bims-orenst Biomed News
on Organs-on-chips and engineered stem cell models
Issue of 2021–10–03
seven papers selected by
Joram Mooiweer, University of Groningen
  1. A bioengineered lymphatic vessel model for studying lymphatic endothelial cell-cell junction and barrier function.
  2. Luminal flow actuation generates coupled shear and strain in a microvessel-on-chip.
  3. A vascularized tumoroid model for human glioblastoma angiogenesis.
  4. Modular operation of microfluidic chips for highly parallelized cell culture and liquid dosing via a fluidic circuit board.
  5. Transport study of interleukin-1 inhibitors using a human in vitro model of the blood-brain barrier.
  6. Culturing patient-derived malignant hematopoietic stem cells in engineered and fully humanized 3D niches.
  7. An Individual Patient's "Body" on Chips-How Organismoid Theory Can Translate Into Your Personal Precision Therapy Approach.
  1. Microcirculation. 2021 Sep 27. e12730
    A bioengineered lymphatic vessel model for studying lymphatic endothelial cell-cell junction and barrier function.
    Aria R Henderson, Isabelle S Ilan, Esak Lee.
       OBJECTIVE: Lymphatic vessels (LVs) maintain fluid homeostasis by draining interstitial fluid. A failure in lymphatic drainage triggers lymphatic diseases such as lymphedema. Since lymphatic drainage is regulated by lymphatic barrier function, developing experimental models that assess lymphatic barrier function is critical for better understanding of lymphatic physiology and disease.
    METHODS: We built a Lymphatic vessel-on-Chip (LV-on-chip) by fabricating a microfluidic device that includes a hollow microchannel embedded in three-dimensional (3D) hydrogel. Employing luminal flow in the microchannel, human lymphatic endothelial cells (LECs) seeded in the microchannel formed an engineered LV exhibiting 3D conduit structure.
    RESULTS: LECs formed relatively permeable junctions in 3D collagen 1. However, adding fibronectin to the collagen 1 apparently tightened LEC junctions. We tested lymphatic barrier function by introducing dextran into LV lumens. While LECs in collagen 1 showed permeable barriers, LECs in fibronectin/collagen 1 showed reduced permeability, which was reversed by integrin α5 inhibition. Mechanistically, LECs expressed inactivated integrin α5 in collagen 1. However, integrin α5 is activated in fibronectin and enhances barrier function. Integrin α5 activation itself also tightened LEC junctions in the absence of fibronectin.
    CONCLUSIONS: LV-on-chip reveals integrin α5 as a regulator of lymphatic barrier function and provides a platform for studying lymphatic barrier function in various conditions.
    Keywords:  3D bioengineered models; LV-on-chip; integrin α5; junctions; lymphatic barrier function; lymphatic endothelial cells
    DOI:  https://doi.org/10.1111/micc.12730
  2. Biofabrication. 2021 Sep 30.
    Luminal flow actuation generates coupled shear and strain in a microvessel-on-chip.
    Claire A Dessalles, Clara Ramon-Lozano, Avin Babataheri, Abdul I Barakat.
      In the microvasculature, blood flow-derived forces are key regulators of vascular structure and function. Consequently, the development of hydrogel-based microvessel-on-chip systems that strive to mimic the in vivo cellular organization and mechanical environment has received great attention in recent years. However, despite intensive efforts, current microvessel-on-chip systems suffer from several limitations, most notably failure to produce physiologically relevant wall strain levels. In this study, a novel microvessel-on-chip based on the templating technique and using luminal flow actuation to generate physiologically relevant levels of wall shear stress and circumferential stretch is presented. Normal forces induced by the luminal pressure compress the surrounding soft collagen hydrogel, dilate the channel, and create large circumferential strain. The fluid pressure gradient in the system drives flow forward and generates realistic pulsatile wall shear stresses. Rigorous characterization of the system reveals the crucial role played by the poroelastic behavior of the hydrogel in determining the magnitudes of the wall shear stress and strain. The experimental measurements are combined with an analytical model of flow in both the lumen and the porous hydrogel to provide an exceptionally versatile user manual for an application-based choice of parameters in microvessels-on-chip. This unique strategy of flow actuation adds a dimension to the capabilities of microvessel-on-chip systems and provides a more general framework for improving hydrogel-based in vitro engineered platforms.
    Keywords:  Endothelial cells; hydrogel; pulsatility; shear stress; strain; flow actuation
    DOI:  https://doi.org/10.1088/1758-5090/ac2baa
  3. Sci Rep. 2021 Oct 01. 11(1): 19550
    A vascularized tumoroid model for human glioblastoma angiogenesis.
