A cellular model for sporadic ALS using patient-derived induced pluripotent stem cells.

doi:10.1016/J.MCN.2013.07.007

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A cellular model for sporadic ALS using patient-derived induced pluripotent stem cells.

Journal Article•DOI•

A cellular model for sporadic ALS using patient-derived induced pluripotent stem cells.

Matthew F. Burkhardt, Fernando J. Martinez, Sarah Wright, Carla Ramos, Dmitri Volfson, Michael Mason, Jeff Garnes, Vu Dang, Jeffery Lievers, Uzma Shoukat-Mumtaz, Rita Martinez, Hui Gai, Robert Blake, Eugeni A. Vaisberg, Marica Grskovic, Charles Johnson, Stefan Irion, Bright Jessica Michelle, Bonnie Cooper, Leane Nguyen, Irene Griswold-Prenner, Ashkan Javaherian - Show less +18 more

01 Sep 2013-Molecular and Cellular Neuroscience (Mol Cell Neurosci)-Vol. 56, pp 355-364

TL;DR: It is demonstrated that motor neurons derived from three sALS patients show de novo TDP-43 aggregation and that the aggregates recapitulate pathology in postmortem tissue from one of the same patients from which the iPSC were derived.

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About: This article is published in Molecular and Cellular Neuroscience.The article was published on 2013-09-01 and is currently open access. It has received 256 citations till now. The article focuses on the topics: Induced pluripotent stem cell & Reprogramming.

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Journal Article•DOI•

Induced pluripotent stem cell technology: a decade of progress

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Yanhong Shi¹, Haruhisa Inoue², Joseph C. Wu³, Shinya Yamanaka²•Institutions (3)

Beckman Research Institute¹, Kyoto University², Cardiovascular Institute of the South³

01 Feb 2017-Nature Reviews Drug Discovery

TL;DR: The progress in applications of iPSC technology that are particularly relevant to drug discovery and regenerative medicine are discussed, and the remaining challenges and the emerging opportunities in the field are considered.

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Abstract: Since the advent of induced pluripotent stem cell (iPSC) technology a decade ago, human iPSCs have been widely used for disease modelling, drug discovery and cell therapy development. This article discusses progress in applications of iPSC technology that are particularly relevant to drug discovery and regenerative medicine, including the powerful combination of human iPSC technology with recent developments in gene editing.

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985 citations

Journal Article•DOI•

Human iPSC-Based Modeling of Late-Onset Disease via Progerin-Induced Aging

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Justine D. Miller¹, Yosif Ganat¹, Sarah Kishinevsky¹, Robert L. Bowman¹, Becky Liu¹, Edmund Y. Tu¹, Pankaj Mandal², Pankaj Mandal³, Elsa Vera¹, Jae-Won Shim¹, Sonja Kriks¹, Tony Taldone¹, Noemi Fusaki⁴, Mark J. Tomishima¹, Dimitri Krainc², Teresa A. Milner⁵, Teresa A. Milner⁶, Derrick J. Rossi³, Derrick J. Rossi², Lorenz Studer¹ - Show less +16 more•Institutions (6)

Kettering University¹, Harvard University², Boston Children's Hospital³, Keio University⁴, Cornell University⁵, Rockefeller University⁶

05 Dec 2013-Cell Stem Cell

TL;DR: It is suggested that progerin-induced aging can be used to reveal late-onset age-related disease features in hiPSC-based disease models.

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597 citations

Additional excerpts

...More recent reports on ALS iPSC models of TDP-43-mutant or sporadic disease are inconsistent with regard to observations of cytoplasmic aggregates, decreased survival, and altered neurite development in the patientderived motoneurons (Bilican et al., 2012; Burkhardt et al., 2013; Egawa et al., 2012)....
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Journal Article•DOI•

Pluripotent stem cells in disease modelling and drug discovery

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Yishai Avior¹, Ido Sagi¹, Nissim Benvenisty¹•Institutions (1)

Hebrew University of Jerusalem¹

01 Mar 2016-Nature Reviews Molecular Cell Biology

TL;DR: The availability of human pluripotent stem cells (PSCs), which are capable of self-renewal and have the potential to differentiate into virtually any cell type, can now help to overcome the limitations of animal models for certain disorders.

