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1. Early human lung immune cell development and its role in epithelial cell fate.

Author

Barnes, Josephine, Yoshida, Masahiro, He, Peng, Worlock, Kaylee, Lindeboom, Rik, Suo, Chenqu, Pett, J, Wilbrey-Clark, Anna, Dann, Emma, Mamanova, Lira, Richardson, Laura, Polanski, Krzysztof, Pennycuick, Adam, Allen-Hyttinen, Jessica, Herczeg, Iván, Arzili, Romina, Hynds, Robert, Teixeira, Vitor, Haniffa, Muzlifah, Lim, Kyungtae, Sun, Dawei, Rawlins, Emma, Oliver, Amanda, Lyons, Paul, Marioni, John, Ruhrberg, Christiana, Tuong, Zewen, Clatworthy, Menna, Reading, James, Janes, Sam, Teichmann, Sarah, Meyer, Kerstin, and Nikolić, Marko

Subjects
Humans, Immunity, Innate, Cell Differentiation, Lung, Killer Cells, Natural, Epithelial Cells
Abstract

Studies of human lung development have focused on epithelial and mesenchymal cell types and function, but much less is known about the developing lung immune cells, even though the airways are a major site of mucosal immunity after birth. An unanswered question is whether tissue-resident immune cells play a role in shaping the tissue as it develops in utero. Here, we profiled human embryonic and fetal lung immune cells using scRNA-seq, smFISH, and immunohistochemistry. At the embryonic stage, we observed an early wave of innate immune cells, including innate lymphoid cells, natural killer cells, myeloid cells, and lineage progenitors. By the canalicular stage, we detected naive T lymphocytes expressing high levels of cytotoxicity genes and the presence of mature B lymphocytes, including B-1 cells. Our analysis suggests that fetal lungs provide a niche for full B cell maturation. Given the presence and diversity of immune cells during development, we also investigated their possible effect on epithelial maturation. We found that IL-1β drives epithelial progenitor exit from self-renewal and differentiation to basal cells in vitro. In vivo, IL-1β-producing myeloid cells were found throughout the lung and adjacent to epithelial tips, suggesting that immune cells may direct human lung epithelial development.

Published
2023

3. SOX9 maintains human foetal lung tip progenitor state by enhancing WNT and RTK signalling.

Author

Sun, Dawei, Llora Batlle, Oriol, van den Ameele, Jelle, Thomas, John, He, Peng, Lim, Kyungtae, Tang, Walfred, Xu, Chufan, Meyer, Kerstin, Teichmann, Sarah, Marioni, John, Jackson, Stephen, Brand, Andrea, and Rawlins, Emma

Subjects
CRISPRi screen, ETVs, Lung organoids, SOX9, Targeted DamID, Humans, Cell Differentiation, Lung, Signal Transduction, SOX9 Transcription Factor, Stem Cells
Abstract

The balance between self-renewal and differentiation in human foetal lung epithelial progenitors controls the size and function of the adult organ. Moreover, progenitor cell gene regulation networks are employed by both regenerating and malignant lung cells, where modulators of their effects could potentially be of therapeutic value. Details of the molecular networks controlling human lung progenitor self-renewal remain unknown. We performed the first CRISPRi screen in primary human lung organoids to identify transcription factors controlling progenitor self-renewal. We show that SOX9 promotes proliferation of lung progenitors and inhibits precocious airway differentiation. Moreover, by identifying direct transcriptional targets using Targeted DamID, we place SOX9 at the centre of a transcriptional network, which amplifies WNT and RTK signalling to stabilise the progenitor cell state. In addition, the proof-of-principle CRISPRi screen and Targeted DamID tools establish a new workflow for using primary human organoids to elucidate detailed functional mechanisms underlying normal development and disease.

