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- Title
Recapitulation of methotrexate hepatotoxicity with induced pluripotent stem cell-derived hepatocytes from patients with rheumatoid arthritis.
- Authors
Kim, Juryun; Kim, Yena; Choi, Jinhyeok; Jung, Hyerin; Lee, Kijun; Kang, Jaewoo; Park, Narae; Rim, Yeri Alice; Nam, Yoojun; Ju, Ji Hyeon
- Abstract
Background: Methotrexate (MTX) is widely used for the treatment of rheumatoid arthritis (RA). The drug is cost-effective, but sometimes causes hepatotoxicity, requiring a physician's attention. In this study, we simulated hepatotoxicity by treating hepatocytes derived from RA patient–derived induced pluripotent stem cells (RA-iPSCs) with MTX. Methods: RA-iPSCs and healthy control iPSCs (HC-iPSCs) were established successfully. RA-iPSCs were differentiated into hepatocytes in two-dimensional (2D) monolayers and three-dimensional (3D) hepatocyte spheroid cultures; this process required growth factors such as BMP4, bFGF, HGF, and OSM. Immunofluorescence staining and flow cytometry were performed to confirm that the mature hepatocytes expressed cytokeratin 18, anti–alpha-1 antitrypsin, and albumin. MTX toxicity was evaluated via monitoring of cell viability, alanine aminotransferase, and mitochondrial status after MTX treatment in 2D and 3D cultures. Results: RA-iPSCs generated from three RA patients suffering from MTX-induced hepatotoxicity differentiated into the endoderm lineage, hepatoblasts, and hepatocytes. In 2D culture, RA-iPSC-derived hepatocytes were more sensitive to MTX than healthy controls. A 3D culture system using hepatocyte spheroids also successfully recapitulated MTX-induced hepatotoxicity. The 3D culture system had several advantages, including longer culture periods under more complex conditions. Conclusions: A patient-derived iPSC platform could recapitulate MTX toxicity. Simulation of drug toxicity in vitro may help clinicians choose safer drugs or less toxic doses.
- Subjects
METHOTREXATE; PLURIPOTENT stem cells; LIVER cells; RHEUMATOID arthritis; HEPATOTOXICOLOGY
- Publication
Stem Cell Research & Therapy, 2018, Vol 9, Issue 1, pN.PAG
- ISSN
1757-6512
- Publication type
Article
- DOI
10.1186/s13287-018-1100-1