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4. Characterization of the COPD alveolar niche using single-cell RNA sequencing

Author

Sauler, Maor, McDonough, John E., Adams, Taylor S., Kothapalli, Neeharika, Barnthaler, Thomas, Werder, Rhiannon B., Schupp, Jonas C., Nouws, Jessica, Robertson, Matthew J., Coarfa, Cristian, Yang, Tao, Chioccioli, Maurizio, Omote, Norihito, Cosme, Jr, Carlos, Poli, Sergio, Ayaub, Ehab A., Chu, Sarah G., Jensen, Klaus H., Gomez, Jose L., Britto, Clemente J., Raredon, Micha Sam B., Niklason, Laura E., Wilson, Andrew A., Timshel, Pascal N., Kaminski, Naftali, and Rosas, Ivan O.

Published
2022
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9. Maternal diet modulates the infant microbiome and intestinal Flt3L necessary for dendritic cell development and immunity to respiratory infection

Author

Sikder, Md. Al Amin, primary, Rashid, Ridwan B., additional, Ahmed, Tufael, additional, Sebina, Ismail, additional, Howard, Daniel R., additional, Ullah, Md. Ashik, additional, Rahman, Muhammed Mahfuzur, additional, Lynch, Jason P., additional, Curren, Bodie, additional, Werder, Rhiannon B., additional, Simpson, Jennifer, additional, Bissell, Alec, additional, Morrison, Mark, additional, Walpole, Carina, additional, Radford, Kristen J., additional, Kumar, Vinod, additional, Woodruff, Trent M., additional, Ying, Tan Hui, additional, Ali, Ayesha, additional, Kaiko, Gerard E., additional, Upham, John W., additional, Hoelzle, Robert D., additional, Cuív, Páraic Ó., additional, Holt, Patrick G., additional, Dennis, Paul G., additional, and Phipps, Simon, additional

Published
2023
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10. Human iPSC-hepatocyte modeling of alpha-1 antitrypsin heterozygosity reveals metabolic dysregulation and cellular heterogeneity

Author

Kaserman, Joseph E., primary, Werder, Rhiannon B., additional, Wang, Feiya, additional, Matte, Taylor, additional, Higgins, Michelle I., additional, Dodge, Mark, additional, Lindstrom-Vautrin, Jonathan, additional, Bawa, Pushpinder, additional, Hinds, Anne, additional, Bullitt, Esther, additional, Caballero, Ignacio S., additional, Shi, Xu, additional, Gerszten, Robert E., additional, Brunetti-Pierri, Nicola, additional, Liesa, Marc, additional, Villacorta-Martin, Carlos, additional, Hollenberg, Anthony N., additional, Kotton, Darrell N., additional, and Wilson, Andrew A., additional

Published
2022
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12. CRISPR interference interrogation of COPD GWAS genes reveals the functional significance of desmoplakin in iPSC-derived alveolar epithelial cells

Author

Werder, Rhiannon B., primary, Liu, Tao, additional, Abo, Kristine M., additional, Lindstrom-Vautrin, Jonathan, additional, Villacorta-Martin, Carlos, additional, Huang, Jessie, additional, Hinds, Anne, additional, Boyer, Nathan, additional, Bullitt, Esther, additional, Liesa, Marc, additional, Silverman, Edwin K., additional, Kotton, Darrell N., additional, Cho, Michael H., additional, Zhou, Xiaobo, additional, and Wilson, Andrew A., additional

Published
2022
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13. Human iPSC-hepatocyte modeling of alpha-1 antitrypsin heterozygosity reveals metabolic dysregulation and cellular heterogeneity [Dataset]

Author

Kaserman, Joseph E., Werder, Rhiannon B., Wang, Feiya, Matte, Taylor, Higgins, Michelle I., Dodge, Mark, Lindstrom-Vautrin, Jonathan, Bawa, Pushpinder, Hinds, Anne, Bullitt, Esther, Caballero, Ignacio S., Shi, Xu, Gerszten, Robert E., Brunetti-Pierri, Nicola, Liesa, Marc, Villacorta-Martin, Carlos, Hollenberg, Anthony N., Kotton, Darrell N., Wilson, Andrew A., Kaserman, Joseph E., Werder, Rhiannon B., Wang, Feiya, Matte, Taylor, Higgins, Michelle I., Dodge, Mark, Lindstrom-Vautrin, Jonathan, Bawa, Pushpinder, Hinds, Anne, Bullitt, Esther, Caballero, Ignacio S., Shi, Xu, Gerszten, Robert E., Brunetti-Pierri, Nicola, Liesa, Marc, Villacorta-Martin, Carlos, Hollenberg, Anthony N., Kotton, Darrell N., and Wilson, Andrew A.

Published
2022

14. CRISPR interference interrogation of COPD GWAS genes reveals the functional significance of desmoplakin in iPSC-derived alveolar epithelial cells [Dataset]

Author

Werder, Rhiannon B., Liu, Tao, Abo, Kristine M., Lindstrom-Vautrin, Jonathan, Villacorta-Martin, Carlos, Huang, Jessie, Hinds, Anne, Boyer, Nathan, Bullitt, Esther, Liesa, Marc, Silverman, Edwin K., Kotton, Darrell N., Cho, Michael H., Zhou, Xiaobo, Wilson, Andrew A., Werder, Rhiannon B., Liu, Tao, Abo, Kristine M., Lindstrom-Vautrin, Jonathan, Villacorta-Martin, Carlos, Huang, Jessie, Hinds, Anne, Boyer, Nathan, Bullitt, Esther, Liesa, Marc, Silverman, Edwin K., Kotton, Darrell N., Cho, Michael H., Zhou, Xiaobo, and Wilson, Andrew A.