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Abstract: Experimental modelling of human disorders enables the definition of the cellular and molecular mechanisms underlying diseases and the development of therapies for treating them. The availability of human pluripotent stem cells (PSCs), which are capable of self-renewal and have the potential to differentiate into virtually any cell type, can now help to overcome the limitations of animal models for certain disorders. The ability to model human diseases using cultured PSCs has revolutionized the ways in which we study monogenic, complex and epigenetic disorders, as well as early- and late-onset diseases. Several strategies are used to generate such disease models using either embryonic stem cells (ES cells) or patient-specific induced PSCs (iPSCs), creating new possibilities for the establishment of models and their use in drug screening.

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484 citations

Journal Article•DOI•

In Silico Labeling: Predicting Fluorescent Labels in Unlabeled Images

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Eric Christiansen¹, Samuel Yang¹, D. Michael Ando¹, Ashkan Javaherian², Gaia Skibinski², Scott Lipnick³, Elliot Mount², Alison O’Neil³, Kevan Shah², Alicia K. Lee², Piyush Goyal², William Fedus⁴, William Fedus¹, Ryan Poplin¹, Andre Esteva⁵, Andre Esteva¹, Marc Berndl¹, Lee L. Rubin³, Philip C. Nelson¹, Steven Finkbeiner², Steven Finkbeiner⁶ - Show less +17 more•Institutions (6)

Google¹, Gladstone Institutes², Harvard University³, Université de Montréal⁴, Stanford University⁵, University of California, San Francisco⁶

19 Apr 2018-Cell

TL;DR: It is shown that a computational machine-learning approach, which is called "in silico labeling" (ISL), reliably predicts some fluorescent labels from transmitted-light images of unlabeled fixed or live biological samples.

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465 citations

Cites methods from "A cellular model for sporadic ALS u..."

...Condition B The human iPSC line KW-4, graciously provided by the Yamanaka lab, was differentiated to motor neurons via a modified version of the protocol in Burkhardt et al. (2013)....
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Journal Article•DOI•

Screening out irrelevant cell-based models of disease

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Peter Horvath¹, Peter Horvath², Nathalie Aulner³, Marc Bickle⁴, Anthony Davies⁵, Anthony Davies⁶, Elaine Del Nery⁷, Daniel Ebner⁸, María C. Montoya⁹, Päivi Östling¹, Päivi Östling¹⁰, Vilja Pietiäinen¹, Leo S. Price¹¹, Spencer L. Shorte³, Gerardo Turcatti¹², Carina von Schantz¹, Neil O. Carragher¹³ - Show less +13 more•Institutions (13)

University of Helsinki¹, Hungarian Academy of Sciences², Pasteur Institute³, Max Planck Society⁴, Queensland University of Technology⁵, Trinity College, Dublin⁶, PSL Research University⁷, University of Oxford⁸, Centro Nacional de Investigaciones Cardiovasculares⁹, Science for Life Laboratory¹⁰, Leiden University¹¹, École Polytechnique Fédérale de Lausanne¹², University of Edinburgh¹³

01 Nov 2016-Nature Reviews Drug Discovery

TL;DR: In this article, the authors propose a set of principles to facilitate the definition and development of disease-relevant assays, and discuss new opportunities for exploiting the latest advances in cell-based assay technologies in drug discovery.

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Abstract: The common and persistent failures to translate promising preclinical drug candidates into clinical success highlight the limited effectiveness of disease models currently used in drug discovery. An apparent reluctance to explore and adopt alternative cell- and tissue-based model systems, coupled with a detachment from clinical practice during assay validation, contributes to ineffective translational research. To help address these issues and stimulate debate, here we propose a set of principles to facilitate the definition and development of disease-relevant assays, and we discuss new opportunities for exploiting the latest advances in cell-based assay technologies in drug discovery, including induced pluripotent stem cells, three-dimensional (3D) co-culture and organ-on-a-chip systems, complemented by advances in single-cell imaging and gene editing technologies. Funding to support precompetitive, multidisciplinary collaborations to develop novel preclinical models and cell-based screening technologies could have a key role in improving their clinical relevance, and ultimately increase clinical success rates.

