bims-orenst 2021-11-28 papers

Issue of 2021–11–28
six papers selected by
Joram Mooiweer, University of Groningen

Biomaterials. 2021 Nov 12. pii: S0142-9612(21)00602-5. [Epub ahead of print] 121245

Organ-on-a-chip model of vascularized human bone marrow niches.

Drew E Glaser, Matthew B Curtis, Peter A Sariano, Zachary A Rollins, Bhupinder S Shergill, Aravind Anand, Alyssa M Deely, Venktesh S Shirure, Leif Anderson, Jeremy M Lowen, Natalie R Ng, Katherine Weilbaecher, Daniel C Link, Steven C George.

Bone marrow niches (endosteal and perivascular) play important roles in both normal bone marrow function and pathological processes such as cancer cell dormancy. Unraveling the mechanisms underlying these events in humans has been severely limited by models that cannot dissect dynamic events at the niche level. Utilizing microfluidic and stem cell technologies, we present a 3D in vitro model of human bone marrow that contains both the perivascular and endosteal niches, complete with dynamic, perfusable vascular networks. We demonstrate that our model can replicate in vivo bone marrow function, including maintenance and differentiation of CD34+ hematopoietic stem/progenitor cells, egress of neutrophils (CD66b+), and niche-specific responses to doxorubicin and granulocyte-colony stimulating factor. Our platform provides opportunities to accelerate current understanding of human bone marrow function and drug response with high spatial and temporal resolution.

Keywords: Breast cancer; Hematopoiesis; Organ-on-a-chip; Tissue engineering

DOI: https://doi.org/10.1016/j.biomaterials.2021.121245

Soft Matter. 2021 Nov 24.

Blood vessel-on-a-chip examines the biomechanics of microvasculature.

Paul F Salipante, Steven D Hudson, Stella Alimperti.

We use a three-dimensional (3D) microvascular platform to measure the elasticity and membrane permeability of the endothelial cell layer. The microfluidic platform is connected with a pneumatic pressure controller to apply hydrostatic pressure. The deformation is measured by tracking the mean vessel diameter under varying pressures up to 300 Pa. We obtain a value for the Young's modulus of the cell layer in low strain where a linear elastic response is observed and use a hyperelastic model that describes the strain hardening observed at larger strains (pressure). A fluorescent dye is used to track the flow through the cell layer to determine the membrane flow resistance as a function of applied pressure. Finally, we track the 3D positions of cell nuclei while the vessel is pressurized to observe local deformation and correlate inter-cell deformation with the local structure of the cell layer. This approach is able to probe the mechanical properties of blood vessels in vitro and provides a methodology for investigating microvascular related diseases.

DOI: https://doi.org/10.1039/d1sm01312b

Biosensors (Basel). 2021 Nov 15. pii: 456. [Epub ahead of print]11(11):

Microfluidic-Chip-Integrated Biosensors for Lung Disease Models.

Shuang Ding, Haijun Zhang, Xuemei Wang.

Lung diseases (e.g., infection, asthma, cancer, and pulmonary fibrosis) represent serious threats to human health all over the world. Conventional two-dimensional (2D) cell models and animal models cannot mimic the human-specific properties of the lungs. In the past decade, human organ-on-a-chip (OOC) platforms-including lung-on-a-chip (LOC)-have emerged rapidly, with the ability to reproduce the in vivo features of organs or tissues based on their three-dimensional (3D) structures. Furthermore, the integration of biosensors in the chip allows researchers to monitor various parameters related to disease development and drug efficacy. In this review, we illustrate the biosensor-based LOC modeling, further discussing the future challenges as well as perspectives in integrating biosensors in OOC platforms.

Keywords: biosensor; lung model; lung-on-a-chip; microfluidics; organ-on-a-chip

DOI: https://doi.org/10.3390/bios11110456

Sci Rep. 2021 Nov 23. 11(1): 22765

A 3D primary human cell-based in vitro model of non-alcoholic steatohepatitis for efficacy testing of clinical drug candidates.

Simon Ströbel, Radina Kostadinova, Katia Fiaschetti-Egli, Jana Rupp, Manuela Bieri, Agnieszka Pawlowska, Donna Busler, Thomas Hofstetter, Katarzyna Sanchez, Sue Grepper, Eva Thoma.