Published
2022

15. Human iPSC-hepatocyte modeling of alpha-1 antitrypsin heterozygosity reveals metabolic dysregulation and cellular heterogeneity

Author

National Health and Medical Research Council (Australia), National Institutes of Health (US), Alpha- Foundation, Kaserman, Joseph E., Werder, Rhiannon B., Wang, Feiya, Matte, Taylor, Higgins, Michelle I., Dodge, Mark, Lindstrom-Vautrin, Jonathan, Bawa, Pushpinder, Hinds, Anne, Bullitt, Esther, Caballero, Ignacio S., Shi, Xu, Gerszten, Robert E., Brunetti-Pierri, Nicola, Liesa, Marc, Villacorta-Martin, Carlos, Hollenberg, Anthony N., Kotton, Darrell N., Wilson, Andrew A., National Health and Medical Research Council (Australia), National Institutes of Health (US), Alpha- Foundation, Kaserman, Joseph E., Werder, Rhiannon B., Wang, Feiya, Matte, Taylor, Higgins, Michelle I., Dodge, Mark, Lindstrom-Vautrin, Jonathan, Bawa, Pushpinder, Hinds, Anne, Bullitt, Esther, Caballero, Ignacio S., Shi, Xu, Gerszten, Robert E., Brunetti-Pierri, Nicola, Liesa, Marc, Villacorta-Martin, Carlos, Hollenberg, Anthony N., Kotton, Darrell N., and Wilson, Andrew A.

Abstract

Individuals homozygous for the “Z” mutation in alpha-1 antitrypsin deficiency are known to be at increased risk for liver disease. It has also become clear that some degree of risk is similarly conferred by the heterozygous state. A lack of model systems that recapitulate heterozygosity in human hepatocytes has limited the ability to study the impact of a single Z alpha-1 antitrypsin (ZAAT) allele on hepatocyte biology. Here, we describe the derivation of syngeneic induced pluripotent stem cells (iPSCs) engineered to determine the effects of ZAAT heterozygosity in iPSC-hepatocytes (iHeps). We find that heterozygous MZ iHeps exhibit an intermediate disease phenotype and share with ZZ iHeps alterations in AAT protein processing and downstream perturbations including altered endoplasmic reticulum (ER) and mitochondrial morphology, reduced mitochondrial respiration, and branch-specific activation of the unfolded protein response in cell subpopulations. Our model of MZ heterozygosity thus provides evidence that a single Z allele is sufficient to disrupt hepatocyte homeostatic function.

Published
2022

16. Air-liquid interface culture promotes maturation and allows environmental exposure of pluripotent stem cell–derived alveolar epithelium

Author

Massachusetts Institute of Technology. Department of Biology, Abo, Kristine M, Sainz de Aja, Julio, Lindstrom-Vautrin, Jonathan, Alysandratos, Konstantinos-Dionysios, Richards, Alexsia, Garcia-de-Alba, Carolina, Huang, Jessie, Hix, Olivia T, Werder, Rhiannon B, Bullitt, Esther, Hinds, Anne, Falconer, Isaac, Villacorta-Martin, Carlos, Jaenisch, Rudolf, Kim, Carla F, Kotton, Darrell N, Wilson, Andrew A, Massachusetts Institute of Technology. Department of Biology, Abo, Kristine M, Sainz de Aja, Julio, Lindstrom-Vautrin, Jonathan, Alysandratos, Konstantinos-Dionysios, Richards, Alexsia, Garcia-de-Alba, Carolina, Huang, Jessie, Hix, Olivia T, Werder, Rhiannon B, Bullitt, Esther, Hinds, Anne, Falconer, Isaac, Villacorta-Martin, Carlos, Jaenisch, Rudolf, Kim, Carla F, Kotton, Darrell N, and Wilson, Andrew A

Abstract

Type 2 alveolar epithelial cells (AT2s), facultative progenitor cells of the lung alveolus, play a vital role in the biology of the distal lung. In vitro model systems that incorporate human cells, recapitulate the biology of primary AT2s, and interface with the outside environment could serve as useful tools to elucidate functional characteristics of AT2s in homeostasis and disease. We and others recently adapted human induced pluripotent stem cell-derived AT2s (iAT2s) for air-liquid interface (ALI) culture. Here, we comprehensively characterize the effects of ALI culture on iAT2s and benchmark their transcriptional profile relative to both freshly sorted and cultured primary human fetal and adult AT2s. We find that iAT2s cultured at ALI maintain an AT2 phenotype while upregulating expression of transcripts associated with AT2 maturation. We then leverage this platform to assay the effects of exposure to clinically significant, inhaled toxicants including cigarette smoke and electronic cigarette vapor.

Published
2022

17. CRISPR interference interrogation of COPD GWAS genes reveals the functional significance of desmoplakin in iPSC-derived alveolar epithelial cells

Author

National Health and Medical Research Council (Australia), National Institutes of Health (US), Werder, Rhiannon B., Liu, Tao, Abo, Kristine M., Lindstrom-Vautrin, Jonathan, Villacorta-Martin, Carlos, Huang, Jessie, Hinds, Anne, Boyer, Nathan, Bullitt, Esther, Liesa, Marc, Silverman, Edwin K., Kotton, Darrell N., Cho, Michael H., Zhou, Xiaobo, Wilson, Andrew A., National Health and Medical Research Council (Australia), National Institutes of Health (US), Werder, Rhiannon B., Liu, Tao, Abo, Kristine M., Lindstrom-Vautrin, Jonathan, Villacorta-Martin, Carlos, Huang, Jessie, Hinds, Anne, Boyer, Nathan, Bullitt, Esther, Liesa, Marc, Silverman, Edwin K., Kotton, Darrell N., Cho, Michael H., Zhou, Xiaobo, and Wilson, Andrew A.

