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Human Induced Pluripotent Stem Cells as a Screening Platform for Drug-Induced Vascular Toxicity

Evaluation of potential vascular injury is an essential part of the safety study during pharmaceutical development. Vascular liability issues are important causes of drug termination during preclinical investigations. Currently, preclinical assessment of vascular toxicity primarily relies on the use...

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Autores principales: Tu, Chengyi, Cunningham, Nathan J., Zhang, Mao, Wu, Joseph C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006367/
https://www.ncbi.nlm.nih.gov/pubmed/33790786
http://dx.doi.org/10.3389/fphar.2021.613837
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author Tu, Chengyi
Cunningham, Nathan J.
Zhang, Mao
Wu, Joseph C.
author_facet Tu, Chengyi
Cunningham, Nathan J.
Zhang, Mao
Wu, Joseph C.
author_sort Tu, Chengyi
collection PubMed
description Evaluation of potential vascular injury is an essential part of the safety study during pharmaceutical development. Vascular liability issues are important causes of drug termination during preclinical investigations. Currently, preclinical assessment of vascular toxicity primarily relies on the use of animal models. However, accumulating evidence indicates a significant discrepancy between animal toxicity and human toxicity, casting doubt on the clinical relevance of animal models for such safety studies. While the causes of this discrepancy are expected to be multifactorial, species differences are likely a key factor. Consequently, a human-based model is a desirable solution to this problem, which has been made possible by the advent of human induced pluripotent stem cells (iPSCs). In particular, recent advances in the field now allow the efficient generation of a variety of vascular cells (e.g., endothelial cells, smooth muscle cells, and pericytes) from iPSCs. Using these cells, different vascular models have been established, ranging from simple 2D cultures to highly sophisticated vascular organoids and microfluidic devices. Toxicity testing using these models can recapitulate key aspects of vascular pathology on molecular (e.g., secretion of proinflammatory cytokines), cellular (e.g., cell apoptosis), and in some cases, tissue (e.g., endothelium barrier dysfunction) levels. These encouraging data provide the rationale for continuing efforts in the exploration, optimization, and validation of the iPSC technology in vascular toxicology.
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spelling pubmed-80063672021-03-30 Human Induced Pluripotent Stem Cells as a Screening Platform for Drug-Induced Vascular Toxicity Tu, Chengyi Cunningham, Nathan J. Zhang, Mao Wu, Joseph C. Front Pharmacol Pharmacology Evaluation of potential vascular injury is an essential part of the safety study during pharmaceutical development. Vascular liability issues are important causes of drug termination during preclinical investigations. Currently, preclinical assessment of vascular toxicity primarily relies on the use of animal models. However, accumulating evidence indicates a significant discrepancy between animal toxicity and human toxicity, casting doubt on the clinical relevance of animal models for such safety studies. While the causes of this discrepancy are expected to be multifactorial, species differences are likely a key factor. Consequently, a human-based model is a desirable solution to this problem, which has been made possible by the advent of human induced pluripotent stem cells (iPSCs). In particular, recent advances in the field now allow the efficient generation of a variety of vascular cells (e.g., endothelial cells, smooth muscle cells, and pericytes) from iPSCs. Using these cells, different vascular models have been established, ranging from simple 2D cultures to highly sophisticated vascular organoids and microfluidic devices. Toxicity testing using these models can recapitulate key aspects of vascular pathology on molecular (e.g., secretion of proinflammatory cytokines), cellular (e.g., cell apoptosis), and in some cases, tissue (e.g., endothelium barrier dysfunction) levels. These encouraging data provide the rationale for continuing efforts in the exploration, optimization, and validation of the iPSC technology in vascular toxicology. Frontiers Media S.A. 2021-03-10 /pmc/articles/PMC8006367/ /pubmed/33790786 http://dx.doi.org/10.3389/fphar.2021.613837 Text en Copyright © 2021 Tu, Cunningham, Zhang and Wu. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Tu, Chengyi
Cunningham, Nathan J.
Zhang, Mao
Wu, Joseph C.
Human Induced Pluripotent Stem Cells as a Screening Platform for Drug-Induced Vascular Toxicity
title Human Induced Pluripotent Stem Cells as a Screening Platform for Drug-Induced Vascular Toxicity
title_full Human Induced Pluripotent Stem Cells as a Screening Platform for Drug-Induced Vascular Toxicity
title_fullStr Human Induced Pluripotent Stem Cells as a Screening Platform for Drug-Induced Vascular Toxicity
title_full_unstemmed Human Induced Pluripotent Stem Cells as a Screening Platform for Drug-Induced Vascular Toxicity
title_short Human Induced Pluripotent Stem Cells as a Screening Platform for Drug-Induced Vascular Toxicity
title_sort human induced pluripotent stem cells as a screening platform for drug-induced vascular toxicity
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006367/
https://www.ncbi.nlm.nih.gov/pubmed/33790786
http://dx.doi.org/10.3389/fphar.2021.613837
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