Population-based high-throughput toxicity screen of human iPSC-derived cardiomyocytes and neurons

Huang, Ching Ying; Nicholson, Martin W.; Wang, Jyun Yuan; Ting, Chien Yu; Tsai, Ming Heng; Cheng, Yu; Liu, Chun Lin; Chan, Darien Zhing Herr; Lee, Yi-Chan; Hsu, Ching Chuan; Hsu, Yu Hung; Yang, Chiou Fong; Chang, Cindy M.; Ruan, Shu Chian; Lin, Po Ju; Lin, Jen Hao; Chen, Li Lun; Hsieh, Marvin L; Cheng, Yuan; Hsu, Wei Hsuan; Lin, Yi-Ling; Chen, Chien Hsiun; Hsu, Yu-Hsiang; Hacker, Timothy A.; Wu, Joseph C.; Kamp, Timothy J.; Hsieh, Patrick C.H.

doi:10.1016/j.celrep.2022.110643

Cited by 20 publications

(19 citation statements)

References 71 publications

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“…The neurons are mainly (~80%) glutamatergic with a small population (~20% GABAergic) of neurons. The cardiomyocytes and neurons used here have been fully characterized in a previous publication [20].…”

Section: Resultsmentioning

confidence: 99%

“…In a previous study, we generated an induced pluripotent cell (iPSC)-based population drug screening platform using human iP-SCs. We generated 13 cell lines that were representative of Taiwans population, based on the high-frequency human leukocyte antigen (HLA) alleles in Taiwan [20]. Using these cell lines, we generated and characterized cardiomyocytes (hiPSC-CMs) and neurons (hiPSC-NEURs).…”

Section: Sars-cov-2 Virus Infection Of Ipsc-derived Cardiomyocytes An...mentioning

confidence: 99%

“…HLA homozygous hiPSCs were generated and provided by the Taiwan Human Disease iPS Cells Service Consortium (accessed on 18 June 2022 http://ipsc.ibms.sinica.edu.tw/index_e.html). They were cultured according to a previously published protocol [20].…”

Section: Human Ipscsmentioning

confidence: 99%

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Cardio- and Neurotoxicity of Selected Anti-COVID-19 Drugs

et al. 2022

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Since December 2019, the novel coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected ~435 million people and caused ~6 million related deaths as of March 2022. To combat COVID-19, there have been many attempts to repurpose FDA-approved drugs or revive old drugs. However, many of the current treatment options have been known to cause adverse drug reactions. We employed a population-based drug screening platform using 13 human leukocyte antigen (HLA) homozygous human induced pluripotent cell (iPSC) lines to assess the cardiotoxicity and neurotoxicity of the first line of anti-COVID-19 drugs. We also infected iPSC-derived cells to understand the viral infection of cardiomyocytes and neurons. We found that iPSC-derived cardiomyocytes express the ACE2 receptor which correlated with a higher infection of the SARS-CoV-2 virus (r = 0.86). However, we were unable to detect ACE2 expression in neurons which correlated with a low infection rate. We then assessed the toxicity of anti-COVID-19 drugs and identified two cardiotoxic compounds (remdesivir and arbidol) and four neurotoxic compounds (arbidol, remdesivir, hydroxychloroquine, and chloroquine). These data show that this platform can quickly and easily be employed to further our understanding of cell-specific infection and identify drug toxicity of potential treatment options helping clinicians better decide on treatment options.

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Section: Resultsmentioning

confidence: 99%

Section: Sars-cov-2 Virus Infection Of Ipsc-derived Cardiomyocytes An...mentioning

confidence: 99%

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Cardio- and Neurotoxicity of Selected Anti-COVID-19 Drugs

et al. 2022

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“…Adverse drug reactions may vary depending on the genetic background of the recipients; however, these adverse drug reactions may not be detectable during conventional drug development or the clinical trial process. In a recent study, Huang et al, 2022, have reported the generation of an HLA-homozygous iPSC bank by screening 1000 healthy donors in Taiwan, and established the first drug screening model representing the Han Chinese population in Taiwan [ 105 ]. The iPSC derivatives were also used to assess the cardiotoxicity and neurotoxicity.…”

Section: Ipsc-based Cell Therapymentioning

confidence: 99%

“…These iPSCs can cover 41% of the Korean population [ 110 ]. Furthermore, 13 HLA homozygous iPSCs, generated by the Taiwan Human Disease iPSC Service Consortium, can cover about 16% of the Taiwanese population based on the HLA-A, HLA-B, and HLA-DRB1 alleles, and was calculated to further represent at least 4.77 million of the world population [ 105 ].…”

Section: Ipsc-based Cell Therapymentioning

confidence: 99%

Utility of iPSC-Derived Cells for Disease Modeling, Drug Development, and Cell Therapy

Nicholson

Ting

Chan

et al. 2022

Cells

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The advent of induced pluripotent stem cells (iPSCs) has advanced our understanding of the molecular mechanisms of human disease, drug discovery, and regenerative medicine. As such, the use of iPSCs in drug development and validation has shown a sharp increase in the past 15 years. Furthermore, many labs have been successful in reproducing many disease phenotypes, often difficult or impossible to capture, in commonly used cell lines or animal models. However, there still remain limitations such as the variability between iPSC lines as well as their maturity. Here, we aim to discuss the strategies in generating iPSC-derived cardiomyocytes and neurons for use in disease modeling, drug development and their use in cell therapy.

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iPS cell therapy 2.0: Preparing for next‐generation regenerative medicine

Hui,

Yamanaka

2024

BioEssays

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This year marks the tenth anniversary of the world's first transplantation of tissue generated from induced pluripotent stem cells (iPSCs). There is now a growing number of clinical trials worldwide examining the efficacy and safety of autologous and allogeneic iPSC‐derived products for treating various pathologic conditions. As we patiently wait for the results from these and future clinical trials, it is imperative to strategize for the next generation of iPSC‐based therapies. This review examines the lessons learned from the development of another advanced cell therapy, chimeric antigen receptor (CAR) T cells, and the possibility of incorporating various new bioengineering technologies in development, from RNA engineering to tissue fabrication, to apply iPSCs not only as a means to achieve personalized medicine but also as designer medical applications.

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Population-based high-throughput toxicity screen of human iPSC-derived cardiomyocytes and neurons

Cited by 20 publications

References 71 publications

Cardio- and Neurotoxicity of Selected Anti-COVID-19 Drugs

Cardio- and Neurotoxicity of Selected Anti-COVID-19 Drugs

Utility of iPSC-Derived Cells for Disease Modeling, Drug Development, and Cell Therapy

iPS cell therapy 2.0: Preparing for next‐generation regenerative medicine

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