Human-Induced Pluripotent Stem Cell-Derived Hepatocytes and their Culturing Methods to Maintain Liver Functions for Pharmacokinetics and Safety Evaluation of Pharmaceuticals

Inoue, Tomoaki; Iwazaki, Norihiko; Araki, Tetsuro; Hitotsumachi, Hiroko

doi:10.2174/1389201021666200131123524

Cited by 8 publications

(7 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Stem cells in cytotoxicity studies are used for biomaterials screening applications and generating comprehensive biomaterials cytotoxicity profiles [67]. In vitro profiling of cytotoxicity effects of food additives, pharmaceutical, and medical devices on stem cells reveals their potential hazards before proceeding to the trials on animals and humans [68]. Historically, cytotoxicity profiling of biomaterials has entirely relied on animals.…”

Section: Stem Cells Models For Cytotoxicity Studiesmentioning

confidence: 99%

Stem cells based in vitro models: trends and prospects in biomaterials cytotoxicity studies

Ahmed¹,

Ahmed²,

Masoud³

et al. 2021

Biomed. Mater.

View full text Add to dashboard Cite

Advanced biomaterials are increasingly used for numerous medical applications from the delivery of cancer-targeted therapeutics to the treatment of cardiovascular diseases. The issues of foreign body reactions induced by biomaterials must be controlled for preventing treatment failure. Therefore, it is important to assess the biocompatibility and cytotoxicity of biomaterials on cell culture systems before proceeding to in vivo studies in animal models and subsequent clinical trials. Direct use of biomaterials on animals create technical challenges and ethical issues and therefore, the use of non-animal models such as stem cell cultures could be useful for determination of their safety. However, failure to recapitulate the complex in vivo microenvironment have largely restricted stem cell cultures for testing the cytotoxicity of biomaterials. Nevertheless, properties of stem cells such as their self-renewal and ability to differentiate into various cell lineages make them an ideal candidate for in vitro screening studies. Furthermore, the application of stem cells in biomaterials screening studies may overcome the challenges associated with the inability to develop a complex heterogeneous tissue using primary cells. Currently, embryonic stem cells, adult stem cells, and induced pluripotent stem cells are being used as in vitro preliminary biomaterials testing models with demonstrated advantages over mature primary cell or cell line based in vitro models. This review discusses the status and future directions of in vitro stem cell-based cultures and their derivatives such as spheroids and organoids for the screening of their safety before their application to animal models and human in translational research.

show abstract

Section: Stem Cells Models For Cytotoxicity Studiesmentioning

confidence: 99%

Stem cells based in vitro models: trends and prospects in biomaterials cytotoxicity studies

Ahmed¹,

Ahmed²,

Masoud³

et al. 2021

Biomed. Mater.

View full text Add to dashboard Cite

show abstract

“…Such facilities are being made available, and cell producing projects are currently ongoing, aiming for clinical applications 62 . For wide clinical application, inducing spheroids at such a large-scale platform would be a promising method, along with hepatocytes induction from induced pluripotent stem cells 63 , artificial organoids 64 , or biomaterials 65 . It should also be considered that the current clinical HCTx is performed in allogeneic settings, in which engrafted cells are exposed to subsequent adoptive immune reactions 66 .…”

