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bioRxiv · 10.1101/2021.02.18.431336

Magnetically-Propelled Fecal Surrogates for Modeling the Impact of Solid-Induced Shear Forces on Primary Colonic Epithelial Cells

Hinman, S. S.·Huling, J.·Wang, Y.·Wang, H.·Bretherton, R. C.·DeForest, C. A.·Allbritton, N. L.
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Abstract

The colonic epithelium is continuously exposed to an array of biological and mechanical stimuli as its luminal contents are guided over the epithelial surface through regulated smooth muscle contraction. In this report, the propulsion of solid fecal contents over the colonic epithelium is recapitulated through noninvasive actuation of magnetic agarose hydrogels over primary intestinal epithelial cultures, in contrast to the vast majority of platforms that apply shear forces through liquid microflow. Software-controlled magnetic stepper motors enable experimental control over the frequency and velocity of these events to match in vivo propulsive contractions, while the integration of standardized well plate spacing facilitates rapid integration into existing assay pipelines. The application of these solid-induced shear forces did not deleteriously affect cell monolayer surface coverage, viability, or transepithelial electrical resistance unless the device parameters were raised to a 50x greater contraction frequency and 4x greater fecal velocity than those observed in healthy humans. At a frequency and velocity that is consistent with average human colonic motility, differentiation of the epithelial cells into absorptive and goblet cell phenotypes was not affected. Protein secretion was modulated with a two-fold increase in luminal mucin-2 secretion and a significant reduction in basal interleukin-8 secretion. F-actin, zonula occludens-1, and E-cadherin were each present in their proper basolateral locations, similar to those of static control cultures. While cellular height was unaffected by magnetic agarose propulsion, several alterations in lateral morphology were observed including decreased circularity and compactness, and an increase in major axis length, which align with surface epithelial cell morphologies observed in vivo and may represent early markers of luminal exfoliation. This platform will be of widespread utility for the investigation of fecal propulsive forces on intestinal physiology, shedding light on how the colonic epithelium responds to mechanical cues. HIGHLIGHTSO_LIMagnetic nanoparticle-embedded agarose hydrogels were developed as surrogates for human feces C_LIO_LISoftware-controlled magnetic motors enable programmable studies of colonic motility C_LIO_LIPropulsive shear forces were optimized for primary cell viability, surface coverage, and electrical resistance C_LIO_LIMucus production and cytokine secretion were modulated by magnetic agarose propulsion C_LIO_LIStructural and cytoskeletal proteins remain properly distributed with alterations in lateral cell morphology C_LI

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Hinman, S. S., Huling, J., Wang, Y., Wang, H., Bretherton, R. C., DeForest, C. A., Allbritton, N. L.. 2021-02-18. Magnetically-Propelled Fecal Surrogates for Modeling the Impact of Solid-Induced Shear Forces on Primary Colonic Epithelial Cells. https://doi.org/10.1101/2021.02.18.431336

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