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Article ; Online: Human organ chips for regenerative pharmacology.

Goyal, Girija / Belgur, Chaitra / Ingber, Donald E

2023 Volume 12, Issue 1, Page(s) e01159

Abstract: Human organs-on-chips (organ chips) are small microfluidic devices that allow human cells to perform complex organ-level functions in vitro by recreating multi-cellular and multi-tissue structures and applying in vivo-like biomechanical cues. Human Organ ...

Abstract	Human organs-on-chips (organ chips) are small microfluidic devices that allow human cells to perform complex organ-level functions in vitro by recreating multi-cellular and multi-tissue structures and applying in vivo-like biomechanical cues. Human Organ Chips are being used for drug discovery and toxicology testing as an alternative to animal models which are ethically challenging and often do not predict clinical efficacy or toxicity. In this mini-review, we summarize our presentation that reviewed the state of the art relating to these microfluidic culture devices designed to mimic specific human organ structures and functions, and the application of Organ Chips to regenerative pharmacology.
MeSH term(s)	Animals ; Humans ; Microphysiological Systems ; Lab-On-A-Chip Devices ; Models, Animal ; Drug Discovery
Language	English
Publishing date	2023-12-23
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2740389-0
ISSN	2052-1707 ; 2052-1707
ISSN (online)	2052-1707
ISSN	2052-1707
DOI	10.1002/prp2.1159
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Safety Profiling of Tumor-targeted T Cell-Bispecific Antibodies with Alveolus Lung- and Colon-on-Chip.

Kerns, Jordan S / Belgur, Chaitra / Kanellias, Marianne / Manatakis, Dimitris V / Barrile, Riccardo / Tien-Street, Will / Ewart, Lorna / Gjorevski, Nikolche / Cabon, Lauriane

Bio-protocol

2023 Volume 13, Issue 1

Abstract: Traditional drug safety assessments often fail to predict complications in humans, especially when the drug targets the immune system. Rodent-based preclinical animal models are often ill-suited for predicting immunotherapy-mediated adverse events in ... ...

Abstract	Traditional drug safety assessments often fail to predict complications in humans, especially when the drug targets the immune system. Rodent-based preclinical animal models are often ill-suited for predicting immunotherapy-mediated adverse events in humans, in part because of the fundamental differences in immunological responses between species and the human relevant expression profile of the target antigen, if it is expected to be present in normal, healthy tissue. While human-relevant cell-based models of tissues and organs promise to bridge this gap, conventional in vitro two-dimensional models fail to provide the complexity required to model the biological mechanisms of immunotherapeutic effects. Also, like animal models, they fail to recapitulate physiologically relevant levels and patterns of organ-specific proteins, crucial for capturing pharmacology and safety liabilities. Organ-on-Chip models aim to overcome these limitations by combining micro-engineering with cultured primary human cells to recreate the complex multifactorial microenvironment and functions of native tissues and organs. In this protocol, we show the unprecedented capability of two human Organs-on-Chip models to evaluate the safety profile of T cell-bispecific antibodies (TCBs) targeting tumor antigens. These novel tools broaden the research options available for a mechanistic understanding of engineered therapeutic antibodies and for assessing safety in tissues susceptible to adverse events. Graphical abstract Figure 1. Graphical representation of the major steps in target-dependent T cell-bispecific antibodies engagement and immunomodulation, as performed in the Colon Intestine-Chip.
Language	English
Publishing date	2023-01-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	2833269-6
ISSN	2331-8325 ; 2331-8325
ISSN (online)	2331-8325
ISSN	2331-8325
DOI	10.21769/BioProtoc.4579
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Article ; Online: Mechanical control of innate immune responses against viral infection revealed in a human lung alveolus chip.

