Featured
-
-
Article
| Open AccessSuperresolution architecture of cornerstone focal adhesions in human pluripotent stem cells
Pluripotent stem cell colonies are encircled by large cornerstone focal adhesions (FAs). Here, using super-resolution imaging, the authors describe features in the nanoscale makeup of these stable FAs such as inverted vinculin, lateral talin segregation and distinct kank protein distributions.
- Aki Stubb
- , Camilo Guzmán
- & Johanna Ivaska
-
Article
| Open AccessMHC matching fails to prevent long-term rejection of iPSC-derived neurons in non-human primates
Matching iPSC donors’ and patients’ HLA haplotypes has been proposed as a way to generate cell therapy products with enhanced immunological compatibility. Here the authors show that MHC matching alone is insufficient to grant long-term survival of neuronal grafts in the lesioned brain of non-human primates.
- Romina Aron Badin
- , Aurore Bugi
- & Anselme L. Perrier
-
Article
| Open AccessSimultaneous measurement of excitation-contraction coupling parameters identifies mechanisms underlying contractile responses of hiPSC-derived cardiomyocytes
Cardiomyocytes obtained from human induced pluripotent stem cells are increasingly used for drug testing, but they are not always predictive of the heart contractile responses. Here the authors develop a method to measure cytosolic calcium, action potentials and contraction simultaneously, to achieve higher sensitivity for drug screenings.
- Berend J. van Meer
- , Ana Krotenberg
- & Christine L. Mummery
-
Article
| Open AccessPluripotency reprogramming by competent and incompetent POU factors uncovers temporal dependency for Oct4 and Sox2
Oct4, along with Sox2 and Klf4 can induce pluripotency, but structurally similar factors like Oct6 cannot. Here, using pluripotency competent and incompetent factors, the authors show that Sox2 plays a dominant role in facilitating chromatin opening at Oct4 bound DNA early during reprogramming to pluripotency.
- Vikas Malik
- , Laura V. Glaser
- & Ralf Jauch
-
Article
| Open AccessThe K219T-Lamin mutation induces conduction defects through epigenetic inhibition of SCN5A in human cardiac laminopathy
Mutation of LMNA, encoding Lamin A/C nuclear proteins, cause dilated cardiomyopathy and conduction disorders. Here, the authors show that patient-specific iPSC-derived CMs carrying the K219T LMNA mutation have downregulated Nav1.5 channels due to dynamic cooperation of Lamin A/C and Polycomb repressor complex 2 at the SCN5A promoter.
- Nicolò Salvarani
- , Silvia Crasto
- & Elisa Di Pasquale
-
Article
| Open AccessSALL3 expression balance underlies lineage biases in human induced pluripotent stem cell differentiation
Human induced pluripotent stem cells (hiPSCs) generate all cell types in the body, but different lines can differ in their potential. Here, the authors determine that higher endogenous levels of SALL3 in hiPSCs lead to ectoderm differentiation bias and reduced mesoderm/endoderm due to DNMT3B mediated DNA methylation.
- Takuya Kuroda
- , Satoshi Yasuda
- & Yoji Sato
-
Article
| Open AccessPrecisely controlling endogenous protein dosage in hPSCs and derivatives to model FOXG1 syndrome
Altered dosage of developmental regulators such as transcription factors can result in disorders, such as FOXG1 syndrome. Here, the authors demonstrate the utility of SMASh technology for modulating protein dosage by modeling FOXG1 syndrome using human pluripotent stem cell-derived neurons and neural organoids.
- Wenliang Zhu
- , Boya Zhang
- & Baoyang Hu
-
Article
| Open AccessGeneration of pluripotent stem cell-derived mouse kidneys in Sall1-targeted anephric rats
The use of pluripotent-stem cell derived organs for transplantation would be promising, if organs can be grown in a suitable host. Here, the authors use interspecific blastocyst complementation to generate a mouse pluripotent stem cell-derived kidney in anephric Sall1 mutant rats.
- Teppei Goto
- , Hiromasa Hara
- & Masumi Hirabayashi
-
Article
| Open Access3D organoid-derived human glomeruli for personalised podocyte disease modelling and drug screening
Studies examining human podocytopathies have utilised 2D cultured primary or immortalised podocyte cell lines. Here, the authors demonstrate that 3D human glomeruli sieved from induced pluripotent stem cell-derived kidney organoids retain an improved podocyte identity in vitro facilitating disease modelling and toxicity testing.
