bims-orenst 2021-11-14 papers

Issue of 2021–11–14
four papers selected by
Joram Mooiweer, University of Groningen

Front Pharmacol. 2021 ;12 718484

Enteric Coronavirus Infection and Treatment Modeled With an Immunocompetent Human Intestine-On-A-Chip.

Many patients infected with coronaviruses, such as SARS-CoV-2 and NL63 that use ACE2 receptors to infect cells, exhibit gastrointestinal symptoms and viral proteins are found in the human gastrointestinal tract, yet little is known about the inflammatory and pathological effects of coronavirus infection on the human intestine. Here, we used a human intestine-on-a-chip (Intestine Chip) microfluidic culture device lined by patient organoid-derived intestinal epithelium interfaced with human vascular endothelium to study host cellular and inflammatory responses to infection with NL63 coronavirus. These organoid-derived intestinal epithelial cells dramatically increased their ACE2 protein levels when cultured under flow in the presence of peristalsis-like mechanical deformations in the Intestine Chips compared to when cultured statically as organoids or in Transwell inserts. Infection of the intestinal epithelium with NL63 on-chip led to inflammation of the endothelium as demonstrated by loss of barrier function, increased cytokine production, and recruitment of circulating peripheral blood mononuclear cells (PBMCs). Treatment of NL63 infected chips with the approved protease inhibitor drug, nafamostat, inhibited viral entry and resulted in a reduction in both viral load and cytokine secretion, whereas remdesivir, one of the few drugs approved for COVID19 patients, was not found to be effective and it also was toxic to the endothelium. This model of intestinal infection was also used to test the effects of other drugs that have been proposed for potential repurposing against SARS-CoV-2. Taken together, these data suggest that the human Intestine Chip might be useful as a human preclinical model for studying coronavirus related pathology as well as for testing of potential anti-viral or anti-inflammatory therapeutics.

Keywords: COVID-19; NL63; SARS–CoV–2; coronavirus; intestine chip; nafamostat; organs on chip; remdesevir

DOI: https://doi.org/10.3389/fphar.2021.718484

Nano Converg. 2021 Nov 08. 8(1): 35

Effect of biochemical and biomechanical factors on vascularization of kidney organoid-on-a-chip.

Han Na Lee, Yoon Young Choi, Jin Won Kim, Young Seo Lee, Ji Wook Choi, Taewook Kang, Yong Kyun Kim, Bong Guen Chung.

Kidney organoids derived from the human pluripotent stem cells (hPSCs) recapitulating human kidney are the attractive tool for kidney regeneration, disease modeling, and drug screening. However, the kidney organoids cultured by static conditions have the limited vascular networks and immature nephron-like structures unlike human kidney. Here, we developed a kidney organoid-on-a-chip system providing fluidic flow mimicking shear stress with optimized extracellular matrix (ECM) conditions. We demonstrated that the kidney organoids cultured in our microfluidic system showed more matured podocytes and vascular structures as compared to the static culture condition. Additionally, the kidney organoids cultured in microfluidic systems showed higher sensitivity to nephrotoxic drugs as compared with those cultured in static conditions. We also demonstrated that the physiological flow played an important role in maintaining a number of physiological functions of kidney organoids. Therefore, our kidney organoid-on-a-chip system could provide an organoid culture platform for in vitro vascularization in formation of functional three-dimensional (3D) tissues.

Keywords: Kidney organoid-on-a-chip; Podocyte; Shear stress; Vascular structure

DOI: https://doi.org/10.1186/s40580-021-00285-4

Adv Healthc Mater. 2021 Nov 07. e2101768

A Bioprinted Tubular Intestine Model using a Colon-Specific Extracellular Matrix Bioink.

Hohyeon Han, Yejin Park, Yoo-Mi Choi, Uijung Yong, Byeongmin Kang, Woojung Shin, Soyoun Min, Hyun Jung Kim, Jinah Jang.

Tremendous advances have been made toward accurate recapitulation of the human intestinal system in vitro to understand its developmental process, and disease progression. However, current in vitro models are often confined to 2D or 2.5D microarchitectures, which is difficult to mimic the systemic level of complexity of the native tissue. To overcome this problem, we develop physiologically relevant intestinal models with a 3D hollow tubular structure using 3D bioprinting strategy. A tissue-specific biomaterial, colon-derived decellularized extracellular matrix (Colon dECM) has been developed and it provides significant maturation-guiding potential to human intestinal cells. To fabricate a perfusable tubular model, we develop a simultaneous printing process of multiple materials through concentrically assembled nozzles and employ a light-activated Colon dECM bioink by supplementing with ruthenium/sodium persulfate as a photoinitiator. The bioprinted intestinal tissue models show spontaneous 3D morphogenesis of the human intestinal epithelium without any external stimuli. In consequence, the printed cells form multicellular aggregates and cysts and then differentiate into several types of enterocytes, building junctional networks. This system can serve as a platform to evaluate the effects of potential drug-induced toxicity on the human intestinal tissue and create a co-culture model with commensal microbes and immune cells for future therapeutics. This article is protected by copyright. All rights reserved.

Keywords: 3D bioprinting; intestinal morphogenesis; material-guided cell maturation; tissue-specific bioinks; tubular intestine models

DOI: https://doi.org/10.1002/adhm.202101768

Am J Physiol Heart Circ Physiol. 2021 Nov 12.

Leveraging avidin/biotin interaction to quantify permeability of microvessels-on-a-chip.

Feng Gao, Haoyu Sun, Xiang Li, Pingnian He.

Microvessels-on-a-chip have enabled in vitro studies to closely simulate in vivo microvessel environment. However, assessing microvessel permeability, a functional measure of microvascular exchange, has not been attainable in nonpermeable microfluidic platforms. This study developed a new approach that enables permeability coefficients (Ps) to be quantified in microvessels developed in nonpermeable chip platforms by integrating avidin/biotin technology. Microvessels were developed on biotinylated fibronectin-coated microfluidic channels. Solute transport was assessed by perfusing microvessels with fluorescence-labeled avidin. Avidin molecules that crossed endothelium were captured by substrate biotin and recorded with real-time confocal images. The Ps was derived from the rate of avidin/biotin accumulation at the substrate relative to solute concentration difference across microvessel wall. Avidin tracers with different physiochemical properties were used to characterize the barrier properties of the microvessel wall. The measured baseline Ps and inflammatory mediator-induced increases in Ps and EC [Ca2+]i resembled those observed in intact microvessels. Importantly, the spatial accumulation of avidin/biotin at substrate defines the transport pathways. Glycocalyx layer is well-formed on endothelium and its degradation increased transcellular transport without affecting EC junctions. This study demonstrated that in vitro microvessels developed in this simply designed microfluidics structurally possess in vivo-like glycocalyx layer and EC junctions and functionally recapitulate basal barrier properties and stimuli-induced responses observed in intact microvessels. This new approach overcomes the limitations of nonpermeable microfluidics and provides an easily executed highly reproducible in vitro microvessel model with in vivo microvessel functionality, suitable for a wide range of applications in blood and vascular research and drug development.

Keywords: Application of avidin/biotin interaction; Glycocalyx; Microvessel permeability; Microvessels-on a-chip; Solute transport pathways

DOI: https://doi.org/10.1152/ajpheart.00478.2021