Bai, Haiqing / Si, Longlong / Jiang, Amanda / Belgur, Chaitra / Zhai, Yunhao / Plebani, Roberto / Oh, Crystal Yuri / Rodas, Melissa / Patil, Aditya / Nurani, Atiq / Gilpin, Sarah E / Powers, Rani K / Goyal, Girija / Prantil-Baun, Rachelle / Ingber, Donald E

Nature communications

2022 Volume 13, Issue 1, Page(s) 1928

Abstract: Mechanical breathing motions have a fundamental function in lung development and disease, but little is known about how they contribute to host innate immunity. Here we use a human lung alveolus chip that experiences cyclic breathing-like deformations to ...

Abstract	Mechanical breathing motions have a fundamental function in lung development and disease, but little is known about how they contribute to host innate immunity. Here we use a human lung alveolus chip that experiences cyclic breathing-like deformations to investigate whether physical forces influence innate immune responses to viral infection. Influenza H3N2 infection of mechanically active chips induces a cascade of host responses including increased lung permeability, apoptosis, cell regeneration, cytokines production, and recruitment of circulating immune cells. Comparison with static chips reveals that breathing motions suppress viral replication by activating protective innate immune responses in epithelial and endothelial cells, which are mediated in part through activation of the mechanosensitive ion channel TRPV4 and signaling via receptor for advanced glycation end products (RAGE). RAGE inhibitors suppress cytokines induction, while TRPV4 inhibition attenuates both inflammation and viral burden, in infected chips with breathing motions. Therefore, TRPV4 and RAGE may serve as new targets for therapeutic intervention in patients infected with influenza and other potential pandemic viruses that cause life-threatening lung inflammation.
MeSH term(s)	Antigens, Neoplasm/metabolism ; Cytokines ; Endothelial Cells ; Humans ; Immunity, Innate ; Influenza A Virus, H3N2 Subtype ; Influenza, Human/immunology ; Lung ; Mitogen-Activated Protein Kinases/metabolism ; TRPV Cation Channels/metabolism
Chemical Substances	Antigens, Neoplasm ; Cytokines ; TRPV Cation Channels ; TRPV4 protein, human ; MOK protein, human (EC 2.7.11.22) ; Mitogen-Activated Protein Kinases (EC 2.7.11.24)
Language	English
Publishing date	2022-04-08
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-29562-4
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Article ; Online: Modeling pulmonary cystic fibrosis in a human lung airway-on-a-chip.

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

Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society

2021 Volume 21, Issue 4, Page(s) 606–615

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Cells, Cultured ; Cystic Fibrosis ; Cystic Fibrosis Transmembrane Conductance Regulator/genetics ; Endothelial Cells ; Humans ; Lab-On-A-Chip Devices ; Lung ; Pseudomonas aeruginosa/physiology
Chemical Substances	Cystic Fibrosis Transmembrane Conductance Regulator (126880-72-6)
Language	English
Publishing date	2021-11-17
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2084724-5
ISSN	1873-5010 ; 1569-1993
ISSN (online)	1873-5010
ISSN	1569-1993
DOI	10.1016/j.jcf.2021.10.004
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Article: Self-assembling short immunostimulatory duplex RNAs with broad-spectrum antiviral activity.

Molecular therapy. Nucleic acids

2022 Volume 29, Page(s) 923–940

Abstract: The current coronavirus disease 2019 (COVID-19) pandemic highlights the need for broad-spectrum antiviral therapeutics. Here we describe a new class of self-assembling immunostimulatory short duplex RNAs that potently induce production of type I and type ...