- Lorna J. Hale
- , Sara E. Howden
- & Melissa H. Little
-
Article
| Open AccessDefining human cardiac transcription factor hierarchies using integrated single-cell heterogeneity analysis
Human induced pluripotent stem cell derived cardiomyocytes are a powerful model for cardiogenesis and disease in vitro. Here the authors comprehensively map cardiac differentiation using multiple modalities, including single-cell RNA seq and CyTOF, in cells with a gain or loss of function in key cardiac transcription factors.
- Jared M. Churko
- , Priyanka Garg
- & Joseph C. Wu
-
Article
| Open AccessExpression-based drug screening of neural progenitor cells from individuals with schizophrenia
Unbiased large scale screening of small molecules for drug discovery in psychiatric disease is technically challenging and financially costly. Here, Readhead and colleagues integrate in silico and in vitro approaches to design and conduct transcriptomic drug screening in schizophrenia patient-derived neural cells, in order to survey novel pathologies and points of intervention.
- Benjamin Readhead
- , Brigham J. Hartley
- & Kristen J. Brennand
-
Article
| Open AccessHSP90-incorporating chaperome networks as biosensor for disease-related pathways in patient-specific midbrain dopamine neurons
The early molecular events that ultimately lead to neuronal cell death in pathologies such as Parkinson’s disease are poorly understood. Here the authors use pluripotent stem-cell-derived human midbrain neurons and chemical biology tools to gain molecular level insight into the events induced by toxic and genetic stresses that mimic those occurring during neurodegeneration.
- Sarah Kishinevsky
- , Tai Wang
- & Lorenz Studer
-
Article
| Open AccessDisrupted alternative splicing for genes implicated in splicing and ciliogenesis causes PRPF31 retinitis pigmentosa
Mutations in pre-mRNA processing factors cause autosomal dominant retinitis pigmentosa. Here the authors provide insights into the pathophysiological mechanisms underlying non-syndromic retinal disease caused by heterozygous mutations in genes encoding ubiquitously expressed splicing factors.
- Adriana Buskin
- , Lili Zhu
- & Majlinda Lako
-
Article
| Open AccessMicroglia innately develop within cerebral organoids
Brain organoid models reported to date lack cells of mesodermal origin, such as microglia. Here, the authors demonstrate that mature microglia-like cells are generated within their cerebral organoid model, providing new avenues for studying human microglia in a three-dimensional brain environment.
- Paul R. Ormel
- , Renata Vieira de Sá
- & R. Jeroen Pasterkamp
-
Article
| Open AccessRapid functional genetics of the oligodendrocyte lineage using pluripotent stem cells
The isolation and propagation of oligodendroglial cells from postnatal animals can be impractical for functional genetic studies. This study highlights the potential of a new approach to rapidly generate oligodendrocytes and their progenitors from mouse embryonic and induced pluripotent stem cells, independent of mouse strain or mutational status.
- Angela M. Lager
- , Olivia G. Corradin
- & Paul J. Tesar
-
Article
| Open AccessATP activates bestrophin ion channels through direct interaction
Human Bestrophin1 (hBest1), a calcium-activated chloride channel in retinal pigment epithelium (RPE), is essential for retina physiology. Using electrophysiological and structural approaches, the authors uncover an ATP-dependent activation mechanism of hBest1, and identify an ATP-binding motif.
- Yu Zhang
- , Alec Kittredge
- & Tingting Yang
-
Article
| Open AccessIn vivo reprogramming drives Kras-induced cancer development
Cellular reprogramming and cancer development share properties. Here, the authors examine the impact of in vivo reprogramming on Kras-induced cancer and show reprogramming-mediated repression of somatic cell enhancers in conjunction with Kras mutation results in rapid PDAC development.
- Hirofumi Shibata
- , Shingo Komura
- & Yasuhiro Yamada
-
Article
| Open AccessIntron retention and nuclear loss of SFPQ are molecular hallmarks of ALS
Intron retention (IR) can increase protein diversity and function, and yet unregulated IR may be detrimental to cellular health. This study shows that aberrant IR occurs in ALS and finds nuclear loss of an RNA-binding protein called SFPQ as a new molecular hallmark in this devastating condition.
- Raphaelle Luisier
- , Giulia E. Tyzack
- & Rickie Patani
-
Article
| Open AccessAssessment of established techniques to determine developmental and malignant potential of human pluripotent stem cells
The International Stem Cell Initiative tests methods in a multisite study to detect pluripotency and teratoma formation (PluriTest, Embryoid Body and Teratoma methods) in human pluripotent stem cells. Here, the authors provide guidelines for their application: only the teratoma assay offers evidence of malignant potential.