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384 citations

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References

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Journal Article•DOI•

Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.

[...]

Kazutoshi Takahashi¹, Shinya Yamanaka¹•Institutions (1)

Kyoto University¹

25 Aug 2006-Cell

TL;DR: Induction of pluripotent stem cells from mouse embryonic or adult fibroblasts by introducing four factors, Oct3/4, Sox2, c-Myc, and Klf4, under ES cell culture conditions is demonstrated and iPS cells, designated iPS, exhibit the morphology and growth properties of ES cells and express ES cell marker genes.

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23,959 citations

"A cellular model for sporadic ALS u..." refers methods in this paper

...We reprogrammed skin fibroblasts from 10 healthy subjects, 8 familial and 16 sporadic ALS patients into iPSCs using retroviruses carrying KLF4, SOX2, OCT4, and cMYC (Dimos et al., 2008; Takahashi and Yamanaka, 2006) (Table S1)....
[...]

Journal Article•DOI•

Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis

[...]

Manuela Neumann¹, Deepak M. Sampathu¹, Linda K. Kwong¹, Adam C. Truax¹, Matthew Micsenyi¹, Thomas T. Chou¹, Jennifer Bruce¹, Theresa Schuck¹, Murray Grossman¹, Christopher M. Clark¹, Leo McCluskey¹, Bruce L. Miller², Eliezer Masliah³, Ian R. A. Mackenzie⁴, Howard Feldman⁴, Wolfgang Feiden, Hans A. Kretzschmar⁵, John Q. Trojanowski¹, Virginia M.-Y. Lee¹ - Show less +15 more•Institutions (5)

University of Pennsylvania¹, University of California, San Francisco², University of California, San Diego³, University of British Columbia⁴, Ludwig Maximilian University of Munich⁵

06 Oct 2006-Science

TL;DR: It is shown that TDP-43 is the major disease protein in both frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis.

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Abstract: Ubiquitin-positive, tau- and alpha-synuclein-negative inclusions are hallmarks of frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis. Although the identity of the ubiquitinated protein specific to either disorder was unknown, we showed that TDP-43 is the major disease protein in both disorders. Pathologic TDP-43 was hyper-phosphorylated, ubiquitinated, and cleaved to generate C-terminal fragments and was recovered only from affected central nervous system regions, including hippocampus, neocortex, and spinal cord. TDP-43 represents the common pathologic substrate linking these neurodegenerative disorders.

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5,440 citations

"A cellular model for sporadic ALS u..." refers background or result in this paper

...…inclusions are the predominant forms of TDP-43 pathology, neuronal intranuclear TDP-43 inclusions have also been reported in postmortem tissue from some patients (Arai et al., 2006; Cairns et al., 2007; Collins et al., 2012; Neumann et al., 2009; Neumann et al., 2007; Neumann et al., 2006)....
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...The most prominent form of pathology present across sALS patients includes changes in TAR DNA-binding protein 43 (TDP-43, TARDBP) expression and subcellular localization (Arai et al., 2006; Mackenzie et al., 2007; Neumann et al., 2009; Neumann et al., 2007; Neumann et al., 2006)....
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...2D) (Inukai et al., 2008; Neumann et al., 2009; Neumann et al., 2006)....
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...While cytoplasmic TDP-43 aggregates are more common than intranuclear aggregates, intranuclear TDP-43 aggregates have been reported in FTLD patients with GRN mutations, fALS patients with VCP mutations, and in some sALS patients (Arai et al., 2006; Cairns et al., 2007; Collins et al., 2012; Neumann et al., 2009; Neumann et al., 2007; Neumann et al., 2006)....
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...Different forms of TDP-43 pathology reported in ALS and FTLD patient central nervous system (CNS) include cytoplasmic mis-localization; hyperphosphorylated, intranuclear and cytoplasmic TDP-43 positive aggregates; TDP-43 and ubiquitin-positive aggregates; and nuclear clearing of TDP-43 (Arai et al., 2006; Arai et al.; Inukai et al., 2008; Neumann et al., 2007; Neumann et al., 2006)....
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Journal Article•DOI•

Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling

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Stuart M. Chambers¹, Christopher A. Fasano¹, Eirini P. Papapetrou¹, Mark J. Tomishima¹, Michel Sadelain¹, Lorenz Studer¹ - Show less +2 more•Institutions (1)

Kettering University¹

01 Mar 2009-Nature Biotechnology

TL;DR: Noggin/SB431542-based neural induction should facilitate the use of hES and hiPS cells in regenerative medicine and disease modeling and obviate the need for protocols based on stromal feeders or embryoid bodies.

