Human-induced pluripotent stem cell (hiPSC)-derived hepatocytes (iHEP) offer an attractive alternative to primary human hepatocytes (PHH) for drug toxicity studies, as PHHs are limited in supply, vary in their metabolic activity between donors, and rapidly lose their functionality in vitro. However, one of the major drawbacks with iHEP cells in drug safety studies is their decreased phenotypic maturity, with lower liver specific enzyme activity compared with that of PHH. Here we evaluated the effects of 3D culture and non-parenchymal cells on the maturation of iHEPs. We describe a serum-free, chemically defined 3D in vitro model using iHEP cells, which is compatible with automation and conventional assay plates. The iHEP cells cultured in this model form polarized aggregates with functional bile canaliculi and strongly increased expression of albumin, urea and genes encoding phase I and II drug metabolism enzymes and bile transporters. Cytochrome P450-mediated metabolism is significantly higher in 3D iHEP aggregates compared to 2D iHEP culture. Furthermore, addition of human liver sinusoidal endothelial cells (sECs) and iPS-derived endothelial cells (iECs) improved mature hepatocyte function and CYP450 enzyme activity. Also, ECs formed endothelial networks within the hepatic 3D cultures, mimicking aspects of an in vivo architecture. Collectively, these results suggest that the iHEP/EC aggregates described here may have the potential to be used for many applications, including as an in vitro model to study liver diseases associated with sinusoidal endothelial cells. STATEMENT OF SIGNIFICANCE: iPS-derived hepatocytes provide an inexhaustible source of cells for drug screening, toxicology studies and cell-based therapies, but lack mature phenotype of adult primary human hepatocytes (PHH). Herein, we show that 3D culture of iPS-derived hepatocytes and their co-culture with human sinusoidal endothelial cells (sECs) to improve their maturity.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.actbio.2019.07.047 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Identification of circadian rhythm-related biomarkers and development of diagnostic models for Crohn's disease using machine learning algorithms.
Comput Methods Biomech Biomed Engin
January 2025
Department of Gastroenterolgy, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, China.
The global rise in Crohn's Disease (CD) incidence has intensified diagnostic challenges. This study identified circadian rhythm-related biomarkers for CD using datasets from the GEO database. Differentially expressed genes underwent Weighted Gene Co-Expression Network Analysis, with 49 hub genes intersected from GeneCards data.
View Article and Find Full Text PDFReceptors for the vasoactive adipokine apelin, termed APJ receptors, are G-protein-coupled receptors and are widely expressed throughout the cardiovascular system. APJ receptors can also signal via G-protein-independent pathways, including G-protein-coupled-receptor kinase 2 (GRK2), which inhibits nitric oxide synthase (eNOS) activity and nitric oxide (NO) production in endothelial cells. Apelin causes endothelium-dependent, NO-mediated relaxation of coronary arteries from normotensive animals, but the effects of activating APJ receptor signaling pathways in hypertensive coronary arteries are largely unknown.
View Article and Find Full Text PDFAdenosine diphosphate stimulates VEGF-independent choroidal endothelial cell proliferation: A potential escape from anti-VEGF therapy.
Proc Natl Acad Sci U S A
January 2025
Department of Pathology, University of California San Diego, La Jolla, CA 92093.
We hypothesized that a strategy employing tissue-specific endothelial cells (EC) might facilitate the identification of tissue- or organ-specific vascular functions of ubiquitous metabolites. An unbiased approach was employed to identify water-soluble small molecules with mitogenic activity on choroidal EC. We identified adenosine diphosphate (ADP) as a candidate, following biochemical purification from mouse EL4 lymphoma extracts.
View Article and Find Full Text PDFAnnexin A8 deficiency delays atherosclerosis progression.
Clin Transl Med
January 2025
Vascular Research Laboratory, IIS-Fundación Jiménez Díaz, Madrid, Spain.
Background: Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipids and leukocytes within the arterial wall. By studying the aortic transcriptome of atherosclerosis-prone apolipoprotein E (ApoE) mice, we aimed to identify novel players in the progression of atherosclerosis.
Methods: RNA-Seq analysis was performed on aortas from ApoE and wild-type mice.
Mechanistic insights into vascular biology via methyltransferase-like 3-driven N-adenosine methylation of RNA.
Front Cell Dev Biol
January 2025
Department of Pediatrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), NHC Key Laboratory of Chronobiology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China.
Recent advancements in the mechanistic comprehension of vascular biology have concentrated on METTL3-mediated N-methyladenosine modification of RNA, which modulates a spectrum of RNA functionalities with precision. Despite extensive investigations into the roles and mechanisms of METTL3 within vascular biology, a holistic review elucidating their interconnections remains absent. This analysis endeavors to meticulously scrutinize the involvement of METTL3 in both the physiological and pathological paradigms of vascular biology.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!