- Thomas F. Allison
- , Peter W. Andrews
- & Shinya Yamanaka
-
Article
| Open AccessNOTCH signaling specifies arterial-type definitive hemogenic endothelium from human pluripotent stem cells
It is unclear whether arterial specification is required for hematopoietic stem cell formation. Here, the authors use a chemically defined human pluripotent stem cell (hPSC) differentiation system to show the role of NOTCH signaling in forming arterial-type hemogenic endothelial cells.
- Gene I. Uenishi
- , Ho Sun Jung
- & Igor I. Slukvin
-
Article
| Open AccessSmall molecules promote CRISPR-Cpf1-mediated genome editing in human pluripotent stem cells
Precise genome editing in human pluripotent stem cells requires the development of methods for rapid and efficient genetic manipulation. Here, the authors screen for small molecules that enhance CRISPR-Cpf1-mediated genome engineering.
- Xiaojie Ma
- , Xi Chen
- & Saiyong Zhu
-
Article
| Open AccessKlf4 glutamylation is required for cell reprogramming and early embryonic development in mice
Embryonic stem cell pluripotency depends upon precise regulation by a core transcription network. Here the authors show that polyglutamylation mediated stabilization of the transcription factor Klf4 by TTLL1 and TTLL4 promotes reprogramming, pluripotency and preimplantation embryonic development.
- Buqing Ye
- , Benyu Liu
- & Zusen Fan
-
Article
| Open AccessHigh-efficiency RNA-based reprogramming of human primary fibroblasts
Induced pluripotent stem cells (iPSCs) have potential for regenerative medicine applications, but are generated with very low efficiency. Here, the authors show highly efficient reprogramming of human primary fibroblasts to iPSCs via the synergistic activity of synthetic modified mRNAs, mature miRNA mimics, and optimized culture methods.
- Igor Kogut
- , Sandra M. McCarthy
- & Ganna Bilousova
-
Article
| Open AccessParallel derivation of isogenic human primed and naive induced pluripotent stem cells
Derivation of human induced pluripotent stem cells (hiPSCs) produces primed hiPSCs that can in turn be converted to naive hiPSCs. Here, the authors directly reprogram somatic cells to form both naive and primed isogenic hiPSCs and confirm the similarity of naive hiPSCs to their in vivo counterparts.
- Stéphanie Kilens
- , Dimitri Meistermann
- & Matthew L. Albert
-
Article
| Open AccessTranscriptional signatures of schizophrenia in hiPSC-derived NPCs and neurons are concordant with post-mortem adult brains
Induced pluripotent stem cell (hiPSC)-based models have inherent variations in their cellular and molecular output and readouts. Here, Hoffman and colleagues devise a method to account for gene expression variations in hiPSC-derived neurons from patients with childhood-onset schizophrenia.
- Gabriel E. Hoffman
- , Brigham J. Hartley
- & Kristen J. Brennand
-
Article
| Open AccessCardiopatch platform enables maturation and scale-up of human pluripotent stem cell-derived engineered heart tissues
Cardiomyocytes derived from human induced pluripotent stem cells could be used to generate cardiac tissues for regenerative purposes. Here the authors describe a method to obtain large bioengineered heart tissues showing advanced maturation, functional features and engraftment capacity.
- Ilya Y. Shadrin
- , Brian W. Allen
- & Nenad Bursac
-
Article
| Open AccessStructural and spatial chromatin features at developmental gene loci in human pluripotent stem cells
Higher-order chromatin organization regulates the expression of transcriptional programs that control cell function. Here, the authors show that chromatin interaction profiles and nuclear positions at developmental gene loci differ between human somatic and pluripotent stem cells.
- Hiroki Ikeda
- , Masamitsu Sone
- & Takuya Yamamoto
-
Article
| Open AccessThe circular RNA circBIRC6 participates in the molecular circuitry controlling human pluripotency
Circular RNAs are abundant in the transcriptome and are implicated in the regulation of a range of biological processes. Here the authors identify circBIRC6 as a microRNA sponge that helps modulate human pluripotency and early lineage differentiation.
- Chun-Ying Yu
- , Tung-Cheng Li
- & Hung-Chih Kuo
-
Article
| Open AccessHuman stem cells alter the invasive properties of somatic cells via paracrine activation of mTORC1
Cell invasion is required for several physiological processes but it is unknown if stem cells induce invasiveness in other cells. Here, the authors show that human stem cells secrete insulin-like growth factor, which in turn activates the mTORC1 pathway, initiating invasive behaviour and attracting other cells.