Abstract	The current coronavirus disease 2019 (COVID-19) pandemic highlights the need for broad-spectrum antiviral therapeutics. Here we describe a new class of self-assembling immunostimulatory short duplex RNAs that potently induce production of type I and type III interferon (IFN-I and IFN-III). These RNAs require a minimum of 20 base pairs, lack any sequence or structural characteristics of known immunostimulatory RNAs, and instead require a unique sequence motif (sense strand, 5'-C; antisense strand, 3'-GGG) that mediates end-to-end dimer self-assembly. The presence of terminal hydroxyl or monophosphate groups, blunt or overhanging ends, or terminal RNA or DNA bases did not affect their ability to induce IFN. Unlike previously described immunostimulatory small interfering RNAs (siRNAs), their activity is independent of Toll-like receptor (TLR) 7/8, but requires the RIG-I/IRF3 pathway that induces a more restricted antiviral response with a lower proinflammatory signature compared with immunostimulant poly(I:C). Immune stimulation mediated by these duplex RNAs results in broad-spectrum inhibition of infections by many respiratory viruses with pandemic potential, including severe acute respiratory syndrome coronavirus (SARS-CoV)-2, SARS-CoV, Middle East respiratory syndrome coronavirus (MERS-CoV), human coronavirus (HCoV)-NL63, and influenza A virus in cell lines, human lung chips that mimic organ-level lung pathophysiology, and a mouse SARS-CoV-2 infection model. These short double-stranded RNAs (dsRNAs) can be manufactured easily, and thus potentially could be harnessed to produce broad-spectrum antiviral therapeutics.
Language	English
Publishing date	2022-08-24
Publishing country	United States
Document type	Journal Article
ZDB-ID	2662631-7
ISSN	2162-2531
ISSN	2162-2531
DOI	10.1016/j.omtn.2022.08.031
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Article ; Online: Mechanical control of innate immune responses against viral infection revealed in a human Lung Alveolus Chip

Bai, Haiqing / Si, Longlong / Jiang, Amanda / Belgur, Chaitra / Plebani, Roberto / Oh, Crystal Yuri / Rodas, Melissa / Nurani, Atiq / Gilpin, Sarah Elizabeth / Powers, Rani K / Goyal, Girija / Prantil-Baun, Rachelle / Ingber, Donald Elliot

bioRxiv

Abstract: Mechanical forces associated with breathing play a fundamental role in lung development and disease but the molecular pathways remain largely unknown. Here, we used a mechanically actuatable Human Lung Alveolus Chip that recapitulates human lung alveolar ...

Abstract	Mechanical forces associated with breathing play a fundamental role in lung development and disease but the molecular pathways remain largely unknown. Here, we used a mechanically actuatable Human Lung Alveolus Chip that recapitulates human lung alveolar type I and type II cell differentiation, alveolar-capillary interface formation, and genome-wide gene expression profiles characteristic of the distal lung to investigate the role of physical forces associated with cyclic breathing motions in lung innate immune responses to viral infection. When the mechanically active Alveolus Chips are infected with the influenza H3N2 virus, a cascade of host responses is elicited on-chip, including increased production of cytokines and expression of inflammation-associated genes in pulmonary epithelial and endothelial cells, resulting in enhanced recruitment of circulating immune cells as occurs during viral infection in vivo. Surprisingly, studies carried out in parallel with static chips revealed that physiological breathing motions suppress viral replication by activating protective innate immune responses in epithelial and endothelial cells. This is mediated at least in part through upregulation of S100 calcium-binding protein A7 (S100A7), which binds to the Receptor for Advanced Glycation End Products (RAGE), an inflammatory mediator that is most highly expressed in the lung alveolus in vivo. This mechano-immunological control mechanism is further supported by the finding that existing RAGE inhibitor drugs can suppress the production of inflammatory cytokines in response to influenza virus infection in this model. S100A7-RAGE interactions and modulation of mechanical ventilation parameters could therefore serve as new targets for therapeutic intervention in patients infected with influenza and other potential pandemic viruses that cause life-threatening lung inflammation.
Keywords	covid19
Language	English
Publishing date	2021-04-27
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2021.04.26.441498
Database	COVID19

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Article: Self-assembling short immunostimulatory duplex RNAs with broad spectrum antiviral activity.

