bims-orenst 2022-05-01 papers

bims-orenst

Biomed News

on Organs-on-chips and engineered stem cell models

Issue of 2022‒05‒01
six papers selected by
Joram Mooiweer
University of Groningen

Autologous Human Immunocompetent White Adipose Tissue-on-Chip.
Endothelial inflammation and neutrophil transmigration are modulated by extracellular matrix composition in an inflammation-on-a-chip model.
A multi-organ chip with matured tissue niches linked by vascular flow.
A modular microfluidic platform to enable complex and customisable in vitro models for neuroscience.
A human cornea-on-a-chip for the study of epithelial wound healing by extracellular vesicles.
Metabolically driven maturation of human-induced-pluripotent-stem-cell-derived cardiac microtissues on microfluidic chips.

Adv Sci (Weinh). 2022 Apr 24. e2104451

Autologous Human Immunocompetent White Adipose Tissue-on-Chip.

Julia Rogal, Julia Roosz, Claudia Teufel, Madalena Cipriano, Raylin Xu, Wiebke Eisler, Martin Weiss, Katja Schenke-Layland, Peter Loskill.

  Obesity and associated diseases, such as diabetes, have reached epidemic proportions globally. In this era of "diabesity", white adipose tissue (WAT) has become a target of high interest for therapeutic strategies. To gain insights into mechanisms of adipose (patho-)physiology, researchers traditionally relied on animal models. Leveraging Organ-on-Chip technology, a microphysiological in vitro model of human WAT is introduced: a tailored microfluidic platform featuring vasculature-like perfusion that integrates 3D tissues comprising all major WAT-associated cellular components (mature adipocytes, organotypic endothelial barriers, stromovascular cells including adipose tissue macrophages) in an autologous manner and recapitulates pivotal WAT functions, such as energy storage and mobilization as well as endocrine and immunomodulatory activities. A precisely controllable bottom-up approach enables the generation of a multitude of replicates per donor circumventing inter-donor variability issues and paving the way for personalized medicine. Moreover, it allows to adjust the model's degree of complexity via a flexible mix-and-match approach. This WAT-on-Chip system constitutes the first human-based, autologous, and immunocompetent in vitro adipose tissue model that recapitulates almost full tissue heterogeneity and can become a powerful tool for human-relevant research in the field of metabolism and its associated diseases as well as for compound testing and personalized- and precision medicine applications.

Keywords:  adipokines; adipose tissue macrophages; adipose tissue-on-chip; endothelial barrier; immunometabolism; mature adipocytes; microfluidics

DOI:  https://doi.org/10.1002/advs.202104451
Sci Rep. 2022 Apr 27. 12(1): 6855

Endothelial inflammation and neutrophil transmigration are modulated by extracellular matrix composition in an inflammation-on-a-chip model.

Rebecca B Riddle, Karin Jennbacken, Kenny M Hansson, Matthew T Harper.

Inflammatory diseases are often characterised by excessive neutrophil infiltration from the blood stream to the site of inflammation, which damages healthy tissue and prevents resolution of inflammation. Development of anti-inflammatory drugs is hindered by lack of in vitro and in vivo models which accurately represent the disease microenvironment. In this study, we used the OrganoPlate to develop a humanized 3D in vitro inflammation-on-a-chip model to recapitulate neutrophil transmigration across the endothelium and subsequent migration through the extracellular matrix (ECM). Human umbilical vein endothelial cells formed confluent vessels against collagen I and geltrex mix, a mix of basement membrane extract and collagen I. TNF-α-stimulation of vessels upregulated inflammatory cytokine expression and promoted neutrophil transmigration. Intriguingly, major differences were found depending on the composition of the ECM. Neutrophils transmigrated in higher number and further in geltrex mix than collagen I, and did not require an N-formyl-methionyl-leucyl-phenylalanine (fMLP) gradient for transmigration. Inhibition of neutrophil proteases inhibited neutrophil transmigration on geltrex mix, but not collagen I. These findings highlight the important role of the ECM in determining cell phenotype and response to inhibitors. Future work could adapt the ECM composition for individual diseases, producing accurate models for drug development.

DOI: https://doi.org/10.1038/s41598-022-10849-x
Nat Biomed Eng. 2022 Apr;6(4): 351-371

A multi-organ chip with matured tissue niches linked by vascular flow.

Kacey Ronaldson-Bouchard, Diogo Teles, Keith Yeager, Daniel Naveed Tavakol, Yimu Zhao, Alan Chramiec, Somnath Tagore, Max Summers, Sophia Stylianos, Manuel Tamargo, Busub Marcus Lee, Susan P Halligan, Erbil Hasan Abaci, Zongyou Guo, Joanna Jacków, Alberto Pappalardo, Jerry Shih, Rajesh K Soni, Shivam Sonar, Carrie German, Angela M Christiano, Andrea Califano, Karen K Hirschi, Christopher S Chen, Andrzej Przekwas, Gordana Vunjak-Novakovic.