- Margit Rosner
- , Ha Thi Thanh Pham
- & Markus Hengstschläger
-
Article
| Open AccessMHC matching improves engraftment of iPSC-derived neurons in non-human primates
Major histocompatibility complex (MHC) matching improves graft survival rates after organ transplantation. Here the authors show that in macaques, MHC-matched iPSC-derived neurons provide better engraftment in the brain, with a lower immune response and higher survival of the transplanted neurons.
- Asuka Morizane
- , Tetsuhiro Kikuchi
- & Jun Takahashi
-
Article
| Open AccessRETRACTED ARTICLE:Endocrine disruptors induce perturbations in endoplasmic reticulum and mitochondria of human pluripotent stem cell derivatives
Harmful chemicals that disrupt the endocrine system and hormone regulation have been associated with obesity. Here the authors apply a human pluripotent stem cell-based platform to study the effects of such compounds on developing gut endocrine and neuroendocrine systems.
- Uthra Rajamani
- , Andrew R. Gross
- & Dhruv Sareen
-
Article
| Open AccessA pluripotent stem cell-based model for post-implantation human amniotic sac development
Early in human embryonic development, it is unclear how amniotic sac formation is regulated. Here, the authors use a human pluripotent stem cell-based model, termed the post-implantation amniotic sac embryoid, to recapitulate early embryogenic events of human amniotic sac development.
- Yue Shao
- , Kenichiro Taniguchi
- & Jianping Fu
-
Article
| Open AccessDisrupted neuronal maturation in Angelman syndrome-derived induced pluripotent stem cells
Angelman syndrome (AS) is characterized by developmental delay and intellectual disability, but the underlying pathophysiology is not well understood. Here the authors use induced pluripotent stem cell-derived neurons from AS patients and find impaired maturation of resting membrane potential and action potential firing, and defects in synaptic activity associated with the disease.
- James J. Fink
- , Tiwanna M. Robinson
- & Eric S. Levine
-
Article
| Open AccessDirect comparison of distinct naive pluripotent states in human embryonic stem cells
Human embryonic stem cells (hESCs) in culture display a state of primed pluripotency, but recent protocols have been developed that enable hESCs to adopt a naive-like pluripotent state. Here the authors perform a side-by-side comparison of methods used to culture naive hESCs and confirm the role of PI3K/AKT/mTORC signalling in facilitating the induction of naive pluripotency.
- S. Warrier
- , M. Van der Jeught
- & B. Heindryckx
-
Article
| Open AccessBulk cell density and Wnt/TGFbeta signalling regulate mesendodermal patterning of human pluripotent stem cells
Differentiation of human pluripotent stem cells (hPSC) mimics aspects of embryonic developmentin vitrobut is poorly understood. Here, the authors identify bulk cell density as a key parameter directing transition from pluripotency to primitive streak-like priming in hPSCs via secreted LEFTY/CERBERUS.
- Henning Kempf
- , Ruth Olmer
- & Robert Zweigerdt
-
Article
| Open AccessBioengineering of injectable encapsulated aggregates of pluripotent stem cells for therapy of myocardial infarction
Stem cell therapy of myocardial infarction is hampered by poor survival of injected cells. Here the authors develop injectable aggregates of stem cells differentiated to an early cardiac stage and encapsulated in a biodegradable micromatrix, and show their enhanced therapeutic efficacy in a heart infarction mouse model.
- Shuting Zhao
- , Zhaobin Xu
- & Xiaoming He
-
Article
| Open AccessPurification of functional human ES and iPSC-derived midbrain dopaminergic progenitors using LRTM1
Midbrain dopaminergic neurons generated from stem cells show promise for the treatment of Parkinson’s disease. Here, the authors use the cell surface marker, LRTM1, to enrich the midbrain dopaminergic progenitors and show improved motor function/cell survival when grafted into rat/monkey brains, respectively.
- Bumpei Samata
- , Daisuke Doi
- & Jun Takahashi
-
Article
| Open AccessCripto is essential to capture mouse epiblast stem cell and human embryonic stem cell pluripotency
Stem cell plasticity is crucial for early embryo development and the differentiation of stem cells. Here, the authors show that the extracellular protein Cripto sustains mouse ESC self-renewal and maintains mouse EpiSC as well as human ESC pluripotency and controls the metabolic reprogramming in ESCs to EpiSC transition.
- Alessandro Fiorenzano
- , Emilia Pascale
- & Gabriella Minchiotti
-
Article
| Open AccessHuman serum-derived protein removes the need for coating in defined human pluripotent stem cell culture
Improved culture methods are needed to reliably grow human pluripotent stem cells (hPSCs) on a large scale. Here, the authors identify a xeno-free medium with a supplement of Inter-α-inhibitor that supports long-term propagation and improved single-cell passaging of hPSCs on uncoated plastic.