Si, Longlong / Bai, Haiqing / Oh, Crystal Yuri / Zhang, Tian / Hong, Fan / Jiang, Amanda / Ye, Yongxin / Jordan, Tristan X / Logue, James / McGrath, Marisa / Belgur, Chaitra / Nurani, Atiq / Cao, Wuji / Prantil-Baun, Rachelle / Gygi, Steven P / Powers, Rani K / Frieman, Matthew / tenOever, Benjamin R / Ingber, Donald E

bioRxiv : the preprint server for biology

2021

Abstract: The current COVID-19 pandemic highlights the need for broad-spectrum antiviral therapeutics. Here we describe a new class of self-assembling immunostimulatory short duplex RNAs that potently induce production of type I and type III interferon (IFN-I and ... ...

Abstract	The current COVID-19 pandemic highlights the need for broad-spectrum antiviral therapeutics. Here we describe a new class of self-assembling immunostimulatory short duplex RNAs that potently induce production of type I and type III interferon (IFN-I and IFN-III), in a wide range of human cell types. These RNAs require a minimum of 20 base pairs, lack any sequence or structural characteristics of known immunostimulatory RNAs, and instead require a unique conserved sequence motif (sense strand: 5'-C, antisense strand: 3'-GGG) that mediates end-to-end dimer self-assembly of these RNAs by Hoogsteen G-G base-pairing. The presence of terminal hydroxyl or monophosphate groups, blunt or overhanging ends, or terminal RNA or DNA bases did not affect their ability to induce IFN. Unlike previously described immunostimulatory siRNAs, their activity is independent of TLR7/8, but requires the RIG-I/IRF3 pathway that induces a more restricted antiviral response with a lower proinflammatory signature compared with poly(I:C). Immune stimulation mediated by these duplex RNAs results in broad spectrum inhibition of infections by many respiratory viruses with pandemic potential, including SARS-CoV-2, SARS-CoV, MERS-CoV, and influenza A, as well as the common cold virus HCoV-NL63 in both cell lines and human Lung Chips that mimic organ-level lung pathophysiology. These short dsRNAs can be manufactured easily, and thus potentially could be harnessed to produce broad-spectrum antiviral therapeutics at low cost.
Language	English
Publishing date	2021-11-22
Publishing country	United States
Document type	Preprint
DOI	10.1101/2021.11.19.469183
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Article ; Online: Human immunocompetent Organ-on-Chip platforms allow safety profiling of tumor-targeted T-cell bispecific antibodies.

Kerns, S Jordan / Belgur, Chaitra / Petropolis, Debora / Kanellias, Marianne / Barrile, Riccardo / Sam, Johannes / Weinzierl, Tina / Fauti, Tanja / Freimoser-Grundschober, Anne / Eckmann, Jan / Hage, Carina / Geiger, Martina / Ng, Patrick Ray / Tien-Street, William / Manatakis, Dimitris V / Micallef, Virginie / Gerard, Regine / Bscheider, Michael / Breous-Nystrom, Ekaterina /

Schneider, Anneliese / Giusti, Anna Maria / Bertinetti-Lapatki, Cristina / Grant, Heather Shannon / Roth, Adrian B / Hamilton, Geraldine A / Singer, Thomas / Karalis, Katia / Moisan, Annie / Bruenker, Peter / Klein, Christian / Bacac, Marina / Gjorevski, Nikolce / Cabon, Lauriane

eLife

2021 Volume 10

Abstract: Traditional drug safety assessment often fails to predict complications in humans, especially when the drug targets the immune system. Here, we show the unprecedented capability of two human Organs-on-Chips to evaluate the safety profile of T-cell ... ...