Abstract

Genome-wide association studies (GWAS) have identified dozens of loci associated with chronic obstructive pulmonary disease (COPD) susceptibility; however, the function of associated genes in the cell type(s) affected in disease remains poorly understood, partly due to a lack of cell models that recapitulate human alveolar biology. Here, we apply CRISPR interference to interrogate the function of nine genes implicated in COPD by GWAS in induced pluripotent stem cell–derived type 2 alveolar epithelial cells (iAT2s). We find that multiple genes implicated by GWAS affect iAT2 function, including differentiation potential, maturation, and/or proliferation. Detailed characterization of the GWAS gene DSP demonstrates that it regulates iAT2 cell-cell junctions, proliferation, mitochondrial function, and response to cigarette smoke–induced injury. Our approach thus elucidates the biological function, as well as disease-relevant consequences of dysfunction, of genes implicated in COPD by GWAS in type 2 alveolar epithelial cells.

Published
2022

18. Air-liquid interface culture promotes maturation and allows environmental exposure of pluripotent stem cell–derived alveolar epithelium

Author

Abo, Kristine M., primary, Sainz de Aja, Julio, additional, Lindstrom-Vautrin, Jonathan, additional, Alysandratos, Konstantinos-Dionysios, additional, Richards, Alexsia, additional, Garcia-de-Alba, Carolina, additional, Huang, Jessie, additional, Hix, Olivia T., additional, Werder, Rhiannon B., additional, Bullitt, Esther, additional, Hinds, Anne, additional, Falconer, Isaac, additional, Villacorta-Martin, Carlos, additional, Jaenisch, Rudolf, additional, Kim, Carla F., additional, Kotton, Darrell N., additional, and Wilson, Andrew A., additional

Published
2022
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19. Human airway lineages derived from pluripotent stem cells reveal the epithelial responses to SARS-CoV-2 infection

Author

Wang, Ruobing, primary, Hume, Adam J., additional, Beermann, Mary Lou, additional, Simone-Roach, Chantelle, additional, Lindstrom-Vautrin, Jonathan, additional, Le Suer, Jake, additional, Huang, Jessie, additional, Olejnik, Judith, additional, Villacorta-Martin, Carlos, additional, Bullitt, Esther, additional, Hinds, Anne, additional, Ghaedi, Mahboobe, additional, Rollins, Stuart, additional, Werder, Rhiannon B., additional, Abo, Kristine M., additional, Wilson, Andrew A., additional, Mühlberger, Elke, additional, Kotton, Darrell N., additional, and Hawkins, Finn J., additional

Published
2022
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20. HMGB1 amplifies ILC2-induced type-2 inflammation and airway smooth muscle remodelling

Author

Loh, Zhixuan, Simpson, Jennifer, Ullah, Ashik, Zhang, Vivian, Gan, Wan J., Lynch, Jason P., Werder, Rhiannon B., Sikder, Al Amin, Lane, Katie, Sim, Choon Boon, Porrello, Enzo, Mazzone, Stuart B., Sly, Peter D., Steptoe, Raymond J., Spann, Kirsten M., Sukkar, Maria B., Upham, John W., Phipps, Simon, Loh, Zhixuan, Simpson, Jennifer, Ullah, Ashik, Zhang, Vivian, Gan, Wan J., Lynch, Jason P., Werder, Rhiannon B., Sikder, Al Amin, Lane, Katie, Sim, Choon Boon, Porrello, Enzo, Mazzone, Stuart B., Sly, Peter D., Steptoe, Raymond J., Spann, Kirsten M., Sukkar, Maria B., Upham, John W., and Phipps, Simon

Abstract

Type-2 immunity elicits tissue repair and homeostasis, however dysregulated type-2 responses cause aberrant tissue remodelling, as observed in asthma. Severe respiratory viral infections in infancy predispose to later asthma, however, the processes that mediate tissue damage-induced type-2 inflammation and the origins of airway remodelling remain illdefined. Here, using a preclinical mouse model of viral bronchiolitis, we find that increased epithelial and mesenchymal high-mobility group box 1 (HMGB1) expression is associated with increased numbers of IL-13-producing type-2 innate lymphoid cell (ILC2s) and the expansion of the airway smooth muscle (ASM) layer. Anti-HMGB1 ablated lung ILC2 numbers and ASM growth in vivo, and inhibited ILC2-mediated ASM cell proliferation in a co-culture model. Furthermore, we identified that HMGB1/RAGE (receptor for advanced glycation endproducts) signalling mediates an ILC2-intrinsic IL-13 auto-amplification loop. In summary, therapeutic targeting of the HMGB1/RAGE signalling axis may act as a novel asthma preventative by dampening ILC2-mediated type-2 inflammation and associated ASM remodelling.

Published
2020

21. Respiratory Syncytial Virus Infection Promotes Necroptosis and HMGB1 Release by Airway Epithelial Cells

Author

Simpson, Jennifer, Loh, Zhixuan, Ullah, Md Ashik, Lynch, Jason P., Werder, Rhiannon B., Collinson, Natasha, Zhang, Vivian, Dondelinger, Yves, Bertrand, Mathieu J.M., Everard, Mark L., Blyth, Christopher C., Hartel, Gunter, Van Oosterhout, Antoon J., Gough, Peter J., Bertin, John, Upham, John W., Spann, Kirsten M., Phipps, Simon, Simpson, Jennifer, Loh, Zhixuan, Ullah, Md Ashik, Lynch, Jason P., Werder, Rhiannon B., Collinson, Natasha, Zhang, Vivian, Dondelinger, Yves, Bertrand, Mathieu J.M., Everard, Mark L., Blyth, Christopher C., Hartel, Gunter, Van Oosterhout, Antoon J., Gough, Peter J., Bertin, John, Upham, John W., Spann, Kirsten M., and Phipps, Simon