Engineered tissues can be used to model human pathophysiology and test the efficacy and safety of drugs. Yet, to model whole-body physiology and systemic diseases, engineered tissues with preserved phenotypes need to physiologically communicate. Here we report the development and applicability of a tissue-chip system in which matured human heart, liver, bone and skin tissue niches are linked by recirculating vascular flow to allow for the recapitulation of interdependent organ functions. Each tissue is cultured in its own optimized environment and is separated from the common vascular flow by a selectively permeable endothelial barrier. The interlinked tissues maintained their molecular, structural and functional phenotypes over 4 weeks of culture, recapitulated the pharmacokinetic and pharmacodynamic profiles of doxorubicin in humans, allowed for the identification of early miRNA biomarkers of cardiotoxicity, and increased the predictive values of clinically observed miRNA responses relative to tissues cultured in isolation and to fluidically interlinked tissues in the absence of endothelial barriers. Vascularly linked and phenotypically stable matured human tissues may facilitate the clinical applicability of tissue chips.

DOI: https://doi.org/10.1038/s41551-022-00882-6
Lab Chip. 2022 Apr 25.

A modular microfluidic platform to enable complex and customisable in vitro models for neuroscience.

D Megarity, R Vroman, M Kriek, P Downey, T J Bushell, M Zagnoni.

Disorders of the central nervous system (CNS) represent a global health challenge and an increased understanding of the CNS in both physiological and pathophysiological states is essential to tackle the problem. Modelling CNS conditions is difficult, as traditional in vitro models fail to recapitulate precise microenvironments and animal models of complex disease often have limited translational validity. Microfluidic and organ-on-chip technologies offer an opportunity to develop more physiologically relevant and complex in vitro models of the CNS. They can be developed to allow precise cellular patterning and enhanced experimental capabilities to study neuronal function and dysfunction. To improve ease-of-use of the technology and create new opportunities for novel in vitro studies, we introduce a modular platform consisting of multiple, individual microfluidic units that can be combined in several configurations to create bespoke culture environments. Here, we report proof-of-concept experiments creating complex in vitro models and performing functional analysis of neuronal activity across modular interfaces. This platform technology presents an opportunity to increase our understanding of CNS disease mechanisms and ultimately aid the development of novel therapies.

DOI: https://doi.org/10.1039/d2lc00115b
iScience. 2022 May 20. 25(5): 104200

A human cornea-on-a-chip for the study of epithelial wound healing by extracellular vesicles.

Zitong Yu, Rui Hao, Jing Du, Xiaoliang Wu, Xi Chen, Yi Zhang, Wei Li, Zhongze Gu, Hui Yang.

  Organs-on-chips are microfluidic devices for cell culturing to simulate tissue-level or organ-level physiology and recapitulate their microenvironment, providing new and significant solutions other than traditional animal tests. In vitro testing platforms for ocular biological studies have been increasingly used in preclinical efficacy and toxicity prediction. Here, we developed a microfluidic platform consisting of human corneal cells and porous membrane, replicating the multi-scale structural organization and biological phenotype. We verified the fully integrated human cornea's barrier effects on the chip. Moreover, we found that extracellular vesicles derived from bone marrow-derived mesenchymal stem cells can significantly accelerate the mild corneal epithelial wound healing, and the decreased expression of matrix metallopeptidase-2 protein indicated that this method effectively inhibits corneal inflammation and angiogenesis. This work improves our ability to simulate the interaction between the human cornea and the external world in vitro and contributes to the future development of new screening platforms for biopharmaceuticals.

Keywords:  Bioengineering; Biotechnology; biological sciences; cell biology; tissue engineering

DOI:  https://doi.org/10.1016/j.isci.2022.104200
Nat Biomed Eng. 2022 Apr;6(4): 372-388

Metabolically driven maturation of human-induced-pluripotent-stem-cell-derived cardiac microtissues on microfluidic chips.

Nathaniel Huebsch, Berenice Charrez, Gabriel Neiman, Brian Siemons, Steven C Boggess, Samuel Wall, Verena Charwat, Karoline H Jæger, David Cleres, Åshild Telle, Felipe T Lee-Montiel, Nicholas C Jeffreys, Nikhil Deveshwar, Andrew G Edwards, Jonathan Serrano, Matija Snuderl, Andreas Stahl, Aslak Tveito, Evan W Miller, Kevin E Healy.

The immature physiology of cardiomyocytes derived from human induced pluripotent stem cells (hiPSCs) limits their utility for drug screening and disease modelling. Here we show that suitable combinations of mechanical stimuli and metabolic cues can enhance the maturation of hiPSC-derived cardiomyocytes, and that the maturation-inducing cues have phenotype-dependent effects on the cells' action-potential morphology and calcium handling. By using microfluidic chips that enhanced the alignment and extracellular-matrix production of cardiac microtissues derived from genetically distinct sources of hiPSC-derived cardiomyocytes, we identified fatty-acid-enriched maturation media that improved the cells' mitochondrial structure and calcium handling, and observed divergent cell-source-dependent effects on action-potential duration (APD). Specifically, in the presence of maturation media, tissues with abnormally prolonged APDs exhibited shorter APDs, and tissues with aberrantly short APDs displayed prolonged APDs. Regardless of cell source, tissue maturation reduced variabilities in spontaneous beat rate and in APD, and led to converging cell phenotypes (with APDs within the 300-450 ms range characteristic of human left ventricular cardiomyocytes) that improved the modelling of the effects of pro-arrhythmic drugs on cardiac tissue.

DOI: https://doi.org/10.1038/s41551-022-00884-4