    Agavi Stavropoulou Tatla, Alexander W Justin, Colin Watts, Athina E Markaki.
      Glioblastoma (GBM) angiogenesis is critical for tumor growth and recurrence, making it a compelling therapeutic target. Here, a disease-relevant, vascularized tumoroid in vitro model with stem-like features and stromal surrounds is reported. The model is used to recapitulate how individual components of the GBM's complex brain microenvironment such as hypoxia, vasculature-related stromal cells and growth factors support GBM angiogenesis. It is scalable, tractable, cost-effective and can be used with biologically-derived or biomimetic matrices. Patient-derived primary GBM cells are found to closely participate in blood vessel formation in contrast to a GBM cell line containing differentiated cells. Exogenous growth factors amplify this effect under normoxia but not at hypoxia suggesting that a significant amount of growth factors is already being produced under hypoxic conditions. Under hypoxia, primary GBM cells strongly co-localize with umbilical vein endothelial cells to form sprouting vascular networks, which has been reported to occur in vivo. These findings demonstrate that our 3D tumoroid in vitro model exhibits biomimetic attributes that may permit its use as a preclinical model in studying microenvironment cues of tumor angiogenesis.
    DOI:  https://doi.org/10.1038/s41598-021-98911-y
  4. Microsyst Nanoeng. 2020 ;6 107
    Modular operation of microfluidic chips for highly parallelized cell culture and liquid dosing via a fluidic circuit board.
    A R Vollertsen, D de Boer, S Dekker, B A M Wesselink, R Haverkate, H S Rho, R J Boom, M Skolimowski, M Blom, R Passier, A van den Berg, A D van der Meer, M Odijk.
      Microfluidic systems enable automated and highly parallelized cell culture with low volumes and defined liquid dosing. To achieve this, systems typically integrate all functions into a single, monolithic device as a "one size fits all" solution. However, this approach limits the end users' (re)design flexibility and complicates the addition of new functions to the system. To address this challenge, we propose and demonstrate a modular and standardized plug-and-play fluidic circuit board (FCB) for operating microfluidic building blocks (MFBBs), whereby both the FCB and the MFBBs contain integrated valves. A single FCB can parallelize up to three MFBBs of the same design or operate MFBBs with entirely different architectures. The operation of the MFBBs through the FCB is fully automated and does not incur the cost of an extra external footprint. We use this modular platform to control three microfluidic large-scale integration (mLSI) MFBBs, each of which features 64 microchambers suitable for cell culturing with high spatiotemporal control. We show as a proof of principle that we can culture human umbilical vein endothelial cells (HUVECs) for multiple days in the chambers of this MFBB. Moreover, we also use the same FCB to control an MFBB for liquid dosing with a high dynamic range. Our results demonstrate that MFBBs with different designs can be controlled and combined on a single FCB. Our novel modular approach to operating an automated microfluidic system for parallelized cell culture will enable greater experimental flexibility and facilitate the cooperation of different chips from different labs.
    Keywords:  Engineering; Nanoscience and technology
    DOI:  https://doi.org/10.1038/s41378-020-00216-z
  5. Brain Behav Immun Health. 2021 Oct;16 100307
    Transport study of interleukin-1 inhibitors using a human in vitro model of the blood-brain barrier.
    Elisabet O Sjöström, Maxime Culot, Lisa Leickt, Mikael Åstrand, Erik Nordling, Fabien Gosselet, Christina Kaiser.
      The proinflammatory cytokine Interleukin-1 (IL-1), with its two isoforms α and β, has important roles in multiple pathogenic processes in the central nervous system. The present study aimed to evaluate and compare the blood-to-brain distribution of anakinra (IL-1 receptor antagonist), bermekimab (IL-1α antagonist) and canakinumab (IL-1β antagonist). A human in vitro model of the blood-brain barrier derived from human umbilical cord blood stem cells was used, where isolated CD34+ cells co-cultured with bovine pericytes were matured into polarized brain-like endothelial cells. Transport rates of the three test items were evaluated after 180 ​min incubation at concentrations 50, 250 and 1250 ​nM in a transwell system. We report herein that anakinra passes the human brain-like endothelial monolayer at a 4-7-fold higher rate than the monoclonal antibodies tested. Both antibodies had similar transport rates at all concentrations. No dose-dependent effects in transport rates were observed, nor any saturation effects at supraphysiological concentrations. The larger propensity of anakinra to pass this model of the human blood-brain barrier supports existing data and confirms that anakinra can reach the brain compartment at clinically relevant concentrations. As anakinra inhibits the actions of both IL-1α and IL-1β, it blocks all effects of IL-1 downstream signaling. The results herein further add to the growing body of evidence of the potential utility of anakinra to treat neuroinflammatory disorders.
