When rejuvenation is a problem: challenges of modeling late-onset neurodegenerative disease

Vera, Elsa; Studer, Lorenz

doi:10.1242/dev.120667

Cited by 39 publications

(30 citation statements)

References 45 publications

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“…For this reason, one could argue that 2D iPSC-derivatives are more suitable for modeling early-age onset diseases than adultonset diseases. Nevertheless, multiple groups have successfully modeled adult-onset diseases such as PD and arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) using various approaches to 'induce ageing' in culture (Kim et al, 2013;Vera and Studer, 2015). These approaches include prolonged culturing in vitro, the use of cellular oxidative stressors, induction of adultlike metabolism and overexpression of the ageing protein progerin (Vera and Studer, 2015).…”

Section: The Progress and Limitations Of Modeling Human Diseases In 2dmentioning

confidence: 99%

Modeling human diseases with induced pluripotent stem cells: from 2D to 3D and beyond

et al. 2018

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The advent of human induced pluripotent stem cells (iPSCs) presents unprecedented opportunities to model human diseases. Differentiated cells derived from iPSCs in two-dimensional (2D) monolayers have proven to be a relatively simple tool for exploring disease pathogenesis and underlying mechanisms. In this Spotlight article, we discuss the progress and limitations of the current 2D iPSC disease-modeling platform, as well as recent advancements in the development of human iPSC models that mimic tissues and organs at the three-dimensional (3D) level. Recent bioengineering approaches have begun to combine different 3D organoid types into a single '4D multi-organ system'. We summarize the advantages of this approach and speculate on the future role of 4D multi-organ systems in human disease modeling.

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Section: The Progress and Limitations Of Modeling Human Diseases In 2dmentioning

confidence: 99%

Modeling human diseases with induced pluripotent stem cells: from 2D to 3D and beyond

et al. 2018

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“…Many laboratory animal models of disease do not accurately recapitulate the underling pathobiology of many human diseases and therefore are not effective for therapeutic development. 38 This is especially apparent for complex human diseases, including development of therapeutics for steatohepatitis and fibrosis in liver disease models 39 , the development of cancer therapeutics 40 , the degeneration of dopamine neurons in human Parkinson's disease 38 and the thickened bronchial secretions which is ultimately fatal in human cystic fibrosis 41 , suggesting that the manifestations of human diseases are species specific. 38 Although animal models may imitate some molecular and phenotypic manifestations of human diseases, it is equally clear that drugs progressing into clinical trials based on safety and efficacy from the same animal models fail, and the failures are dominated by a lack of clinical efficacy.…”

Section: The Mps-db As a Resource For Developing Disease Modelsmentioning

confidence: 99%

Applications of the Microphysiology Systems Database for Experimental ADME-Tox and Disease Models

Schurdak

Vernetti

Bergenthal

et al. 2019

Preprint

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To accelerate the development and application of Microphysiological Systems (MPS) in biomedical research and drug discovery/development, a centralized resource is required to provide the detailed design, application, and performance data that enables industry and research scientists to select, optimize, and/or develop new MPS solutions, as well as to harness data from MPS models. We have previously implemented an open source Microphysiology Systems Database (MPS-Db), with a simple icon driven interface, as a resource for MPS researchers and drug discovery/development scientists (https://mps.csb.pitt.edu). The MPS-Db captures and aggregates data from MPS, ranging from static microplate models to integrated, multi-organ microfluidic models, and associates those data with reference data from chemical, biochemical, preclinical, clinical and post-marketing sources to support the design, development, validation, application and interpretation of the models. The MPS-Db enables users to manage their multifactor, multichip studies, then upload, analyze, review, computationally model and share data. Here we discuss how the sharing of MPS study data in the MS-Db is under user control and can be kept private to the individual user, shared with a select group of collaborators, or be made accessible to the general scientific community. We also present a test case using our liver acinus MPS model (LAMPS) as an example and discuss the use of the MPS-Db in managing, designing, and analyzing MPS study data, assessing the reproducibility of MPS models, and evaluating the concordance of MPS model results with clinical findings. We introduce the Disease Portal module with links to resources for the design of MPS disease models and studies and discuss the integration of computational models for the prediction of PK/PD and disease pathways using data generated from MPS models. 45

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“…In addition, earlier disease onset is predictively more successfully modeled in vitro than late onset phenotypes, as these require accumulation of other genetic, environmental, or aging factors to trigger degeneration. It is widely known that reprograming erases age‐related molecular markers such as loss of nuclear LAP2α, heterochromatin markers tri‐methylated H3K9 (H3K9me3) and heterochromatin protein 1 gamma (H3K9me3, HP1γ), as well as reactive oxygen species (ROS) accumulation , and these need to be induced de novo in cell culture. Possibly, direct differentiation between somatic cells as shown recently could preserve age related markers, but full photoreceptor cellular identity has yet to be achieved from somatic sources.…”

Section: The Faithfulness Of Hipsc Based Disease Modelsmentioning

confidence: 99%

Concise Review: Human Induced Pluripotent Stem Cell Models of Retinitis Pigmentosa

et al. 2018

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Hereditary retinal dystrophies, specifically retinitis pigmentosa (RP) are clinically and genetically heterogeneous diseases affecting primarily retinal cells and retinal pigment epithelial cells with blindness as a final outcome. Understanding the pathogenicity behind these diseases has been largely precluded by the unavailability of affected tissue from patients, large genetic heterogeneity and animal models that do not faithfully represent some human diseases. A landmark discovery of human induced pluripotent stem cells (hiPSCs) permitted the derivation of patientspecific cells. These cells have unlimited self-renewing capacity and the ability to differentiate into RP-affected cell types, allowing the studies of disease mechanism, drug discovery, and cell replacement therapies, both as individual cell types and organoid cultures. Together with precise genome editing, the patient specific hiPSC technology offers novel strategies for targeting the pathogenic mutations and design therapies toward retinal dystrophies. This study summarizes current hiPSC-based RP models and highlights key achievements and challenges of these cellular models, as well as questions that still remain unanswered. STEM CELLS 2018;36:474-481 SIGNIFICANCE STATEMENTHereditary retinal dystrophies including retinitis pigmentosa (RP) are clinically and genetically heterogeneous disease affecting primarily retinal cells and retinal pigment epithelial cells, with blindness as a final outcome. Discovery of human induced pluripotent stem cells (hiPSCs) permitted the derivation of patient-specific stem cells with unlimited self-renewing capacity and ability to differentiate into RP-affected cell types allowing studies of disease mechanism, drug discovery, and cell replacement therapies both as individual cell types and organoid cultures. Together with precise genome editing in these cells, this study can correct the pathogenic mutations and design therapies to cure these diseases. This study summarizes current hiPSCbased RP models discussing the major achievements as well as challenges about these cellular models.

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When rejuvenation is a problem: challenges of modeling late-onset neurodegenerative disease

Cited by 39 publications

References 45 publications

Modeling human diseases with induced pluripotent stem cells: from 2D to 3D and beyond

Modeling human diseases with induced pluripotent stem cells: from 2D to 3D and beyond

Applications of the Microphysiology Systems Database for Experimental ADME-Tox and Disease Models

Concise Review: Human Induced Pluripotent Stem Cell Models of Retinitis Pigmentosa

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