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Abstract: Current neural induction protocols for human embryonic stem (hES) cells rely on embryoid body formation, stromal feeder co-culture or selective survival conditions. Each strategy has considerable drawbacks, such as poorly defined culture conditions, protracted differentiation and low yield. Here we report that the synergistic action of two inhibitors of SMAD signaling, Noggin and SB431542, is sufficient to induce rapid and complete neural conversion of >80% of hES cells under adherent culture conditions. Temporal fate analysis reveals the appearance of a transient FGF5(+) epiblast-like stage followed by PAX6(+) neural cells competent to form rosettes. Initial cell density determines the ratio of central nervous system and neural crest progeny. Directed differentiation of human induced pluripotent stem (hiPS) cells into midbrain dopamine and spinal motoneurons confirms the robustness and general applicability of the induction protocol. Noggin/SB431542-based neural induction should facilitate the use of hES and hiPS cells in regenerative medicine and disease modeling and obviate the need for protocols based on stromal feeders or embryoid bodies.

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3,152 citations

Additional excerpts

...1C and 1D) (Chambers et al., 2009; Dimos et al., 2008)....
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Journal Article•DOI•

TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis

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Jemeen Sreedharan¹, Ian P. Blair², Vineeta B. Tripathi¹, Xun Hu¹, Caroline Vance¹, Boris Rogelj¹, Steven Ackerley¹, Steven Ackerley³, Jennifer C Durnall, Kelly L. Williams, Emanuele Buratti⁴, Francisco E. Baralle⁴, Jacqueline de Belleroche⁵, J. Douglas Mitchell, P. Nigel Leigh¹, Ammar Al-Chalabi¹, Christopher C.J. Miller³, Christopher C.J. Miller¹, Garth A. Nicholson⁶, Garth A. Nicholson², Christopher Shaw¹ - Show less +17 more•Institutions (6)

Medical Research Council¹, University of Sydney², King's College London³, International Centre for Genetic Engineering and Biotechnology⁴, Imperial College London⁵, Concord Repatriation General Hospital⁶

21 Mar 2008-Science

TL;DR: The evidence suggests a pathophysiological link between TDP-43 and ALS, and neighboring mutations in a highly conserved region of TARDBP in sporadic and familial ALS cases.

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Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder characterized pathologically by ubiquitinated TAR DNA binding protein (TDP-43) inclusions. The function of TDP-43 in the nervous system is uncertain, and a mechanistic role in neurodegeneration remains speculative. We identified neighboring mutations in a highly conserved region of TARDBP in sporadic and familial ALS cases. TARDBPM337V segregated with disease within one kindred and a genome-wide scan confirmed that linkage was restricted to chromosome 1p36, which contains the TARDBP locus. Mutant forms of TDP-43 fragmented in vitro more readily than wild type and, in vivo, caused neural apoptosis and developmental delay in the chick embryo. Our evidence suggests a pathophysiological link between TDP-43 and ALS.

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2,425 citations

Journal Article•DOI•

TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis

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Tetsuaki Arai, Masato Hasegawa, Haruhiko Akiyama, Kenji Ikeda, Takashi Nonaka, Hiroshi Mori¹, David M. A. Mann², Kuniaki Tsuchiya³, Mari Yoshida⁴, Yoshio Hashizume⁴, Tatsuro Oda - Show less +7 more•Institutions (4)

Osaka City University¹, University of Manchester², Tokyo Metropolitan Matsuzawa Hospital³, Aichi Medical University⁴

22 Dec 2006-Biochemical and Biophysical Research Communications

TL;DR: The common occurrence of intracellular accumulations of TDP-43 supports the hypothesis that these disorders represent a clinicopathological entity of a single disease, and suggests that they can be newly classified as a proteinopathy of T DP-43.

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2,263 citations