    Keywords:  Acute brain injury; Anakinra; In vitro blood-brain barrier; Inflammation; Interleukin-1; Interleukin-1 receptor antagonist; Neuronal injury; Stroke
    DOI:  https://doi.org/10.1016/j.bbih.2021.100307
  6. Proc Natl Acad Sci U S A. 2021 Oct 05. pii: e2114227118. [Epub ahead of print]118(40):
    Culturing patient-derived malignant hematopoietic stem cells in engineered and fully humanized 3D niches.
    Andrés García-García, Thibaut Klein, Gordian Born, Morgane Hilpert, Arnaud Scherberich, Claudia Lengerke, Radek C Skoda, Paul E Bourgine, Ivan Martin.
      Human malignant hematopoietic stem and progenitor cells (HSPCs) reside in bone marrow (BM) niches, which remain challenging to explore due to limited in vivo accessibility and constraints with humanized animal models. Several in vitro systems have been established to culture patient-derived HSPCs in specific microenvironments, but they do not fully recapitulate the complex features of native bone marrow. Our group previously reported that human osteoblastic BM niches (O-N), engineered by culturing mesenchymal stromal cells within three-dimensional (3D) porous scaffolds under perfusion flow in a bioreactor system, are capable of maintaining, expanding, and functionally regulating healthy human cord blood-derived HSPCs. Here, we first demonstrate that this 3D O-N can sustain malignant CD34+ cells from acute myeloid leukemia (AML) and myeloproliferative neoplasm patients for up to 3 wk. Human malignant cells distributed in the bioreactor system mimicking the spatial distribution found in native BM tissue, where most HSPCs remain linked to the niches and mature cells are released to the circulation. Using human adipose tissue-derived stromal vascular fraction cells, we then generated a stromal-vascular niche and demonstrated that O-N and stromal-vascular niche differentially regulate leukemic UCSD-AML1 cell expansion, immunophenotype, and response to chemotherapy. The developed system offers a unique platform to investigate human leukemogenesis and response to drugs in customized environments, mimicking defined features of native hematopoietic niches and compatible with the establishment of personalized settings.
    Keywords:  3D perfusion bioreactors; AML/MPN; engineering stem cell niches; osteoblastic niche; stromal-vascular niche
    DOI:  https://doi.org/10.1073/pnas.2114227118
  7. Front Med (Lausanne). 2021 ;8 728866
    An Individual Patient's "Body" on Chips-How Organismoid Theory Can Translate Into Your Personal Precision Therapy Approach.
    Uwe Marx, Enrico Accastelli, Rhiannon David, Hendrik Erfurth, Leopold Koenig, Roland Lauster, Anja Patricia Ramme, Petra Reinke, Hans-Dieter Volk, Annika Winter, Eva-Maria Dehne.
      The first concepts for reproducing human systemic organismal biology in vitro were developed over 12 years ago. Such concepts, then called human- or body-on-a-chip, claimed that microphysiological systems would become the relevant technology platform emulating the physiology and morphology of human organisms at the smallest biologically acceptable scale in vitro and, therefore, would enable the selection of personalized therapies for any patient at unprecedented precision. Meanwhile, the first human organoids-stem cell-derived complex three-dimensional organ models that expand and self-organize in vitro-have proven that in vitro self-assembly of minute premature human organ-like structures is feasible, once the respective stimuli of ontogenesis are provided to human stem cells. Such premature organoids can precisely reflect a number of distinct physiological and pathophysiological features of their respective counterparts in the human body. We now develop the human-on-a-chip concepts of the past into an organismoid theory. We describe the current concept and principles to create a series of organismoids-minute, mindless and emotion-free physiological in vitro equivalents of an individual's mature human body-by an artificially short process of morphogenetic self-assembly mimicking an individual's ontogenesis from egg cell to sexually mature organism. Subsequently, we provide the concept and principles to maintain such an individual's set of organismoids at a self-sustained functional healthy homeostasis over very long time frames in vitro. Principles how to perturb a subset of healthy organismoids by means of the natural or artificial induction of diseases are enrolled to emulate an individual's disease process. Finally, we discuss using such series of healthy and perturbed organismoids in predictively selecting, scheduling and dosing an individual patient's personalized therapy or medicine precisely. The potential impact of the organismoid theory on our healthcare system generally and the rapid adoption of disruptive personalized T-cell therapies particularly is highlighted.
    Keywords:  advanced therapies; immune-oncology; microphysiological systems; organ-on-chip; organismoid; organoid; patient-on-chip; real world data
    DOI:  https://doi.org/10.3389/fmed.2021.728866
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