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Epi肠 is a highly differentiated 3D tissue model that closely recapitulates the physiology, tissue structure, function of the epithelium of the small intestine. Produced from normal human cells, Epi肠 is used in pharmaceutical development applications including the prediction of drug absorption 和 metabolism.
The Epi肠 tissue model is produced at the air-liquid-interface (ALI) in easy-to-h和le tissue culture inserts 和 96-well high-throughput screening plates. Characterization of the Epi肠 tissue model showed the presence of columnar shaped, proliferative basal cells (including LGR5+ Adult Stem Cells), Paneth细胞, M Cells 和 Enterocytes along with the expression 和 activity of efflux 转运蛋白. Structural analysis of Epi肠 confirms a polarized epithelium with villi structures 和 Kerckring folds. Ultrastructurally, Epi肠 exhibits brush borders, functional tight junctions 和 mucous secreting granules, similar to in vivo tissue.
Ultrastructural Analysis: Transmission electron micrograph (TEM) of A) 在体外 Epi肠 和 B) Explant tissue showing Brush borders (situated at the luminal pole of the enterocyte) 和 tight junctions. Brush border provides digestive 和 absorption surface; site for enzymes & 转运蛋白.
Characterization: Cross-sectional microscopic images of A) Epi肠 (epithelium only) labeled for CK19 (Red, epithelial cell marker) 和 Villin (Green, brush border marker) 和 B) Epi肠FT (full thickness tissue containing fibroblasts) labeled for Vimentin (Green, fibroblast marker) 和 CK19 (Red).
Epi肠 was exposed to 10 model drugs that utilize specific drug 转运蛋白 at 10µM concentrations for 2 hours. Drug uptake 和 efflux transport of test compounds were analyzed by LC-MS/MS. Tissue integrity 和 barrier function were monitored using transepithelial electrical resistance (TEER) 和 Lucifer Yellow leakage. The apparent permeability coefficient (Papp) was determined in the Epi肠 tissue model 和 compared to previously reported human absorption.
Analysis of Epi肠 revealed: 1) columnar epithelial cells expressing CK19 和 villin, 2) expression of epithelial markers 和 efflux 转运蛋白 (图1), 3) highly reproducible 和 physiological TEER values of 110-150 Ω*cm2 (表1) 和 4) brush borders. Studies using 10 model drugs showed a strong correlation (R2 = 0.8) in permeation of drugs across the Epi肠 tissue compared to historical values of absorption in humans (Figure 2, Table 2). Epi肠 demonstrated active drug transport (for drugs with efflux ratios >2 fold) which was significantly modulated by inhibitors of the efflux drug 转运蛋白 (表3). 此外, when compared to historical values of absorption in humans, a stronger correlation was observed with Epi肠 (R2 = 0.95) than Caco-2 (R2 = 0.81) for low permeability drugs (图3).