Modeling Progressive Fibrosis with Pluripotent Stem Cells Identifies an Anti-fibrotic Small Molecule

Vijayaraj, Preethi; Minasyan, Aspram; Durra, Abdo; Saravanan, Konda Mani; Mehrabi, Mehrsa; Aros, Cody J.; Ahadome, Sarah D.; Shia, David W.; Chung, Katherine; Sandlin, Jenna M.; Darmawan, Kelly F.; Bhatt, Kush; Manze, Chase C.; Paul, Manash K.; Wilkinson, Dan; Wang, Yan; Clark, Amander T.; Rickabaugh, Tammy M.; Wallace, W. Dean; Graeber, Thomas G.; Damoiseaux, Robert; Gomperts, Brigitte N.

doi:10.1016/j.celrep.2019.11.019

Cited by 22 publications

(22 citation statements)

References 98 publications

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“…In between, in a variety of studies, especially hiPSC-derived cells have been used for testing the efficacy and toxicity of different compounds [ 34 , 37 ]: hiPSC-derived cortical neurons were used to test the impact of 3838 compounds in Lesch-Nyhan disease [ 39 ] and 17,000 small molecules were tested for their anti-fibrotic effects in mesenchymal-like cells [ 40 ]. hiPSC-derived neurons, neural progenitor cells, and motor neurons have been generated to study the effects of the R33 molecule for Alzheimer’s disease, the effects of 135 compounds for Schizophrenia, and 1416 drugs for Amyotrophic lateral sclerosis, respectively [ 41 , 42 , 43 ].…”

Section: Human Pluripotent Stem Cellsmentioning

confidence: 99%

Human Embryo Models and Drug Discovery

Rosner¹,

Reithofer²,

Fink³

et al. 2021

IJMS

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For obvious reasons, such as, e.g., ethical concerns or sample accessibility, model systems are of highest importance to study the underlying molecular mechanisms of human maladies with the aim to develop innovative and effective therapeutic strategies. Since many years, animal models and highly proliferative transformed cell lines are successfully used for disease modelling, drug discovery, target validation, and preclinical testing. Still, species-specific differences regarding genetics and physiology and the limited suitability of immortalized cell lines to draw conclusions on normal human cells or specific cell types, are undeniable shortcomings. The progress in human pluripotent stem cell research now allows the growth of a virtually limitless supply of normal and DNA-edited human cells, which can be differentiated into various specific cell types. However, cells in the human body never fulfill their functions in mono-lineage isolation and diseases always develop in complex multicellular ecosystems. The recent advances in stem cell-based 3D organoid technologies allow a more accurate in vitro recapitulation of human pathologies. Embryoids are a specific type of such multicellular structures that do not only mimic a single organ or tissue, but the entire human conceptus or at least relevant components of it. Here we briefly describe the currently existing in vitro human embryo models and discuss their putative future relevance for disease modelling and drug discovery.

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Section: Human Pluripotent Stem Cellsmentioning

confidence: 99%

Human Embryo Models and Drug Discovery

Rosner¹,

Reithofer²,

Fink³

et al. 2021

IJMS

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“…Furthermore, hPSCs aid in drug discovery, for example by implementing high-throughput screening platforms (figure 2b). High-throughput screening platforms using automated equipment can help to rapidly test a high number of samples, facilitating screening for new biomarkers and/or optimal treatment in in vitro disease models [34,40].…”

Section: Macrophages and Dendritic Cellsmentioning

confidence: 99%

“…This way, hPSCs aid in understanding the molecular mechanism of HPS in vitro [36]. Furthermore, hPSCs from HPS patients and their gene-corrected variant were generated and differentiated VIJAYARAJ [40] Viral infection DCs hPSC-derived DCs were made IRF5-deficient using CRISPR-Cas9 and then infected with influenza A. Compared to control DCs, IRF5-deficient DCs show reduced virus-induced inflammatory cytokine production.…”

Section: Rare Mutationsmentioning

confidence: 99%

“…Fibrosis can be mimicked in mesenchymal organoids using several techniques, without known genetic alterations [39,40]. A first method to mimic PF in the small airways is by using TGF-β in concentrations that would induce cell alterations.…”

Section: Pulmonary Fibrosismentioning

confidence: 99%

“…For both hPSC-derived cells and organoids models, human in vitro models will have to be validated before the new models can be integrated into research and drug developmental studies. Many studies validate their human in vitro models in vivo in mice, ex vivo in human slices, and in vitro with primary cells [40,42,62]. Another opportunity for validation is by running organoid studies next to clinical trials that have been scheduled already, to get a more accurate validation if human in vivo responses are similar to human in vitro responses [63].…”

Section: Validation Of Modelsmentioning

confidence: 99%

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Human pluripotent stem cells for the modelling and treatment of respiratory diseases

et al. 2021

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Respiratory diseases are among the leading causes of morbidity and mortality worldwide, representing a major unmet medical need. New chemical entities rarely make it into the clinic to treat respiratory diseases, which is partially due to a lack of adequate predictive disease models and the limited availability of human lung tissues to model respiratory disease. Human pluripotent stem cells (hPSCs) may help fill this gap by serving as a scalable human in vitro model. In addition, human in vitro models of rare genetic mutations can be generated using hPSCs. hPSC-derived epithelial cells and organoids have already shown great potential for the understanding of disease mechanisms, for finding new potential targets by using high-throughput screening platforms, and for personalised treatments. These potentials can also be applied to other hPSC-derived lung cell types in the future. In this review, we will discuss how hPSCs have brought, and may continue to bring, major changes to the field of respiratory diseases by understanding the molecular mechanisms of the pathology and by finding efficient therapeutics.

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Engineering Advanced In Vitro Models of Systemic Sclerosis for Drug Discovery and Development

et al. 2021

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Systemic sclerosis (SSc) is a complex multisystem disease with the highest case‐specific mortality among all autoimmune rheumatic diseases, yet without any available curative therapy. Therefore, the development of novel therapeutic antifibrotic strategies that effectively decrease skin and organ fibrosis is needed. Existing animal models are cost‐intensive, laborious and do not recapitulate the full spectrum of the disease and thus commonly fail to predict human efficacy. Advanced in vitro models, which closely mimic critical aspects of the pathology, have emerged as valuable platforms to investigate novel pharmaceutical therapies for the treatment of SSc. This review focuses on recent advancements in the development of SSc in vitro models, sheds light onto biological (e.g., growth factors, cytokines, coculture systems), biochemical (e.g., hypoxia, reactive oxygen species) and biophysical (e.g., stiffness, topography, dimensionality) cues that have been utilized for the in vitro recapitulation of the SSc microenvironment, and highlights future perspectives for effective drug discovery and validation.

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Modeling Progressive Fibrosis with Pluripotent Stem Cells Identifies an Anti-fibrotic Small Molecule

Cited by 22 publications

References 98 publications

Human Embryo Models and Drug Discovery

Human Embryo Models and Drug Discovery

Human pluripotent stem cells for the modelling and treatment of respiratory diseases

Engineering Advanced In Vitro Models of Systemic Sclerosis for Drug Discovery and Development

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