- Sara Pijuan-Galitó
- , Christoffer Tamm
- & Cecilia Annerén
-
Article
| Open AccessTumour resistance in induced pluripotent stem cells derived from naked mole-rats
The naked mole-rat exhibits an exceptional resistance to cancer. Here, the authors show that induced pluripotent stem cells derived from the naked mole-rat lack teratoma-forming tumorigenicity due to a naked mole-rat-specific ARF-dependent tumour-suppression mechanism.
- Shingo Miyawaki
- , Yoshimi Kawamura
- & Kyoko Miura
-
Article
| Open AccessGeneration of stem cell-derived β-cells from patients with type 1 diabetes
Pancreatic β cells can be generated from pluripotent stem cells. Here, the authors show that human induced pluripotent stem cells from patients with type 1 diabetes can be differentiated into β-like cells that have no detectable differences compared with cells from non-diabetic individuals.
- Jeffrey R. Millman
- , Chunhui Xie
- & Douglas A. Melton
-
Article
| Open AccessA programmable synthetic lineage-control network that differentiates human IPSCs into glucose-sensitive insulin-secreting beta-like cells
Synthetic biology offers the potential for the design and implementation of rationally designed, complex genetic programmes. Here the authors design a genetic network to trigger the differentiation of patient derived IPSCs into beta-like cells.
- Pratik Saxena
- , Boon Chin Heng
- & Martin Fussenegger
-
Article
| Open AccessLarge-scale production of megakaryocytes from human pluripotent stem cells by chemically defined forward programming
Platelets are blood circulating corpuscles generated from megakaryocytes that initiate wound healing. Here, Moreau et al. describe a way of producing large quantities of megakaryocytes from human pluripotent stem cells in the laboratory, moving us a step closer to manufacturing transfusion products.
- Thomas Moreau
- , Amanda L. Evans
- & Cedric Ghevaert
-
Article
| Open AccessGeneration and transplantation of reprogrammed human neurons in the brain using 3D microtopographic scaffolds
Human pluripotent stem cell derived neurons have the potential for cell replacement therapy for brain injury and disease but problems on transplantation need to be overcome. Here, the authors use a microtopographic scaffold to graft neurons into both hippocampal organoids and the mouse brain striatum.
- Aaron L. Carlson
- , Neal K. Bennett
- & Prabhas V. Moghe
-
Article
| Open AccessWhole-genome mutational burden analysis of three pluripotency induction methods
It is feared that reprogramming may introduce DNA mutations. Here Bhutani et al. take three different reprogramming methods and using comparative whole genome analyses do identify nucleotide variations that are different in reprogrammed cells from the original fibroblasts, but none convey oncogenic potential.
- Kunal Bhutani
- , Kristopher L. Nazor
- & Jeanne F. Loring
-
Article
| Open AccessNon-CG DNA methylation is a biomarker for assessing endodermal differentiation capacity in pluripotent stem cells
The methylation of non-CpG residues is a poorly understood marker of pluripotent cells, gradually lost as cells differentiate. Here the authors show non-CG methylation can be used as a marker of differentiation potential.
- Lee M. Butcher
- , Mitsuteru Ito
- & Stephan Beck
-
Article
| Open AccessA draft map of the mouse pluripotent stem cell spatial proteome
The spatial location of proteins within a cell is a key element of protein function. Here the authors describe hyperLOPIT—a proteomics workflow that allows the simultaneous assignment of thousands of proteins to subcellular niches with high resolution—and apply it to mouse pluripotent stem cells.
- Andy Christoforou
- , Claire M. Mulvey
- & Kathryn S. Lilley
-
Article
| Open AccessReprogramming triggers endogenous L1 and Alu retrotransposition in human induced pluripotent stem cells
Genetic and epigenetic abnormalities have been found to result from reprogramming of differentiated cells into human induced pluripotent stem cells (hiPSCs). Here, Klawitter et al.identify endogenous L1, Alu and SVA mobilization during reprogramming, highlighting the risk of insertional mutagens in hiPSCs.
- Sabine Klawitter
- , Nina V. Fuchs
- & Gerald G. Schumann
-
Article
| Open AccessGenetically engineering self-organization of human pluripotent stem cells into a liver bud-like tissue using Gata6
There has been limited success in generating tissues from human induced pluripotent stem cells (hiPSCs). Here, the authors genetically engineer expression of the transcription factor Gata6 in a single isogenic hiPSC population resulting in complex tissue structures that exhibit liver bud-like properties.
- Patrick Guye
- , Mohammad R. Ebrahimkhani
- & Ron Weiss