Section: Discussionmentioning

confidence: 99%

The Efficacy of the Hepatocyte Spheroids for Hepatocyte Transplantation

et al. 2021

View full text Add to dashboard Cite

The safety and short-term efficacy of hepatocyte transplantation (HCTx) have been widely proven. However, issues such as reduced viability and/or function of hepatocytes, insufficient engraftment, and lack of a long-term effect have to be overcome for widespread application of HCTx. In this study, we evaluated hepatocyte spheroids (HSs), formed by self-aggregation of hepatocytes, as an alternative to hepatocytes in single-cell suspension. Hepatocytes were isolated from C57BL/6 J mice liver using a three-step collagenase perfusion technique and HSs were formed by the hanging drop method. After the spheroids formation, the HSs showed significantly higher mRNA expression of albumin, ornithine transcarbamylase, glucose-6-phosphate, alpha-1-antitrypsin, low density lipoprotein receptor, coagulation factors, and apolipoprotein E (ApoE) than 2 dimensional (2D)-cultured hepatocytes ( p < 0.05). Albumin production by HSs was significantly higher than that by 2D-cultured hepatocytes (9.5 ± 2.5 vs 3.5 ± 1.8 μg/dL, p < 0.05). The HSs, but not single hepatocytes, maintained viability and albumin mRNA expression in suspension (92.0 ± 2.8% and 1.03 ± 0.09 at 6 h). HSs (3.6 × 106 cells) or isolated hepatocytes (fSH, 3.6 × 106 cells) were transplanted into the liver of ApoE knockout (KO-/-) mice via the portal vein. Following transplantation, serum ApoE concentration (ng/mL) of HS-transplanted mice (1w: 63.1 ± 56.7, 4w: 17.0 ± 10.9) was higher than that of fSH-transplanted mice (1 w: 33.4 ± 13.0, 4w: 13.7 ± 9.6). In both groups, the mRNA levels of pro-inflammatory cytokines (IL-6, IL-1β, TNF-α, MCP-1, and MIP-1β) were upregulated in the liver following transplantation; however, no significant differences were observed. Pathologically, transplanted HSs were observed as flat cell clusters in contact with the portal vein wall on day 7. Additionally, ApoE positive cells were observed in the liver parenchyma distant from the portal vein on day 28. Our results indicate that HS is a promising alternative to single hepatocytes and can be applied for HCTx.

show abstract

“…Many factors affect pharmacokinetics and pharmacodynamics, such as genetic polymorphisms for drug-metabolizing enzymes and transporters, ion channels and receptors, epigenetic alterations, environmental factors, and concomitant diseases. A powerful strategy to overcome this issue is represented by induced pluripotent stem cells (iPSCs), discovered by K. Takahashi and Yamanaka (2006), which offer a versatile tool to study ADRs in personalized assays (Inoue et al, 2020;Wills & Rajagopalan, 2020). iPSCs are stem cells generated by reprogramming differentiated cells, usually adult somatic cells, which can be easily obtained from peripheral blood samples.…”

Section: Introductionmentioning

confidence: 99%

iPSCs as a groundbreaking tool for the study of adverse drug reactions: A new avenue for personalized therapy

Rispoli,

Scandiuzzi Piovesan,

Decorti

et al. 2023

WIREs Mechanisms of Disease

View full text Add to dashboard Cite

Induced pluripotent stem cells (iPSCs), obtained by reprogramming different somatic cell types, represent a promising tool for the study of drug toxicities, especially in the context of personalized medicine. Indeed, these cells retain the same genetic heritage of the donor, allowing the development of personalized models. In addition, they represent a useful tool for the study of adverse drug reactions (ADRs) in special populations, such as pediatric patients, which are often poorly represented in clinical trials due to ethical issues. Particularly, iPSCs can be differentiated into any tissue of the human body, following several protocols which use different stimuli to induce specific differentiation processes. Differentiated cells also maintain the genetic heritage of the donor, and therefore are suitable for personalized pharmacological studies; moreover, iPSC‐derived differentiated cells are a valuable tool for the investigation of the mechanisms underlying the physiological differentiation processes. iPSCs‐derived organoids represent another important tool for the study of ADRs. Precisely, organoids are in vitro 3D models which better represent the native organ, both from a structural and a functional point of view. Moreover, in the same way as iPSC‐derived 2D models, iPSC‐derived organoids are appropriate personalized models since they retain the genetic heritage of the donor. In comparison to other in vitro models, iPSC‐derived organoids present advantages in terms of versatility, patient‐specificity, and ethical issues. This review aims to provide an updated report of the employment of iPSCs, and 2D and 3D models derived from these, for the study of ADRs.This article is categorized under: Cancer > Stem Cells and Development

show abstract

Human-Induced Pluripotent Stem Cell-Derived Hepatocytes and their Culturing Methods to Maintain Liver Functions for Pharmacokinetics and Safety Evaluation of Pharmaceuticals

Cited by 8 publications

References 57 publications

Stem cells based in vitro models: trends and prospects in biomaterials cytotoxicity studies

Stem cells based in vitro models: trends and prospects in biomaterials cytotoxicity studies

The Efficacy of the Hepatocyte Spheroids for Hepatocyte Transplantation

iPSCs as a groundbreaking tool for the study of adverse drug reactions: A new avenue for personalized therapy

Contact Info

Product

Resources

About