Abstract

Rationale: Respiratory syncytial virus (RSV) bronchiolitis causes significant infant mortality. Bronchiolitis is characterized by airway epithelial cell (AEC) death; however, the mode of death remains unknown. Objectives: To determine whether necroptosis contributes to RSV bronchiolitis pathogenesis via HMGB1 (high mobility group box 1) release. Methods: Nasopharyngeal samples were collected from children presenting to the hospital with acute respiratory infection. Primary humanAECs andneonatalmicewere inoculatedwithRSVandmurine Pneumovirus, respectively. Necroptosis was determined via viability assays and immunohistochemistry for RIPK1 (receptor-interacting protein kinase-1), MLKL (mixed lineage kinase domain-like pseudokinase) protein, and caspase-3. Necroptosis was blocked using pharmacological inhibitors and RIPK1 kinase-dead knockin mice. Measurements and Main Results: HMGB1 levels were elevated in nasopharyngeal samples of children with acute RSV infection. RSV-induced epithelial cell death was associated with increased phosphorylated RIPK1 and phosphorylated MLKL but not active caspase-3 expression. Inhibition of RIPK1 or MLKL attenuated RSV-induced HMGB1 translocation and release, and lowered viral load. MLKL inhibition increased active caspase-3 expression in a caspase-8/9 dependent manner. In susceptible mice, Pneumovirus infection upregulated RIPK1 and MLKL expression in the airway epithelium at 8 to 10 days after infection, coinciding with AEC sloughing, HMGB1 release, and neutrophilic inflammation. Genetic or pharmacological inhibition of RIPK1 or MLKL attenuated these pathologies, lowered viral load, and prevented type 2 inflammation and airway remodeling. Necroptosis inhibition in early life ameliorated asthma progression induced by viral or allergen challenge in later life. Conclusions: Pneumovirus infection induces AEC necroptosis. Inhibition of necroptosis may be a viable strategy to limit the severity of viral bronchiolitis and break its nexus

Published
2020

22. Actionable Cytopathogenic Host Responses of Human Alveolar Type 2 Cells to SARS-CoV-2

Author

Hekman, Ryan M., primary, Hume, Adam J., additional, Goel, Raghuveera Kumar, additional, Abo, Kristine M., additional, Huang, Jessie, additional, Blum, Benjamin C., additional, Werder, Rhiannon B., additional, Suder, Ellen L., additional, Paul, Indranil, additional, Phanse, Sadhna, additional, Youssef, Ahmed, additional, Alysandratos, Konstantinos D., additional, Padhorny, Dzmitry, additional, Ojha, Sandeep, additional, Mora-Martin, Alexandra, additional, Kretov, Dmitry, additional, Ash, Peter E.A., additional, Verma, Mamta, additional, Zhao, Jian, additional, Patten, J.J., additional, Villacorta-Martin, Carlos, additional, Bolzan, Dante, additional, Perea-Resa, Carlos, additional, Bullitt, Esther, additional, Hinds, Anne, additional, Tilston-Lunel, Andrew, additional, Varelas, Xaralabos, additional, Farhangmehr, Shaghayegh, additional, Braunschweig, Ulrich, additional, Kwan, Julian H., additional, McComb, Mark, additional, Basu, Avik, additional, Saeed, Mohsan, additional, Perissi, Valentina, additional, Burks, Eric J., additional, Layne, Matthew D., additional, Connor, John H., additional, Davey, Robert, additional, Cheng, Ji-Xin, additional, Wolozin, Benjamin L., additional, Blencowe, Benjamin J., additional, Wuchty, Stefan, additional, Lyons, Shawn M., additional, Kozakov, Dima, additional, Cifuentes, Daniel, additional, Blower, Michael, additional, Kotton, Darrell N., additional, Wilson, Andrew A., additional, Mühlberger, Elke, additional, and Emili, Andrew, additional

Published
2021
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23. Actionable Cytopathogenic Host Responses of Human Alveolar Type 2 Cells to SARS-CoV-2

Author

Hekman, Ryan M., primary, Hume, Adam J., additional, Goel, Raghuveera Kumar, additional, Abo, Kristine M., additional, Huang, Jessie, additional, Blum, Benjamin C., additional, Werder, Rhiannon B., additional, Suder, Ellen L., additional, Paul, Indranil, additional, Phanse, Sadhna, additional, Youssef, Ahmed, additional, Alysandratos, Konstantinos D., additional, Padhorny, Dzmitry, additional, Ojha, Sandeep, additional, Mora-Martin, Alexandra, additional, Kretov, Dmitry, additional, Ash, Peter E.A., additional, Verma, Mamta, additional, Zhao, Jian, additional, Patten, J.J., additional, Villacorta-Martin, Carlos, additional, Bolzan, Dante, additional, Perea-Resa, Carlos, additional, Bullitt, Esther, additional, Hinds, Anne, additional, Tilston-Lunel, Andrew, additional, Varelas, Xaralabos, additional, Farhangmehr, Shaghayegh, additional, Braunschweig, Ulrich, additional, Kwan, Julian H., additional, McComb, Mark, additional, Basu, Avik, additional, Saeed, Mohsan, additional, Perissi, Valentina, additional, Burks, Eric J., additional, Layne, Matthew D., additional, Connor, John H., additional, Davey, Robert, additional, Cheng, Ji-Xin, additional, Wolozin, Benjamin L., additional, Blencowe, Benjamin J., additional, Wuchty, Stefan, additional, Lyons, Shawn M., additional, Kozakov, Dima, additional, Cifuentes, Daniel, additional, Blower, Michael, additional, Kotton, Darrell N., additional, Wilson, Andrew A., additional, Mühlberger, Elke, additional, and Emili, Andrew, additional

Published
2020
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24. SARS-CoV-2 Infection of Pluripotent Stem Cell-Derived Human Lung Alveolar Type 2 Cells Elicits a Rapid Epithelial-Intrinsic Inflammatory Response

Author

Huang, Jessie, primary, Hume, Adam J., additional, Abo, Kristine M., additional, Werder, Rhiannon B., additional, Villacorta-Martin, Carlos, additional, Alysandratos, Konstantinos-Dionysios, additional, Beermann, Mary Lou, additional, Simone-Roach, Chantelle, additional, Lindstrom-Vautrin, Jonathan, additional, Olejnik, Judith, additional, Suder, Ellen L., additional, Bullitt, Esther, additional, Hinds, Anne, additional, Sharma, Arjun, additional, Bosmann, Markus, additional, Wang, Ruobing, additional, Hawkins, Finn, additional, Burks, Eric J., additional, Saeed, Mohsan, additional, Wilson, Andrew A., additional, Mühlberger, Elke, additional, and Kotton, Darrell N., additional

Published
2020
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25. Human airway lineages derived from pluripotent stem cells reveal the epithelial responses to SARS-CoV-2 infection.

