bims-orenst 2021-11-21 papers

Issue of 2021–11–21
three papers selected by
Joram Mooiweer, University of Groningen

J Cyst Fibros. 2021 Nov 16. pii: S1569-1993(21)02106-8. [Epub ahead of print]

Modeling pulmonary cystic fibrosis in a human lung airway-on-a-chip: Cystic fibrosis airway chip.

Roberto Plebani, Ratnakar Potla, Mercy Soong, Haiqing Bai, Zohreh Izadifar, Amanda Jiang, Renee N Travis, Chaitra Belgur, Alexandre Dinis, Mark J Cartwright, Rachelle Prantil-Baun, Pawan Jolly, Sarah E Gilpin, Mario Romano, Donald E Ingber.

BACKGROUND: Cystic fibrosis (CF) is a genetic disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), which results in impaired airway mucociliary clearance, inflammation, infection, and respiratory insufficiency. The development of new therapeutics for CF are limited by the lack of reliable preclinical models that recapitulate the structural, immunological, and bioelectrical features of human CF lungs.
METHODS: We leveraged organ-on-a-chip technology to develop a microfluidic device lined by primary human CF bronchial epithelial cells grown under an air-liquid interface and interfaced with pulmonary microvascular endothelial cells (CF Airway Chip) exposed to fluid flow. The responses of CF and healthy Airway Chips were analyzed in the presence or absence of polymorphonuclear leukocytes (PMNs) and the bacterial pathogen, Pseudomonas aeruginosa.
RESULTS: The CF Airway Chip faithfully recapitulated many features of the human CF airways, including enhanced mucus accumulation, increased cilia density, and a higher ciliary beating frequency compared to chips lined by healthy bronchial epithelial cells. The CF chips also secreted higher levels of IL-8, which was accompanied by enhanced PMN adhesion to the endothelium and transmigration into the airway compartment. In addition, CF Airway Chips provided a more favorable environment for Pseudomonas aeruginosa growth, which resulted in enhanced secretion of inflammatory cytokines and recruitment of PMNs to the airway.
CONCLUSIONS: The human CF Airway Chip may provide a valuable preclinical tool for pathophysiology studies as well as for drug testing and personalized medicine.

Keywords: Cystic fibrosis; Microfluidics; Neutrophils; Organ chip; Pseudomonas

DOI: https://doi.org/10.1016/j.jcf.2021.10.004

Biomaterials. 2021 Nov 13. pii: S0142-9612(21)00605-0. [Epub ahead of print] 121248

Physiologic flow-conditioning limits vascular dysfunction in engineered human capillaries.

Kristina Haase, Filippo Piatti, Minerva Marcano, Yoojin Shin, Roberta Visone, Alberto Redaelli, Marco Rasponi, Roger D Kamm.

Hemodynamics play a central role in the health and disease of the coronary and peripheral vascular systems. Vessel-lining endothelial cells are known mechanosensors, responding to disturbances in flow - with mechanosensitivity hypothesized to change in response to metabolic demands. The health of our smallest microvessels have been lauded as a prognostic marker for cardiovascular health. Yet, despite numerous animal models, studying these small vessels has proved difficult. Microfluidic technologies have allowed a number of 3D vascular models to be developed and used to investigate human vessels. Here, two such systems are employed for examining 1) interstitial flow effects on neo-vessel formation, and 2) the effects of flow-conditioning on vascular remodeling following sustained static culture. Interstitial flow is shown to enhance early vessel formation via significant remodeling of vessels and interconnected tight junctions of the endothelium. In formed vessels, continuous flow maintains a stable vascular diameter and causes significant remodeling, contrasting the continued anti-angiogenic decline of statically cultured vessels. This study is the first to couple complex 3D computational flow distributions and microvessel remodeling from microvessels grown on-chip (exposed to flow or no-flow conditions). Flow-conditioned vessels (WSS < 1Pa for 30 μm vessels) increase endothelial barrier function, result in significant changes in gene expression and reduce reactive oxygen species and anti-angiogenic cytokines. Taken together, these results demonstrate microvessel mechanosensitivity to flow-conditioning, which limits deleterious vessel regression in vitro, and could have implications for future modeling of reperfusion/no-flow conditions.

Keywords: Computational fluid dynamics; Flow-conditioning; Hemodynamics; In vitro vessels; Interstitial flow; Perfusion; Shear flow; Vascular remodeling

DOI: https://doi.org/10.1016/j.biomaterials.2021.121248

Cancer Genet. 2021 Nov 05. pii: S2210-7762(21)00220-9. [Epub ahead of print]258-259 151-156

Tumor-intrinsic FABP5 is a novel driver for colon cancer cell growth via the HIF-1 signaling pathway.

Jieun Seo, JeongEun Yun, Junji Fukuda, Yang-Sook Chun.

Dysfunctional lipid metabolism is a known cause of cancer development and progression, yet little is known about the underlying molecular mechanisms that contribute to cancer progression. In this study, we demonstrate that fatty acid binding protein 5 (FABP5) is elevated in colon cancer tissue and this increased expression is linked to upregulation of the hypoxia-inducible factor-1 (HIF-1) signaling pathway. Under physiologically in vivo mimicked conditions via a polydimethylsiloxane (PDMS)-based three-dimensional (3D) culture chip, FABP5-knockdown colon cancer cells exhibited attenuated cell growth throughout the culture period. FABP5 was found to regulate HIF-1α protein levels and gene expression levels within the HIF-1α signaling pathway under hypoxic conditions. Our results provide evidence that supports the use of FABP5 as a prognostic factor in colon cancer. The FABP5/HIF-1α axis is a promising target for ameliorating fatty acid-triggered cancer progression.

Keywords: Cancer proliferation; Colon cancer; Fatty acid binding protein 5; Hypoxia; Hypoxia-inducible factor-1 alpha; Three-dimensional cell culture

DOI: https://doi.org/10.1016/j.cancergen.2021.11.001