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Scalable production oftissue-like vascularised liver organoids from human PSCs.

ABSTRACT: Organoid models have been developed for a number of tissues including the liver. Currenthepatic organoid models are generally simplistic, composed of hepatocytes orcholangiocytes, rendering them less physiologically relevant when compared to nativetissue. To address this we have developed an approach that does not require 2Dpatterning, which is ECM independent and growth factor free, to mimic embryonic liverdevelopment that produces massive quantities of liver like organoids. Using single-cell RNAsequencing and immunofluorescence we demonstrate a liver-like cellular repertoire,presenting with vascular luminal structures,and a population of resident macrophage – theKupffer cells. The organoids exhibit key liver functions including drug metabolism, serumprotein production, urea synthesis and coagulation factor production, which preservedpost-translational modifications such as N-glycosylation and functionality. The organoidscan be transplanted and maintained inmice producing human albumin long term.Theorganoids exhibit a complex cellular repertoire reflective of the organ, havede novovascularization, and liver like function. This isa pre-requisite for a myriad of applicationsfrom cellular therapy, tissue engineering, drug toxicity assessment, disease modeling, tobasic developmental biology.

ORGANISM(S): Homo sapiens

PROVIDER: GSE245379 | GEO | 2023/10/18

REPOSITORIES: GEO

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Project description:In Rspondin-based three-dimensional cultures, Lgr5 stem cells from multiple organs form ever-expanding epithelial organoids that retain their tissue identity. Here we report the establishment of tumor organoid cultures from 20 consecutive colorectal carcinoma (CRC) patients. For most, organoids were also generated from adjacent normal tissue. Organoids closely resemble the original tumor. The spectrum of genetic changes within the 'living biobank' agrees well with previous large-scale mutational analyses of CRC. Gene expression analysis indicates that the major CRC molecular subtypes are represented. Tumor organoids are amenable to high-throughput drug screens allowing detection of gene-drug associations. As an example, a single organoid culture was exquisitely sensitive to Wnt secretion (porcupine) inhibitors and carried a mutation in the negative Wnt feedback regulator RNF43, rather than in APC. Organoid technology may fill the gap between cancer genetics and patient trials, complement cell line- and xenograft-based drug studies and allow personalized therapy design. Self-renewal of the intestinal epithelium is driven by Lgr5 stem cells located in crypts. We have recently developed a long-term culture system that maintains basic crypt physiology. Wnt signals are required for the maintenance of active crypt stem cells. Indeed, the Wnt agonist R-spondin1 induces dramatic crypt hyperplasia in vivo. R-spondin-1 is the ligand for Lgr5. Epidermal growth factor (EGF) signaling is associated with intestinal proliferation, while transgenic expression of Noggin induces a dramatic increase in crypt numbers. The combination of R-spondin-1, EGF, and Noggin in Matrigel sustains ever-expanding small intestinal organoids, which display all hallmarks of the original tissue in terms of architecture, cell type composition, and self-renewal dynamics. We adapted the culture condition for long-term expansion of human colonic epithelium and primary colonic adenocarcinoma, by adding nicotinamide, A83-01 (Alk inhibitor), Prostaglandin E2 and the p38 inhibitor SB202190. Of note, a two-dimensional culture method for cells from normal and malignant primary tissue has been described by Schlegel and colleagues. Here, we explore organoid technology to routinely establish and phenotypically annotate ‘paired organoids’ derived from adjacent tumor and healthy epithelium from CRC patients.

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Scalable production oftissue-like vascularised liver organoids from human PSCs.

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