Author

Ruobing Wang, Hume, Adam J., Beermann, Mary Lou, Simone-Roach, Chantelle, Lindstrom-Vautrin, Jonathan, Le Suer, Jake, Huang, Jessie, Olejnik, Judith, Villacorta-Martin, Carlos, Bullitt, Esther, Hinds, Anne, Ghaedi, Mahboobe, Rollins, Stuart, Werder, Rhiannon B., Abo, Kristine M., Wilson, Andrew A., Mühlberger, Elke, Kotton, Darrell N., and Hawkins, Finn J.

Subjects
PLURIPOTENT stem cells, INDUCED pluripotent stem cells, EPITHELIAL cells, SARS-CoV-2, ANGIOTENSIN converting enzyme
Abstract

There is an urgent need to understand how SARS-CoV-2 infects the airway epithelium and in a subset of individuals leads to severe illness or death. Induced pluripotent stem cells (iPSCs) provide a near limitless supply of human cells that can be differentiated into cell types of interest, including airway epithelium, for disease modeling. We present a human iPSC-derived airway epithelial platform, composed of the major airway epithelial cell types, that is permissive to SARS-CoV-2 infection. Subsets of iPSC-airway cells express the SARS-CoV-2 entry factors angiotensin-converting enzyme 2 (ACE2), and transmembrane protease serine 2 (TMPRSS2). Multiciliated cells are the primary initial target of SARS-CoV-2 infection. On infection with SARS-CoV-2, iPSC-airway cells generate robust interferon and inflammatory responses, and treatment with remdesivir or camostat mesylate causes a decrease in viral propagation and entry, respectively. In conclusion, iPSC-derived airway cells provide a physiologically relevant in vitro model system to interrogate the pathogenesis of, and develop treatment strategies for, COVID-19 pneumonia. [ABSTRACT FROM AUTHOR]

Published
2022
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27. HMGB1 amplifies ILC2-induced type-2 inflammation and airway smooth muscle remodelling

Author

Loh, Zhixuan, primary, Simpson, Jennifer, additional, Ullah, Ashik, additional, Zhang, Vivian, additional, Gan, Wan J., additional, Lynch, Jason P., additional, Werder, Rhiannon B., additional, Sikder, Al Amin, additional, Lane, Katie, additional, Sim, Choon Boon, additional, Porrello, Enzo, additional, Mazzone, Stuart B., additional, Sly, Peter D., additional, Steptoe, Raymond J., additional, Spann, Kirsten M., additional, Sukkar, Maria B., additional, Upham, John W., additional, and Phipps, Simon, additional

Published
2020
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28. Reconstructed Single-Cell Fate Trajectories Define Lineage Plasticity Windows during Differentiation of Human PSC-Derived Distal Lung Progenitors

Author

Hurley, Killian, primary, Ding, Jun, additional, Villacorta-Martin, Carlos, additional, Herriges, Michael J., additional, Jacob, Anjali, additional, Vedaie, Marall, additional, Alysandratos, Konstantinos D., additional, Sun, Yuliang L., additional, Lin, Chieh, additional, Werder, Rhiannon B., additional, Huang, Jessie, additional, Wilson, Andrew A., additional, Mithal, Aditya, additional, Mostoslavsky, Gustavo, additional, Oglesby, Irene, additional, Caballero, Ignacio S., additional, Guttentag, Susan H., additional, Ahangari, Farida, additional, Kaminski, Naftali, additional, Rodriguez-Fraticelli, Alejo, additional, Camargo, Fernando, additional, Bar-Joseph, Ziv, additional, and Kotton, Darrell N., additional

Published
2020
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29. Plasmacytoid dendritic cells protect from viral bronchiolitis and asthma through semaphorin 4a–mediated T reg expansion

Author

Lynch, Jason P., primary, Werder, Rhiannon B., additional, Loh, Zhixuan, additional, Sikder, Md. Al Amin, additional, Curren, Bodie, additional, Zhang, Vivian, additional, Rogers, Matthew J., additional, Lane, Katie, additional, Simpson, Jennifer, additional, Mazzone, Stuart B., additional, Spann, Kirsten, additional, Hayball, John, additional, Diener, Kerrilyn, additional, Everard, Mark L., additional, Blyth, Christopher C., additional, Forstner, Christian, additional, Dennis, Paul G., additional, Murtaza, Nida, additional, Morrison, Mark, additional, Ó Cuív, Páraic, additional, Zhang, Ping, additional, Haque, Ashraful, additional, Hill, Geoffrey R., additional, Sly, Peter D., additional, Upham, John W., additional, and Phipps, Simon, additional

Published
2017
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30. Gene-based analysis of regulatory variants identifies four putative novel asthma risk genes related to nucleotide synthesis and signaling

Author

Ferreira, Manuel A.R., Jansen, Rick, Willemsen, Gonneke, Penninx, Brenda, Bain, Lisa M, Vicente, Cristina T, Revez, Joana A, Matheson, Melanie C., Hui, Jennie, Tung, Joyce Y., Baltic, Svetlana, Le Souëf, Peter, Montgomery, Grant W., Martin, Nicholas G., Robertson, Colin F., James, Alan, Thompson, Philip J., Boomsma, Dorret I., Hopper, John L., Hinds, David A., Werder, Rhiannon B., and Phipps, Simon

