Priming adult human hepatocytes as organoids for liver tissue engineering
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ABSTRACT:
PROVIDER: PRJNA855466 | ENA |
REPOSITORIES: ENA
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Project description:While human hepatocytes in the adult liver perform hundreds of life-sustaining functions, culture methods to support their phenotype and function in vitro remain elusive. Here, we describe establishment of an organoid culture system for adult human hepatocytes and demonstrate its robustness by generating organoids from eight different adult donors. Organoids accurately model the phenotype and morphology of hepatocytes in the adult liver, express a mature liver transcriptome distinct from fetal hepatocytes, and exhibit mature functions such as inducible cytochrome activity. Finally, hepatocyte organoids efficiently engraft in vivo in engineered tissues, exhibiting up to 25-fold greater functionality after engraftment compared to previous adult hepatocyte models. Furthermore, organoids negate the need for inclusion of exogenous non-parenchymal cells in engineered tissues to support engraftment, an important translational milestone. These results demonstrate the potential of adult human hepatocyte organoids for basic and translational applications such as pharmaceutical screening and hepatic regenerative medicine.
2025-07-02 | GSE207434 | GEO
Project description:Adult primary human hepatocytes (PHHs) are the gold standard in ex vivo toxicological studies and possess the clinical potential to treat patients with liver disease as advanced therapy medicinal products (ATMPs). However, the utility of this valuable cell type has been limited by short-term functionality and limited expansion potential in vitro. While notable advances have been made in the long-term maintenance of primary hepatocytes, there has been limited success in driving the efficient generation and expansion of adult PHH-derived organoids which recapitulate both liver tissue architecture and function, hampering in vitro studies and regenerative medicine applications. Here we describe the mass generation and long-term expansion of hepatocyte organoids with functionally interconnected hepatic and biliary-like structures from adult primary human hepatocytes. Hepatocyte organoids retain the expression of lineage and functional markers, closely resembling PHH, while also acquiring the expression of regeneration, fetal and biliary markers. Organoids perform key hepatocyte functions while proliferating and can be matured to enhance their functionality. As a proof-of-principle, we demonstrate that hepatocyte organoids can recapitulate hallmarks of cholestasis and steatosis in vitro. Moreover, we show that hepatocytes can be transfected, transduced and gene edited in 3D prior to organoid generation, facilitating a wide range of applications. Our novel hepatocyte organoid system bridges the gap between short-term functionality of primary human hepatocytes and the need for scalable, long-term organoid models of the adult liver, offering immense potential for drug testing, disease modeling, and advanced therapeutic applications.
2025-07-23 | GSE298576 | GEO
Project description:Mass generation and long-term expansion of hepatocyte organoids from adult primary hepatocytes
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Project description:Pluripotent stem cell (PSC)-derived organoids are emerging as novel human-based microphysiological models but display immature phenotypes with limited subsets of endothelial or stromal cells. Here we demonstrate that in vitro manipulation of gene regulatory networks (GRNs) in PSC-derived liver organoids selected either through computational analysis or targeted tissue design can advance tissue maturation in vitro. Through an unbiased comparison with the genetic signature of mature livers, we identify downregulated GRNs in fetal liver organoids compared to adult livers. We demonstrate that overexpression of PROX1 and ATF5, together with targeted CRISPR-based transcriptional activation of endogenous CYP3A4, drives maturation in vitro. Single cell analyses reveal hepatobiliary-, endothelial-, and stellate-like cell populations. The engineered organoids demonstrate enhanced vasculogenesis, capture native liver characteristics (e.g. FXR signaling, CYP3A4 activity), and exhibit therapeutic potential in mice. Collectively, our approach provides a genetically guided framework for engineering developmentally advanced multilineage tissues from hiPSCs.
2020-12-07 | GSE159491 | GEO
Project description:Gene expression profiling of adult human hepatocytes
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Project description:Intestinal failure (IF), following extensive anatomical or functional loss of small intestine (SI), hasdebilitating long-term consequences on children1. Priority of care is to increase the child’s length of functional intestine, jejunum in particular, to promote nutritional independence2. Here we construct autologous jejunal mucosal grafts using primary patient biomaterials. We show that organoids derived from patients can be expanded efficiently in vitro. In parallel, we generate decellularized human intestinal matrix with intact nanotopography, which form optimal biological scaffolds. Remarkably, proteomic and Raman spectroscopy analyses reveal highly analogous biochemical profiles of human SI and colon scaffolds, indicating that both can be used interchangeably as platforms for intestinal engineering. Indeed, seeding jejunal organoids onto either scaffold type reliably reconstructs grafts that exhibit several aspects of physiological jejunal function with potential to survive after transplantation. Our findings provide proof-of-concept data for engineering IF patient-specific jejunal grafts, ultimately aiding in restoration of nutritional autonomy.
2020-09-16 | PXD019816 | Pride
Project description:To analyze stem/progenitor cell function, we purified hepatocytes derived from adult livers and fetal hepatoblasts derived from embryonic day 13 livers. Compared gene expression in E13 hepatoblasts and adult hepatocytes derived from C57BL/6NCr mice
2014-04-11 | E-GEOD-56734 | biostudies-arrayexpress
Project description:We found that hepatocytes isolated from adult mouse livers can dedifferentiate into progenitor-like cells and exhibit a hybrid epithelial/mesenchymal phenotype in monolayer culture. dediHeps can re-differentiate into mature hepatocytes by forming aggregates and fetal intestinal progenitor cells (FIPCs) by forming organoids in three-dimensional culture. We conducted RNA-seq analyses to investigate the characteristincs of hepatocytes, dediHeps, dediHep aggregates, dediHep derived spherical organoids, dediHep derived budding organoids, FIPC derived spherical organoids, intestinal stem cell (ISC) derived budding organoids, and CLiP cells (Katsuda, 2016).
2024-04-02 | GSE248554 | GEO
Project description:Understanding gene expression profile and transcriptional regulation of healthy adult human hepatocytes Gene expression was analyzed
2018-06-07 | GSE115410 | GEO