niall D. Geoghegan
- & Jennifer Zenker
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| Open AccessThe NuRD complex cooperates with SALL4 to orchestrate reprogramming
Somatic reprogramming involves both transcriptional and epigenetic resetting, but we don’t yet fully understand this process. Here they show that Jdp2, Glis1, Esrrb, and Sall4 can mediate reprogramming by recruiting the NuRD complex to close chromatin, highlighting a potential role in cell fate control.
- Bo Wang
- , Chen Li
- & Duanqing Pei
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Article
| Open AccessTranscriptomics 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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Article
| Open AccessRewired 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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Article
| Open AccessEngraftment 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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Article
| Open AccessZBTB12 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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| Open AccessEpigenetic 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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Article
| Open AccessMultimodal 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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Article
| Open AccessGlucose 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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Article
| Open AccessRetrotransposon 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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| Open AccessGreater genetic diversity is needed in human pluripotent stem cell models
While there are a growing number of human pluripotent stem cell repositories, genetic diversity remains limited in most collections and studies. Here, we discuss the importance of incorporating diverse ancestries in these models to improve equity and accelerate biological discovery.
- Sulagna Ghosh
- , Ralda Nehme
- & Lindy E. Barrett
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Article
| Open AccessA 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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Article
| Open AccessNorepinephrine 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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Article
| Open AccessCHD7 regulates otic lineage specification and hair cell differentiation in human inner ear organoids
Mutations in the chromatin remodeler CHD7 cause CHARGE syndrome, affecting development of several organs including the inner ear. Here, the authors recapitulated pathogenesis of this disease with human inner ear organoids and found that CHD7 is indispensable for proper otic lineage specification and hair cell differentiation.
- Jing Nie
- , Yoshitomo Ueda
- & Eri Hashino
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Article
| Open AccessHuman 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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Article
| Open AccessEnhanced 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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Article
| Open AccessEvolutionary origin of vertebrate OCT4/POU5 functions in supporting pluripotency
By constructing an evolutionary trajectory of the cyclostome-gnathostome Pou5 gene family and comparing the structural and phenotypic protein variations, the authors uncover the origin of functional characteristics for the pluripotency factor Oct4.
- Woranop Sukparangsi
- , Elena Morganti
- & Joshua M. Brickman
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Article
| Open AccessImprinting 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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Article
| Open AccessPCGF6 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
| Open AccessA 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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Article
| Open AccessTranscriptomic 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