Subjects
Nucleotides, Receptors, Purinergic P2, Quantitative Trait Loci, Genetic Variation, Mitochondrial Proton-Translocating ATPases, Article, Asthma, Mice, Inbred C57BL, Mice, Receptors, Purinergic P2Y, Animals, Humans, Genetic Predisposition to Disease, Software, Genome-Wide Association Study
Abstract

Hundreds of genetic variants are thought to contribute to variation in asthma risk by modulating gene expression. Methods that increase the power of genome-wide association studies (GWASs) to identify risk-associated variants are needed.We sought to develop a method that aggregates the evidence for association with disease risk across expression quantitative trait loci (eQTLs) of a gene and use this approach to identify asthma risk genes.We developed a gene-based test and software package called EUGENE that (1) is applicable to GWAS summary statistics; (2) considers both cis- and trans-eQTLs; (3) incorporates eQTLs identified in different tissues; and (4) uses simulations to account for multiple testing. We applied this approach to 2 published asthma GWASs (combined n = 46,044) and used mouse studies to provide initial functional insights into 2 genes with novel genetic associations.We tested the association between asthma and 17,190 genes that were found to have cis- and/or trans-eQTLs across 16 published eQTL studies. At an empirical FDR of 5%, 48 genes were associated with asthma risk. Of these, for 37, the association was driven by eQTLs located in established risk loci for allergic disease, including 6 genes not previously implicated in disease cause (eg, LIMS1, TINF2, and SAFB). The remaining 11 significant genes represent potential novel genetic associations with asthma. The association with 4 of these replicated in an independent GWAS: B4GALT3, USMG5, P2RY13, and P2RY14, which are genes involved in nucleotide synthesis or nucleotide-dependent cell activation. In mouse studies, P2ry13 and P2ry14-purinergic receptors activated by adenosine 5-diphosphate and UDP-sugars, respectively-were upregulated after allergen challenge, notably in airway epithelial cells, eosinophils, and neutrophils. Intranasal exposure with receptor agonists induced the release of IL-33 and subsequent eosinophil infiltration into the lungs.We identified novel associations between asthma and eQTLs for 4 genes related to nucleotide synthesis/signaling and demonstrated the power of gene-based analyses of GWASs.

Published
2016

31. Allergen-encoding bone marrow transfer inactivates allergic T cell responses, alleviating airway inflammation

Author

AL-Kouba, Jane, primary, Wilkinson, Andrew N., additional, Starkey, Malcolm R., additional, Rudraraju, Rajeev, additional, Werder, Rhiannon B., additional, Liu, Xiao, additional, Law, Soi-Cheng, additional, Horvat, Jay C., additional, Brooks, Jeremy F., additional, Hill, Geoffrey R., additional, Davies, Janet M., additional, Phipps, Simon, additional, Hansbro, Philip M., additional, and Steptoe, Raymond J., additional

Published
2017
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34. RAGE deficiency predisposes mice to virus-induced paucigranulocytic asthma

Author

Arikkatt, Jaisy, primary, Ullah, Md Ashik, additional, Short, Kirsty Renfree, additional, Zhang, Vivan, additional, Gan, Wan Jun, additional, Loh, Zhixuan, additional, Werder, Rhiannon B, additional, Simpson, Jennifer, additional, Sly, Peter D, additional, Mazzone, Stuart B, additional, Spann, Kirsten M, additional, Ferreira, Manuel AR, additional, Upham, John W, additional, Sukkar, Maria B, additional, and Phipps, Simon, additional

Published
2017
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35. Coinfection with Blood-Stage Plasmodium Promotes Systemic Type I Interferon Production during Pneumovirus Infection but Impairs Inflammation and Viral Control in the Lung

Author

Edwards, Chelsea L., primary, Zhang, Vivian, additional, Werder, Rhiannon B., additional, Best, Shannon E., additional, Sebina, Ismail, additional, James, Kylie R., additional, Faleiro, Rebecca J., additional, de Labastida Rivera, Fabian, additional, Amante, Fiona H., additional, Engwerda, Christian R., additional, Phipps, Simon, additional, and Haque, Ashraful, additional

Published
2015
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36. 196

Author

Werder, Rhiannon B., primary, Lynch, Jason P., additional, Simpson, Jennifer, additional, Loh, Ken, additional, Zhang, Vivian, additional, Spann, Kirsten, additional, Sly, Peter D., additional, Mazzone, Stuart, additional, Upham, John W., additional, and Phipps, Simon, additional

Published
2014
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37. Plasmacytoid dendritic cells protect from viral bronchiolitis and asthma through semaphorin 4a–mediated T reg expansion

Author

Lynch, Jason P., Werder, Rhiannon B., Loh, Zhixuan, Sikder, Md. Al Amin, Curren, Bodie, Zhang, Vivian, Rogers, Matthew J., Lane, Katie, Simpson, Jennifer, Mazzone, Stuart B., Spann, Kirsten, Hayball, John, Diener, Kerrilyn, Everard, Mark L., Blyth, Christopher C., Forstner, Christian, Dennis, Paul G., Murtaza, Nida, Morrison, Mark, Ó Cuív, Páraic, Zhang, Ping, Haque, Ashraful, Hill, Geoffrey R., Sly, Peter D., Upham, John W., and Phipps, Simon

Abstract

Respiratory syncytial virus–bronchiolitis is a major independent risk factor for subsequent asthma, but the causal mechanisms remain obscure. We identified that transient plasmacytoid dendritic cell (pDC) depletion during primary Pneumovirus infection alone predisposed to severe bronchiolitis in early life and subsequent asthma in later life after reinfection. pDC depletion ablated interferon production and increased viral load; however, the heightened immunopathology and susceptibility to subsequent asthma stemmed from a failure to expand functional neuropilin-1+ regulatory T (T reg) cells in the absence of pDC-derived semaphorin 4a (Sema4a). In adult mice, pDC depletion predisposed to severe bronchiolitis only after antibiotic treatment. Consistent with a protective role for the microbiome, treatment of pDC-depleted neonates with the microbial-derived metabolite propionate promoted Sema4a-dependent T reg cell expansion, ameliorating both diseases. In children with viral bronchiolitis, nasal propionate levels were decreased and correlated with an IL-6high/IL-10low microenvironment. We highlight a common but age-related Sema4a-mediated pathway by which pDCs and microbial colonization induce T reg cell expansion to protect against severe bronchiolitis and subsequent asthma.