Published
2022

4. Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk

Author

Shrine, Nick, Izquierdo, Abril G., Chen, Jing, Packer, Richard, Hall, Robert J., Guyatt, Anna L., Batini, Chiara, Thompson, Rebecca J., Pavuluri, Chandan, Malik, Vidhi, Hobbs, Brian D., Moll, Matthew, Kim, Wonji, Tal-Singer, Ruth, Bakke, Per, Fawcett, Katherine A., John, Catherine, Coley, Kayesha, Piga, Noemi Nicole, Pozarickij, Alfred, Lin, Kuang, Millwood, Iona Y., Chen, Zhengming, Li, Liming, Wijnant, Sara R. A., Lahousse, Lies, Brusselle, Guy, Uitterlinden, Andre G., Manichaikul, Ani, Oelsner, Elizabeth C., Rich, Stephen S., Barr, R. Graham, Kerr, Shona M., Vitart, Veronique, Brown, Michael R., Wielscher, Matthias, Imboden, Medea, Jeong, Ayoung, Bartz, Traci M., Gharib, Sina A., Flexeder, Claudia, Karrasch, Stefan, Gieger, Christian, Peters, Annette, Stubbe, Beate, Hu, Xiaowei, Ortega, Victor E., Meyers, Deborah A., Bleecker, Eugene R., Gabriel, Stacey B., Gupta, Namrata, Smith, Albert Vernon, Luan, Jian’an, Zhao, Jing-Hua, Hansen, Ailin F., Langhammer, Arnulf, Willer, Cristen, Bhatta, Laxmi, Porteous, David, Smith, Blair H., Campbell, Archie, Sofer, Tamar, Lee, Jiwon, Daviglus, Martha L., Yu, Bing, Lim, Elise, Xu, Hanfei, O’Connor, George T., Thareja, Gaurav, Albagha, Omar M. E., Suhre, Karsten, Granell, Raquel, Faquih, Tariq O., Hiemstra, Pieter S., Slats, Annelies M., Mullin, Benjamin H., Hui, Jennie, James, Alan, Beilby, John, Patasova, Karina, Hysi, Pirro, Koskela, Jukka T., Wyss, Annah B., Jin, Jianping, Sikdar, Sinjini, Lee, Mikyeong, May-Wilson, Sebastian, Pirastu, Nicola, Kentistou, Katherine A., Joshi, Peter K., Timmers, Paul R. H. J., Williams, Alexander T., Free, Robert C., Wang, Xueyang, Morrison, John L., Gilliland, Frank D., Chen, Zhanghua, Wang, Carol A., Foong, Rachel E., Harris, Sarah E., Taylor, Adele, Redmond, Paul, Cook, James P., Mahajan, Anubha, Lind, Lars, Palviainen, Teemu, Lehtimäki, Terho, Raitakari, Olli T., Kaprio, Jaakko, Rantanen, Taina, Pietiläinen, Kirsi H., Cox, Simon R., Pennell, Craig E., Hall, Graham L., Gauderman, W. James, Brightling, Chris, Wilson, James F., Vasankari, Tuula, Laitinen, Tarja, Salomaa, Veikko, Mook-Kanamori, Dennis O., Timpson, Nicholas J., Zeggini, Eleftheria, Dupuis, Josée, Hayward, Caroline, Brumpton, Ben, Langenberg, Claudia, Weiss, Stefan, Homuth, Georg, Schmidt, Carsten Oliver, Probst-Hensch, Nicole, Jarvelin, Marjo-Riitta, Morrison, Alanna C., Polasek, Ozren, Rudan, Igor, Lee, Joo-Hyeon, Sayers, Ian, Rawlins, Emma L., Dudbridge, Frank, Silverman, Edwin K., Strachan, David P., Walters, Robin G., Morris, Andrew P., London, Stephanie J., Cho, Michael H., Wain, Louise V., Hall, Ian P., and Tobin, Martin D.

Published
2023
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5. Author Correction: Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk

