bims-orenst 2022-10-16 papers

Issue of 2022‒10‒16
three papers selected by
Joram Mooiweer
University of Groningen

Sci Rep. 2022 Oct 08. 12(1): 16930

High-throughput 3D microvessel-on-a-chip model to study defective angiogenesis in systemic sclerosis.

Bart Kramer, Claudio Corallo, Angelique van den Heuvel, Justin Crawford, Thomas Olivier, Edo Elstak, Nicola Giordano, Paul Vulto, Henriette L Lanz, Richard A J Janssen, Michela A Tessari.

In early systemic sclerosis (Scleroderma, SSc), the vasculature is impaired. Although the exact etiology of endothelial cell damage in SSc remains unclear, it is hypothesized that endothelial to mesenchymal transition (EndoMT) plays a key role. To perform physiologically relevant angiogenic studies, we set out to develop an angiogenesis-on-a-chip platform that is suitable for assessing disease parameters that are relevant to SSc and other vasculopathies. In the model, we substituted Fetal Bovine Serum (FBS) with Human Serum without impairing the stability of the culture. We showed that 3D microvessels and angiogenic factor-induced sprouts exposed to key pro-inflammatory and pro-fibrotic cytokines (TNFα and TGFβ) undergo structural alterations consisting of destructive vasculopathy (loss of small vessels). We also showed that these detrimental effects can be prevented by compound-mediated inhibition of TGFβ-ALK5 signaling or addition of a TNFα neutralizing antibody to the 3D cultures. This demonstrates that our in vitro model is suitable for compound testing and identification of new drugs that can protect from microvascular destabilization or regression in disease-mimicking conditions. To support this, we demonstrated that sera obtained from SSc patients can exert an anti-angiogenic effect on the 3D vessel model, opening the doors to screening for potential SSc drugs, enabling direct patient translatability and personalization of drug treatment.

DOI: https://doi.org/10.1038/s41598-022-21468-x

Biofabrication. 2022 Oct 12.

Study of paraquat-induced pulmonary fibrosis using biomimetic micro-lung chips.

Jingjing Xia, Zhuo Xiong, Jiaxuan Guo, Yongan Wang, Yuan Luo, Yangyang Sun, Zhongwei Guo, Bingchuan Lu, Ting Zhang, Wei Sun.

Paraquat poisoning induces pulmonary fibrosis in vivo. The pathogenesis of pulmonary fibrosis is complex, which has prevented the development of specific treatments. Pulmonary fibrosis shows several characteristics including epithelial-mesenchymal transition (EMT), fibroblast activation, and extracellular matrix (ECM) deposition. To investigate pulmonary fibrosis, we designed a biomimetic multichannel micro-lung chip to imitate the in vivo interface between the lung epithelium and the lung interstitium. In our model, A549 lung epithelial cells and MRC-5 lung fibroblasts were used to test the efficacy of our chip-based model. Rat tail type I collagen and hyaluronic acid were used to simulate ECM and to provide a 3D microenvironment. The micro-lung chips were cultured with paraquat (0, 75, 150, 300, and 400 µM). The viability of A549 and MRC-5 cells significantly decreased with increasing paraquat concentrations. There were significant changes in surfactant proteins C (SP-C), alpha smooth muscle actin protein (α-SMA), and vimentin protein levels during paraquat-induced pulmonary fibrosis. SP-C levels were decreased in A549 cells, while those of α-SMA and vimentin were increased in A549 cells and MRC-5 cells treated with paraquat in the micro-lung chip. We also designed a reference model without interaction between the lung epithelial cells and fibroblasts. Compared to the non-contact model, co-culturing A549 and MRC-5 cells in chips induced more severe EMT in A549 cells after treatment with 75 µM paraquat and together defended against paraquat-induced damage. Thus, our novel co-culture micro-lung chip that models the lung epithelium and interstitium may provide a new approach for studying lung fibrosis and will facilitate drug development.

Keywords: epithelial-mesenchymal transition; micro-lung chip; paraquat; pulmonary fibrosis

DOI: https://doi.org/10.1088/1758-5090/ac999e

Nat Commun. 2022 Oct 12. 13(1): 6021

Differential ABC transporter expression during hematopoiesis contributes to neutrophil-biased toxicity of Aurora kinase inhibitors.

David B Chou, Brooke A Furlong, Ryan R Posey, Christos Kyprianou, Lucy R O'Sullivan, Rhiannon David, Suzanne J Randle, Urszula M Polanska, Jon Travers, Jelena Urosevic, John N Hutchinson, Jianwei Che, Anna M Howley, Robert P Hasserjian, Rachelle Prantil-Baun, Donald E Ingber.

Drug-induced cytopenias are a prevalent and significant issue that worsens clinical outcomes and hinders the effective treatment of cancer. While reductions in blood cell numbers are classically associated with traditional cytotoxic chemotherapies, they also occur with newer targeted small molecules and the factors that determine the hematotoxicity profiles of oncologic drugs are not fully understood. Here, we explore why some Aurora kinase inhibitors cause preferential neutropenia. By studying drug responses of healthy human hematopoietic cells in vitro and analyzing existing gene expression datasets, we provide evidence that the enhanced vulnerability of neutrophil-lineage cells to Aurora kinase inhibition is caused by early developmental changes in ATP-binding cassette (ABC) transporter expression. These data show that hematopoietic cell-intrinsic expression of ABC transporters may be an important factor that determines how some Aurora kinase inhibitors affect the bone marrow.

DOI: https://doi.org/10.1038/s41467-022-33672-4