Non-alcoholic steatohepatitis (NASH) is a progressive and severe liver disease, characterized by lipid accumulation, inflammation, and downstream fibrosis. Despite its increasing prevalence, there is no approved treatment yet available for patients. This has been at least partially due to the lack of predictive preclinical models for studying this complex disease. Here, we present a 3D in vitro microtissue model that uses spheroidal, scaffold free co-culture of primary human hepatocytes, Kupffer cells, liver endothelial cells and hepatic stellate cells. Upon exposure to defined and clinically relevant lipotoxic and inflammatory stimuli, these microtissues develop key pathophysiological features of NASH within 10 days, including an increase of intracellular triglyceride content and lipids, and release of pro-inflammatory cytokines. Furthermore, fibrosis was evident through release of procollagen type I, and increased deposition of extracellular collagen fibers. Whole transcriptome analysis revealed changes in the regulation of pathways associated with NASH, such as lipid metabolism, inflammation and collagen processing. Importantly, treatment with anti-NASH drug candidates (Selonsertib and Firsocostat) decreased the measured specific disease parameter, in accordance with clinical observations. These drug treatments also significantly changed the gene expression patterns of the microtissues, thus providing mechanisms of action and revealing therapeutic potential. In summary, this human NASH model represents a promising drug discovery tool for understanding the underlying complex mechanisms in NASH, evaluating efficacy of anti-NASH drug candidates and identifying new approaches for therapeutic interventions.

DOI: https://doi.org/10.1038/s41598-021-01951-7

Adv Sci (Weinh). 2021 Nov 23. e2100031

Establishment of Trophoblast-Like Tissue Model from Human Pluripotent Stem Cells in Three-Dimensional Culture System.

Kangli Cui, Yujuan Zhu, Yang Shi, Tingwei Chen, Hui Wang, Yaqiong Guo, Pengwei Deng, Haitao Liu, Xiaoguang Shao, Jianhua Qin.

The placenta has a lifelong impact on the health of both the mother and fetus. Despite its significance, human early placental development is poorly understood due to the limited models. The models that can reflect the key features of early human placental development, especially at early gestation, are still lacking. Here, the authors report the generation of trophoblast-like tissue model from human pluripotent stem cells (hPSCs) in three-dimensional (3D) cultures. hPSCs efficiently self-organize into blastocoel-like cavities under defined conditions, which produce different trophoblast subtypes, including cytotrophoblasts (CTBs), syncytiotrophoblasts (STBs), and invasive extravillous trophoblasts (EVTs). The 3D cultures can exhibit microvilli structure and secrete human placenta-specific hormone. Single-cell RNA sequencing analysis further identifies the presence of major cell types of trophoblast-like tissue as existing in vivo. The results reveal the feasibility to establish 3D trophoblast-like tissue model from hPSCs in vitro, which is not obtained by monolayer culture. This new model system can not only facilitate to dissect the underlying mechanisms of early human placental development, but also imply its potential for study in developmental biology and gestational disorders.

Keywords: human pluripotent stem cells; matrices; placenta development; three-dimensional cultures; trophoblast tissues

DOI: https://doi.org/10.1002/advs.202100031

Toxins (Basel). 2021 Nov 02. pii: 775. [Epub ahead of print]13(11):

Gut-Kidney Axis on Chip for Studying Effects of Antibiotics on Risk of Hemolytic Uremic Syndrome by Shiga Toxin-Producing Escherichia coli.

Yugyeong Lee, Min-Hyeok Kim, David Rodrigues Alves, Sejoong Kim, Luke P Lee, Jong Hwan Sung, Sungsu Park.

Shiga toxin-producing Escherichia coli (STEC) infects humans by colonizing the large intestine, and causes kidney damage by secreting Shiga toxins (Stxs). The increased secretion of Shiga toxin 2 (Stx2) by some antibiotics, such as ciprofloxacin (CIP), increases the risk of hemolytic-uremic syndrome (HUS), which can be life-threatening. However, previous studies evaluating this relationship have been conflicting, owing to the low frequency of EHEC infection, very small number of patients, and lack of an appropriate animal model. In this study, we developed gut-kidney axis (GKA) on chip for co-culturing gut (Caco-2) and kidney (HKC-8) cells, and observed both STEC O157:H7 (O157) infection and Stx intoxication in the gut and kidney cells on the chip, respectively. Without any antibiotic treatment, O157 killed both gut and kidney cells in GKA on the chip. CIP treatment reduced O157 infection in the gut cells, but increased Stx2-induced damage in the kidney cells, whereas the gentamycin treatment reduced both O157 infection in the gut cells and Stx2-induced damage in the kidney cells. This is the first report to recapitulate a clinically relevant situation, i.e., that CIP treatment causes more damage than gentamicin treatment. These results suggest that GKA on chip is very useful for simultaneous observation of O157 infections and Stx2 poisoning in gut and kidney cells, making it suitable for studying the effects of antibiotics on the risk of HUS.

Keywords: Escherichia coli infection; Shiga toxin; antibiotics; hemolytic–uremic syndrome (HUS); multi-organ-on-a-chip

DOI: https://doi.org/10.3390/toxins13110775