Author

Shrine, Nick, Izquierdo, Abril G., Chen, Jing, Packer, Richard, Hall, Robert J., Guyatt, Anna L., Batini, Chiara, Thompson, Rebecca J., Pavuluri, Chandan, Malik, Vidhi, Hobbs, Brian D., Moll, Matthew, Kim, Wonji, Tal-Singer, Ruth, Bakke, Per, Fawcett, Katherine A., John, Catherine, Coley, Kayesha, Piga, Noemi Nicole, Pozarickij, Alfred, Lin, Kuang, Millwood, Iona Y., Chen, Zhengming, Li, Liming, Wijnant, Sara R. A., Lahousse, Lies, Brusselle, Guy, Uitterlinden, Andre G., Manichaikul, Ani, Oelsner, Elizabeth C., Rich, Stephen S., Barr, R. Graham, Kerr, Shona M., Vitart, Veronique, Brown, Michael R., Wielscher, Matthias, Imboden, Medea, Jeong, Ayoung, Bartz, Traci M., Gharib, Sina A., Flexeder, Claudia, Karrasch, Stefan, Gieger, Christian, Peters, Annette, Stubbe, Beate, Hu, Xiaowei, Ortega, Victor E., Meyers, Deborah A., Bleecker, Eugene R., Gabriel, Stacey B., Gupta, Namrata, Smith, Albert Vernon, Luan, Jian’an, Zhao, Jing-Hua, Hansen, Ailin F., Langhammer, Arnulf, Willer, Cristen, Bhatta, Laxmi, Porteous, David, Smith, Blair H., Campbell, Archie, Sofer, Tamar, Lee, Jiwon, Daviglus, Martha L., Yu, Bing, Lim, Elise, Xu, Hanfei, O’Connor, George T., Thareja, Gaurav, Albagha, Omar M. E., Suhre, Karsten, Granell, Raquel, Faquih, Tariq O., Hiemstra, Pieter S., Slats, Annelies M., Mullin, Benjamin H., Hui, Jennie, James, Alan, Beilby, John, Patasova, Karina, Hysi, Pirro, Koskela, Jukka T., Wyss, Annah B., Jin, Jianping, Sikdar, Sinjini, Lee, Mikyeong, May-Wilson, Sebastian, Pirastu, Nicola, Kentistou, Katherine A., Joshi, Peter K., Timmers, Paul R. H. J., Williams, Alexander T., Free, Robert C., Wang, Xueyang, Morrison, John L., Gilliland, Frank D., Chen, Zhanghua, Wang, Carol A., Foong, Rachel E., Harris, Sarah E., Taylor, Adele, Redmond, Paul, Cook, James P., Mahajan, Anubha, Lind, Lars, Palviainen, Teemu, Lehtimäki, Terho, Raitakari, Olli T., Kaprio, Jaakko, Rantanen, Taina, Pietiläinen, Kirsi H., Cox, Simon R., Pennell, Craig E., Hall, Graham L., Gauderman, W. James, Brightling, Chris, Wilson, James F., Vasankari, Tuula, Laitinen, Tarja, Salomaa, Veikko, Mook-Kanamori, Dennis O., Timpson, Nicholas J., Zeggini, Eleftheria, Dupuis, Josée, Hayward, Caroline, Brumpton, Ben, Langenberg, Claudia, Weiss, Stefan, Homuth, Georg, Schmidt, Carsten Oliver, Probst-Hensch, Nicole, Jarvelin, Marjo-Riitta, Morrison, Alanna C., Polasek, Ozren, Rudan, Igor, Lee, Joo-Hyeon, Sayers, Ian, Rawlins, Emma L., Dudbridge, Frank, Silverman, Edwin K., Strachan, David P., Walters, Robin G., Morris, Andrew P., London, Stephanie J., Cho, Michael H., Wain, Louise V., Hall, Ian P., and Tobin, Martin D.

Published
2023
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6. Deterministic nuclear reprogramming of mammalian nuclei to a totipotency-like state by Amphibian meiotic oocytes for stem cell therapy in humans

Author

Wen, Ming-Hsuan, primary, Barbosa Triana, Hector, additional, Butler, Richard, additional, Hu, Hsiang-Wei, additional, Dai, Yang-Hong, additional, Lawrence, Nicola, additional, Hong, Jun-Jie, additional, Garrett, Nigel, additional, Jones-Green, Rue, additional, Rawlins, Emma L., additional, Dong, Ziqi, additional, Koziol, Magdalena J., additional, and Gurdon, J. B., additional

Published
2024
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7. A novel human fetal lung-derived alveolar organoid model reveals mechanisms of surfactant protein C maturation relevant to interstitial lung disease

Author

Lim, Kyungtae, primary, Rutherford, Eimear N, additional, Sun, Dawei, additional, Van den Boomen, Dick JH, additional, Edgar, James R, additional, Bang, JaeHak, additional, Matesic, Lydia E, additional, Lee, Joo-Hyeon, additional, Lehner, Paul J, additional, Marciniak, Stefan J, additional, Rawlins, Emma L, additional, and Dickens, Jennifer A, additional

Published
2023
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10. The characterization of dominant second site modifiers of an activated atonal phenotype in Drosophila melanogaster