Published
2018
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39. Coinfection with Blood-Stage PlasmodiumPromotes Systemic Type I Interferon Production during Pneumovirus Infection but Impairs Inflammation and Viral Control in the Lung

Author

Edwards, Chelsea L., Zhang, Vivian, Werder, Rhiannon B., Best, Shannon E., Sebina, Ismail, James, Kylie R., Faleiro, Rebecca J., de Labastida Rivera, Fabian, Amante, Fiona H., Engwerda, Christian R., Phipps, Simon, and Haque, Ashraful

Abstract

ABSTRACTAcute lower respiratory tract infections (ALRTI) are the leading cause of global childhood mortality, with human respiratory syncytial virus (hRSV) being a major cause of viral ALRTI in young children worldwide. In sub-Saharan Africa, many young children experience severe illnesses due to hRSV or Plasmodiuminfection. Although the incidence of malaria in this region has decreased in recent years, there remains a significant opportunity for coinfection. Recent data show that febrile young children infected with Plasmodiumare often concurrently infected with respiratory viral pathogens but are less likely to suffer from pneumonia than are non-Plasmodium-infected children. Here, we hypothesized that blood-stage Plasmodiuminfection modulates pulmonary inflammatory responses to a viral pathogen but does not aid its control in the lung. To test this, we established a novel coinfection model in which mice were simultaneously infected with pneumovirus of mice (PVM) (to model hRSV) and blood-stage Plasmodium chabaudi chabaudiAS (PcAS) parasites. We found that PcAS infection was unaffected by coinfection with PVM. In contrast, PVM-associated weight loss, pulmonary cytokine responses, and immune cell recruitment to the airways were substantially reduced by coinfection with PcAS. Importantly, PcAS coinfection facilitated greater viral dissemination throughout the lung. Although Plasmodiumcoinfection induced low levels of systemic interleukin-10 (IL-10), this regulatory cytokine played no role in the modulation of lung inflammation or viral dissemination. Instead, we found that Plasmodiumcoinfection drove an early systemic beta interferon (IFN-ß) response. Therefore, we propose that blood-stage Plasmodiumcoinfection may exacerbate viral dissemination and impair inflammation in the lung by dysregulating type I IFN-dependent responses to respiratory viruses.

Published
2015
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40. Human iPSC-hepatocyte modeling of alpha-1 antitrypsin heterozygosity reveals metabolic dysregulation and cellular heterogeneity

Author

Joseph E. Kaserman, Rhiannon B. Werder, Feiya Wang, Taylor Matte, Michelle I. Higgins, Mark Dodge, Jonathan Lindstrom-Vautrin, Pushpinder Bawa, Anne Hinds, Esther Bullitt, Ignacio S. Caballero, Xu Shi, Robert E. Gerszten, Nicola Brunetti-Pierri, Marc Liesa, Carlos Villacorta-Martin, Anthony N. Hollenberg, Darrell N. Kotton, Andrew A. Wilson, Kaserman, Joseph E, Werder, Rhiannon B, Wang, Feiya, Matte, Taylor, Higgins, Michelle I, Dodge, Mark, Lindstrom-Vautrin, Jonathan, Bawa, Pushpinder, Hinds, Anne, Bullitt, Esther, Caballero, Ignacio S, Shi, Xu, Gerszten, Robert E, Brunetti-Pierri, Nicola, Liesa, Marc, Villacorta-Martin, Carlo, Hollenberg, Anthony N, Kotton, Darrell N, Wilson, Andrew A, National Health and Medical Research Council (Australia), National Institutes of Health (US), and Alpha- Foundation

Subjects
alpha-1 antitrypsin deficiency, metabolic dysregulation, induced pluripotent stem cell, Liver fibrosis, Induced Pluripotent Stem Cells, liver fibrosi, unfolded protein response, proteostasi, General Biochemistry, Genetics and Molecular Biology, CP: Metabolism, CP: Stem cell research, iPSC-derived hepatocytes, cellular heterogeneity, mitochondrial dysfunction, Proteostasis, Hepatocytes, Humans, ER stre, ER stress, iPSC-derived hepatocyte
Abstract

Individuals homozygous for the “Z” mutation in alpha-1 antitrypsin deficiency are known to be at increased risk for liver disease. It has also become clear that some degree of risk is similarly conferred by the heterozygous state. A lack of model systems that recapitulate heterozygosity in human hepatocytes has limited the ability to study the impact of a single Z alpha-1 antitrypsin (ZAAT) allele on hepatocyte biology. Here, we describe the derivation of syngeneic induced pluripotent stem cells (iPSCs) engineered to determine the effects of ZAAT heterozygosity in iPSC-hepatocytes (iHeps). We find that heterozygous MZ iHeps exhibit an intermediate disease phenotype and share with ZZ iHeps alterations in AAT protein processing and downstream perturbations including altered endoplasmic reticulum (ER) and mitochondrial morphology, reduced mitochondrial respiration, and branch-specific activation of the unfolded protein response in cell subpopulations. Our model of MZ heterozygosity thus provides evidence that a single Z allele is sufficient to disrupt hepatocyte homeostatic function., This work was supported by an Alpha-1 Foundation John W. Walsh Translational Research Award (to J.E.K.); a CJ Martin Early Career Fellowship from the Australian National Health and Medical Research Council (to R.B.W.); NIH grant R01HL095993 (to D.N.K.); and NIH grants R01DK101501 (to A.A.W.) and R01DK117940 (to A.N.H. and A.A.W.). iPSC distribution and disease modeling is supported by NIH grants U01TR001810 (to D.N.K. and A.A.W.) and N0175N92020C00005 (to D.N.K.); and by The Alpha-1 Project (TAP), a wholly owned subsidiary of the Alpha-1 Foundation (to D.N.K. and A.A.W.).

