A feasibility study of the toxic responses of human induced pluripotent stem cell-derived hepatocytes to phytochemicals

Smutný, Tomás̆; Harjumäki, Riina; Kanninen, Liisa; Pávek, Petr; Lou, Yan-Ru

doi:10.1016/j.tiv.2018.06.012

Cited by 8 publications

(2 citation statements)

References 39 publications

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“…To improve the performance of the HLC model, the authors suggested to culture cells in a 3D rather than the current 2D monolayer, because the 3D model has been shown to improve the performance of PHH[68]. In 2018, Smutný et al[69] used HLCs to study the toxicity of phytochemicals saikosaponin D, triptolide, deoxycalyciphylline B and monocrotaline known to cause DILI, in comparison with hepatoblastoma-derived HepG2 cells and long-term culture of primary human hepatocytes (LTHHs). In order to compare the cytotoxic effects of the tested phytochemicals, the authors analyzed hepatocyte key markers in the HLCs compared to the HepG2 and LTHHs controls.…”

Section: Gastrointestinal Toxicitymentioning

confidence: 99%

Induced pluripotent stem cells for therapy personalization in pediatric patients: Focus on drug-induced adverse events

Genova¹,

Cavion²,

Lucafò³

et al. 2019

WJSC

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Adverse drug reactions (ADRs) are major clinical problems, particularly in special populations such as pediatric patients. Indeed, ADRs may be caused by a plethora of different drugs leading, in some cases, to hospitalization, disability or even death. In addition, pediatric patients may respond differently to drugs with respect to adults and may be prone to developing different kinds of ADRs, leading, in some cases, to more severe consequences. To improve the comprehension, and thus the prevention, of ADRs, the set-up of sensitive and personalized assays is urgently needed. Important progress is represented by the possibility of setting up groundbreaking patient-specific assays. This goal has been powerfully achieved using induced pluripotent stem cells (iPSCs). Due to their genetic and physiological species-specific differences and their ability to be differentiated ideally into all tissues of the human body, this model may be accurate in predicting drug toxicity, especially when this toxicity is related to individual genetic differences. This review is an up-to-date summary of the employment of iPSCs as a model to study ADRs, with particular attention to drugs used in the pediatric field. We especially focused on the intestinal, hepatic, pancreatic, renal, cardiac, and neuronal levels, also discussing progress in organoids creation. The latter are three-dimensional in vitro culture systems derived from pluripotent or adult stem cells simulating the architecture and functionality of native organs such as the intestine, liver, pancreas, kidney, heart, and brain. Based on the existing knowledge, these models are powerful and promising tools in multiple clinical applications including toxicity screening, disease modeling, personalized and regenerative medicine.

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Section: Gastrointestinal Toxicitymentioning

confidence: 99%

Induced pluripotent stem cells for therapy personalization in pediatric patients: Focus on drug-induced adverse events

Genova¹,

Cavion²,

Lucafò³

et al. 2019

WJSC

View full text Add to dashboard Cite

show abstract

“…Despite the clinical benefits of SSs in a variety of disease models, clinical use of Radix bupleuri products produce several severe adverse effects, including pain, allergy, low blood pressure, dizziness, convulsion as well as limb twitching (Ikegami et al, 2006), untoward effects that have precipitated a black box warning on injectable formulations of Radix bupleuri by China Food and Drug Administration on May 29 th , 2018 (http://cnda.cfda.gov.cn/WS04/CL2050/228214.html). Results from toxicological studies demonstrate that SSd induces cells death in human LO2 hepatocytes and pluripotent stem cell-derived hepatocytes, possibly through disrupting platelet-derived growth factor-β receptor/p38 and activating Fas death receptor within the concentration range capable of producing therapeutic effects (Chen et al, 2013; Li et al, 2017c; Smutny et al, 2018; Zhang et al, 2016). Most recently, SSd has also been demonstrated to produce neurotoxicity.…”

Section: Introductionmentioning

confidence: 99%

Saikosaponin d causes apoptotic death of cultured neocortical neurons by increasing membrane permeability and elevating intracellular Ca2+ concentration

et al. 2019

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Saikosaponins (SSs) are a class of naturally occurring oleanane-type triterpenoid saponins found in Radix bupleuri that has been widely used in traditional Chinese medicine. As the main active principals of Radix bupleuri, SSs have been shown to suppress mouse motor activity, impair learning and memory, and decrease hippocampal neurogenesis. In the present study, we investigated the effect of five SSs (SSa, SSb1, SSb2, SSc, and SSd) on neuronal viability and the underlying mechanisms in cultured murine neocortical neurons. We demonstrate that SSa, SSb1 and SSd produce concentration-dependent apoptotic neuronal death and induce robust increase in intracellular Ca2+ concentration ([Ca2+]i) at low micromolar concentrations with a rank order of SSd > SSa > SSb1, whereas SSb2 and SSc have no detectable effect on both neuronal survival and [Ca2+]i. Mechanistically, SSd-induced elevation in [Ca2+]i is the primary result of enhanced extracellular Ca2+ influx, which likely triggers Ca2+-induced Ca2+ release through ryanodine receptor activation, but not SERCA inhibition. SSd-induced Ca2+ entry occurs through a non-selective mechanism since blockers of major neuronal Ca2+ entry pathways, including L-type Ca2+ channel, NMDA receptor, AMPA receptor, Na+-Ca2+ exchanger, and TRPV1, all failed to attenuate the Ca2+ response to SSd. Further studies demonstrate that SSd increases calcein efflux and induces an inward current in neocortical neurons. Together, these data demonstrate that SSd elevates [Ca2+]i due to its ability to increase membrane permeability, likely by forming pores in the surface membrane, which leads to massive Ca2+ influx and apoptotic neuronal death in neocortical neurons.

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Advances in Human Induced Pluripotent Stem Cell-Derived Hepatocytes for Use in Toxicity Testing

Wills

Rajagopalan

2019

Ann Biomed Eng

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A feasibility study of the toxic responses of human induced pluripotent stem cell-derived hepatocytes to phytochemicals

Cited by 8 publications

References 39 publications

Induced pluripotent stem cells for therapy personalization in pediatric patients: Focus on drug-induced adverse events

Induced pluripotent stem cells for therapy personalization in pediatric patients: Focus on drug-induced adverse events

Saikosaponin d causes apoptotic death of cultured neocortical neurons by increasing membrane permeability and elevating intracellular Ca2+ concentration

Advances in Human Induced Pluripotent Stem Cell-Derived Hepatocytes for Use in Toxicity Testing

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