Author

Rawlins, Emma

Subjects
591.35
Abstract

Sensory neuron fate specification in Drosophila requires the expression of one of the proneural genes (achaete-scute, atonal, or amos) in small groups of ectodermal cells, the proneural clusters. Subsequent resolution of proneural gene expression to a single neural precursor cell is essential for correct fate specification. The proneural gene atonal also has other later roles in the neural precursors. These have been well studied in the chordotonal organ precursors where Atonal activities the Egfr signalling pathway to recruit additional cells to the chordotonal precursor fate. Experimental misexpression of atonal in the developing R8 photoreceptor results in phenotypes that reflect its roles both in terms of R8 fate specification and R8 function. In order to determine more specifically the roles of Atonal in the R8 photoreceptor a number of modifiers of the atonal misexpression phenotype have been characterised. One of these was found to correspond to a mutation in the gene echinoid which encodes a neural cell adhesion molecule. Subsequent analysis has revealed that Echinoid functions specifically in the restriction of neural fate in both atonal and achaete/scute-dependent proneural clusters. Analysis of Echinoid function has revealed a hitherto unsuspected complexity in the process of R8 photoreceptor fate determination. Surprisingly, its mutant phenotype is caused by inappropriate EGF receptor signalling suggesting that its wildtype function is to suppress such activity. The close relationship between this finding and Atonal function is explored.

Published
2001

12. Organoid modeling of human fetal lung alveolar development reveals mechanisms of cell fate patterning and neonatal respiratory disease

Author

Lim, Kyungtae, primary, Donovan, Alex P.A., additional, Tang, Walfred, additional, Sun, Dawei, additional, He, Peng, additional, Pett, J. Patrick, additional, Teichmann, Sarah A., additional, Marioni, John C., additional, Meyer, Kerstin B., additional, Brand, Andrea H., additional, and Rawlins, Emma L., additional

Published
2023
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13. Early human lung immune cell development and its role in epithelial cell fate

Author

Barnes, Josephine L., primary, He, Peng, additional, Yoshida, Masahiro, additional, Worlock, Kaylee B., additional, Lindeboom, Rik G.H., additional, Suo, Chenqu, additional, Pett, J. Patrick, additional, Wilbrey-Clark, Anna, additional, Dann, Emma, additional, Mamanova, Lira, additional, Richardson, Laura, additional, Oliver, Amanda J., additional, Pennycuick, Adam, additional, Allen-Hyttinen, Jessica, additional, Herczeg, Iván T., additional, Hynds, Robert E., additional, Teixeira, Vitor H., additional, Haniffa, Muzlifah, additional, Lim, Kyungtae, additional, Sun, Dawei, additional, Rawlins, Emma L., additional, Polanski, Krzysztof, additional, Lyons, Paul A., additional, Marioni, John C., additional, Tuong, Zewen Kelvin, additional, Clatworthy, Menna R., additional, Reading, James L., additional, Janes, Sam M., additional, Teichmann, Sarah A., additional, Meyer, Kerstin B., additional, and Nikolić, Marko Z., additional

Published
2022
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14. A human fetal lung cell atlas uncovers proximal-distal gradients of differentiation and key regulators of epithelial fates

Author

He, Peng, primary, Lim, Kyungtae, additional, Sun, Dawei, additional, Pett, Jan Patrick, additional, Jeng, Quitz, additional, Polanski, Krzysztof, additional, Dong, Ziqi, additional, Bolt, Liam, additional, Richardson, Laura, additional, Mamanova, Lira, additional, Dabrowska, Monika, additional, Wilbrey-Clark, Anna, additional, Madissoon, Elo, additional, Tuong, Zewen Kelvin, additional, Dann, Emma, additional, Suo, Chenqu, additional, Goh, Isaac, additional, Yoshida, Masahiro, additional, Nikolić, Marko Z., additional, Janes, Sam M., additional, He, Xiaoling, additional, Barker, Roger A., additional, Teichmann, Sarah A., additional, Marioni, John C., additional, Meyer, Kerstin B., additional, and Rawlins, Emma L., additional

Published
2022
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15. Open questions in human lung organoid research

Author

Hughes, Tessa, Dijkstra, Krijn K, Rawlins, Emma L, Hynds, Robert E, Apollo - University of Cambridge Repository, and Hynds, Robert E [0000-0002-2170-8791]