Published
2022

41. Plasmacytoid dendritic cells protect from viral bronchiolitis and asthma through semaphorin 4a–mediated T reg expansion

Author

Peter D. Sly, Nida Murtaza, John D. Hayball, Al Amin Sikder, K. Lane, Paul G. Dennis, Christian Forstner, Matthew J. Rogers, Ashraful Haque, Christopher C Blyth, Vivian Zhang, Stuart B. Mazzone, Kerrilyn R. Diener, Rhiannon B. Werder, Mark L. Everard, Páraic Ó Cuív, Mark Morrison, Simon Phipps, Zhixuan Loh, Jennifer Simpson, Kirsten Spann, Geoffrey R. Hill, John W. Upham, Bodie F. Curren, Jason P. Lynch, Ping Zhang, Lynch, Jason P, Werder, Rhiannon B, Loh, Zhixuan, Sikder, Md Al Amin, Hayball, John, Diener, Kerrilyn, and Phipps, Simon

Subjects
Male, 0301 basic medicine, Receptor, Interferon alpha-beta, Semaphorins, Plasmacytoid dendritic cell, T-Lymphocytes, Regulatory, Mice, 0302 clinical medicine, immune system diseases, Immunopathology, Immunology and Allergy, Child, Research Articles, Microbiota, hemic and immune systems, Pneumovirus, Interleukin-10, 3. Good health, Interleukin 10, Child, Preschool, 030220 oncology & carcinogenesis, Female, medicine.symptom, Viral load, Immunology, Mice, Transgenic, Inflammation, Respiratory Syncytial Virus Infections, macromolecular substances, Article, 03 medical and health sciences, viral bronchiolitis, medicine, Animals, Bronchiolitis, Viral, Humans, Asthma, business.industry, Dendritic Cells, asthma, Fatty Acids, Volatile, medicine.disease, digestive system diseases, respiratory tract diseases, Mice, Inbred C57BL, T reg cell, Disease Models, Animal, 030104 developmental biology, Animals, Newborn, Bronchiolitis, business
Abstract

Lynch et al. provide evidence of a causal relationship between RSV-bronchiolitis and asthma development and highlight a common but age-related Sema4a-mediated pathway by which pDCs and microbial colonization induce T reg cell expansion to confer protection against severe bronchiolitis and asthma., Respiratory syncytial virus–bronchiolitis is a major independent risk factor for subsequent asthma, but the causal mechanisms remain obscure. We identified that transient plasmacytoid dendritic cell (pDC) depletion during primary Pneumovirus infection alone predisposed to severe bronchiolitis in early life and subsequent asthma in later life after reinfection. pDC depletion ablated interferon production and increased viral load; however, the heightened immunopathology and susceptibility to subsequent asthma stemmed from a failure to expand functional neuropilin-1+ regulatory T (T reg) cells in the absence of pDC-derived semaphorin 4a (Sema4a). In adult mice, pDC depletion predisposed to severe bronchiolitis only after antibiotic treatment. Consistent with a protective role for the microbiome, treatment of pDC-depleted neonates with the microbial-derived metabolite propionate promoted Sema4a-dependent T reg cell expansion, ameliorating both diseases. In children with viral bronchiolitis, nasal propionate levels were decreased and correlated with an IL-6high/IL-10low microenvironment. We highlight a common but age-related Sema4a-mediated pathway by which pDCs and microbial colonization induce T reg cell expansion to protect against severe bronchiolitis and subsequent asthma.

Published
2017

42. Human airway lineages derived from pluripotent stem cells reveal the epithelial responses to SARS-CoV-2 infection.

Author

Wang R, Hume AJ, Beermann ML, Simone-Roach C, Lindstrom-Vautrin J, Le Suer J, Huang J, Olejnik J, Villacorta-Martin C, Bullitt E, Hinds A, Ghaedi M, Rollins S, Werder RB, Abo KM, Wilson AA, Mühlberger E, Kotton DN, and Hawkins FJ

Subjects
Epithelial Cells, Humans, SARS-CoV-2, COVID-19, Induced Pluripotent Stem Cells, Pluripotent Stem Cells
Abstract

There is an urgent need to understand how SARS-CoV-2 infects the airway epithelium and in a subset of individuals leads to severe illness or death. Induced pluripotent stem cells (iPSCs) provide a near limitless supply of human cells that can be differentiated into cell types of interest, including airway epithelium, for disease modeling. We present a human iPSC-derived airway epithelial platform, composed of the major airway epithelial cell types, that is permissive to SARS-CoV-2 infection. Subsets of iPSC-airway cells express the SARS-CoV-2 entry factors angiotensin-converting enzyme 2 ( ACE2 ), and transmembrane protease serine 2 ( TMPRSS2 ). Multiciliated cells are the primary initial target of SARS-CoV-2 infection. On infection with SARS-CoV-2, iPSC-airway cells generate robust interferon and inflammatory responses, and treatment with remdesivir or camostat mesylate causes a decrease in viral propagation and entry, respectively. In conclusion, iPSC-derived airway cells provide a physiologically relevant in vitro model system to interrogate the pathogenesis of, and develop treatment strategies for, COVID-19 pneumonia.

Published
2022
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