Abstract	Traditional drug safety assessment often fails to predict complications in humans, especially when the drug targets the immune system. Here, we show the unprecedented capability of two human Organs-on-Chips to evaluate the safety profile of T-cell bispecific antibodies (TCBs) targeting tumor antigens. Although promising for cancer immunotherapy, TCBs are associated with an on-target, off-tumor risk due to low levels of expression of tumor antigens in healthy tissues. We leveraged in vivo target expression and toxicity data of TCBs targeting folate receptor 1 (FOLR1) or carcinoembryonic antigen (CEA) to design and validate human immunocompetent Organs-on-Chips safety platforms. We discovered that the Lung-Chip and Intestine-Chip could reproduce and predict target-dependent TCB safety liabilities, based on sensitivity to key determinants thereof, such as target expression and antibody affinity. These novel tools broaden the research options available for mechanistic understandings of engineered therapeutic antibodies and assessing safety in tissues susceptible to adverse events.
MeSH term(s)	Animals ; Antibodies, Bispecific/adverse effects ; Female ; HEK293 Cells ; HeLa Cells ; Humans ; Immunotherapy/methods ; Lab-On-A-Chip Devices/statistics & numerical data ; Mice ; T-Lymphocytes/immunology
Chemical Substances	Antibodies, Bispecific
Language	English
Publishing date	2021-08-11
Publishing country	England
Document type	Evaluation Study ; Journal Article
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.67106
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Article ; Online: Self-assembling short immunostimulatory duplex RNAs with broad spectrum antiviral activity

Si, Longlong / Bai, Haiqing / Oh, Crystal Yuri / Zhang, Tian / Jiang, Amanda / Hong, Fan / Ye, Yongxin / Jordan, Tristan X / Logue, James / McGrath, Marisa / Belgur, Chaitra / Nurani, Atiq / Cao, Wuji / Powers, Rani K / Prantil-Baun, Rachelle / Gygi, Steven P / Frieman, Matthew / tenOever, Benjamin R / Ingber, Donald Elliot

bioRxiv

Abstract	The current COVID-19 pandemic highlights the need for broad-spectrum antiviral therapeutics. Here we describe a new class of self-assembling immunostimulatory short duplex RNAs that potently induce production of type I and type III interferon (IFN-I and IFN-III), in a wide range of human cell types. These RNAs require a minimum of 20 base pairs, lack any sequence or structural characteristics of known immunostimulatory RNAs, and instead require a unique conserved sequence motif (sense strand: 59-C, antisense strand: 39-GGG) that mediates end-to-end dimer self-assembly of these RNAs by Hoogsteen G-G base-pairing. The presence of terminal hydroxyl or monophosphate groups, blunt or overhanging ends, or terminal RNA or DNA bases did not affect their ability to induce IFN. Unlike previously described immunostimulatory siRNAs, their activity is independent of TLR7/8, but requires the RIG-I/IRF3 pathway that induces a more restricted antiviral response with a lower proinflammatory signature compared with poly(I:C). Immune stimulation mediated by these duplex RNAs results in broad spectrum inhibition of infections by many respiratory viruses with pandemic potential, including SARS-CoV-2, SARS-CoV, MERS-CoV, and influenza A, as well as the common cold virus HCoV-NL63 in both cell lines and human Lung Chips that mimic organ-level lung pathophysiology. These short dsRNAs can be manufactured easily, and thus potentially could be harnessed to produce broad-spectrum antiviral therapeutics at low cost.
Keywords	covid19
Language	English
Publishing date	2021-11-22
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2021.11.19.469183
Database	COVID19

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Article ; Online: Human organ chips for regenerative pharmacology.

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Article ; Online: Safety Profiling of Tumor-targeted T Cell-Bispecific Antibodies with Alveolus Lung- and Colon-on-Chip.

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Article ; Online: Mechanical control of innate immune responses against viral infection revealed in a human lung alveolus chip.

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Article ; Online: Modeling pulmonary cystic fibrosis in a human lung airway-on-a-chip.

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Article: Self-assembling short immunostimulatory duplex RNAs with broad-spectrum antiviral activity.

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Article ; Online: Mechanical control of innate immune responses against viral infection revealed in a human Lung Alveolus Chip

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Inter-library loan at ZB MED

Article: Self-assembling short immunostimulatory duplex RNAs with broad spectrum antiviral activity.

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Article ; Online: Human immunocompetent Organ-on-Chip platforms allow safety profiling of tumor-targeted T-cell bispecific antibodies.

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Article ; Online: Self-assembling short immunostimulatory duplex RNAs with broad spectrum antiviral activity

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Inter-library loan at ZB MED