K. Flynn, F. Rinaldi, D. Galitz, M. Anderson, S. Tousey, G. Herr, S. Baltes, C. Anderson, C. Sagarsky, J. Sabat, J. Cooper, and J. Aho
Preclinical drug screening* and toxicology studies in immortalized cell lines and 2-D cell culture systems often yield promising results that fail in human clinical trials. This highlights the need for tissue culture systems that can faithfully reflect the in vivo environment and more accurately identify potential treatments for human disease. Here we introduce MimEX™ GI, a novel 3-D gastrointestinal model system for toxicology, drug discovery, and disease modeling. This system has the advantages of more complex models like gastrointestinal organoids in recapitulating the native intestinal cytoarchitecture and mimicking physiological attributes of the tissue. However, MimEX GI circumvents difficulties often encountered in organoid systems including variability, tissue viability, and experimental accessibility. By overcoming these obstacles, MimEX GI provides researchers with a simple incorporation of 3-D tissues into high throughput toxicity, drug screening, and disease modeling workflows. MimEX GI harnesses the unique characteristics of adult “ground-state” (GS) stem cells to generate 3-D gastrointestinal organ tissue on a 2-D surface. This provides another advantage whereby pure populations of adult stem cells can be easily cultured, maintained, and characterized independently of differentiated cell types. GS stem cells can be readily isolated from the epithelium of any region of the adult gastrointestinal tract, clonally expanded, and differentiated back into the tissue of origin with region-specific characteristics. This differentiation is oriented such that the apical surface of the mucosa is accessible within the well. Using a high throughput permeability assay, we demonstrate the barrier function of MimEX GI tissue, and its response to different molecules, as evidence for the flexibility of this tissue in high throughput drug screening. Moreover, we show that GS stem cells can be isolated from Crohn’s disease patients and potentially used to study disease mechanisms ex vivo.
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