Subjects
Chemical Biology & High Throughput, Pharmacology, 3D cell culture, Human Biology & Physiology, Genome Integrity & Repair, Tumour Biology, epithelial cells, respiratory biology, Signalling & Oncogenes, Ecology,Evolution & Ethology, Pharmacology (medical), lung stem cells, Genetics & Genomics, Computational & Systems Biology, in vitro models
Abstract

Peer reviewed: True, Organoids have become a prominent model system in pulmonary research. The ability to establish organoid cultures directly from patient tissue has expanded the repertoire of physiologically relevant preclinical model systems. In addition to their derivation from adult lung stem/progenitor cells, lung organoids can be derived from fetal tissue or induced pluripotent stem cells to fill a critical gap in modelling pulmonary development in vitro. Recent years have seen important progress in the characterisation and refinement of organoid culture systems. Here, we address several open questions in the field, including how closely organoids recapitulate the tissue of origin, how well organoids recapitulate patient cohorts, and how well organoids capture diversity within a patient. We advocate deeper characterisation of models using single cell technologies, generation of more diverse organoid biobanks and further standardisation of culture media.

Published
2023
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20. RTK signalling promotes epithelial columnar cell shape and apical junction maintenance in human lung progenitor cells.

Author

Shuyu Liu, Dawei Sun, Butler, Richard, and Rawlins, Emma L.

Subjects
CELL morphology, PROGENITOR cells, EPITHELIAL cells, PI3K/AKT pathway, CELLULAR signal transduction, TIGHT junctions, CELL adhesion
Abstract

Multipotent epithelial progenitor cells can be expanded from human embryonic lungs as organoids and maintained in a self-renewing state using a defined medium. The organoid cells are columnar, resembling the cell morphology of the developing lung tip epithelium in vivo. Cell shape dynamics and fate are tightly coordinated during development. We therefore used the organoid system to identify signalling pathways that maintain the columnar shape of human lung tip progenitors. We found that EGF, FGF7 and FGF10 have distinct functions in lung tip progenitors. FGF7 activates MAPK/ERK and PI3K/AKT signalling, and is sufficient to promote columnar cell shape in primary tip progenitors. Inhibitor experiments show that MAPK/ERK and PI3K/AKT signalling are key downstream pathways, regulating cell proliferation, columnar cell shape and cell junctions. We identified integrin signalling as a key pathway downstream of MAPK/ERK in the tip progenitors; disrupting integrin alters polarity, cell adhesion and tight junction assembly. By contrast, stimulation with FGF10 or EGF alone is not sufficient to maintain organoid columnar cell shape. This study employs organoids to provide insight into the cellular mechanisms regulating human lung development. [ABSTRACT FROM AUTHOR]

Published
2023
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21. A functional genetic toolbox for human tissue-derived organoids

Author

Rawlins, Emma, Rawlins, Emma [0000-0001-7426-3792], and Apollo - University of Cambridge Repository

Subjects
Organoids, CRISPRa, developmental biology, homologous gene targeting, Gene Knockdown Techniques, Gene Targeting, Humans, human, CRISPR-Cas9, CRISPR-Cas Systems, inducible CRISPRi, lung
Abstract

Human organoid systems recapitulate key features of organs offering platforms for modelling developmental biology and disease. Tissue-derived organoids have been widely used to study the impact of extrinsic niche factors on stem cells. However, they are rarely used to study endogenous gene function due to the lack of efficient gene manipulation tools. Previously, we established a human foetal lung organoid system (Nikolić et al., 2017). Here, using this organoid system as an example we have systematically developed and optimised a complete genetic toolbox for use in tissue-derived organoids. This includes “Organoid Easytag”, our efficient workflow for targeting all types of gene loci through CRISPR-mediated homologous recombination followed by flow cytometry for enriching correctly-targeted cells. Our toolbox also incorporates conditional gene knock-down or overexpression using tightly-inducible CRISPR interference and CRISPR activation which is the first efficient application of these techniques to tissue-derived organoids. These tools will facilitate gene perturbation studies in tissue-derived organoids facilitating human disease modelling and providing a functional counterpart to many on-going descriptive studies, such as the Human Cell Atlas Project.

Published
2021

22. Multi-ancestry genome-wide association study improves resolution of genes, pathways and pleiotropy for lung function and chronic obstructive pulmonary disease

Author

Shrine, Nick, primary, Izquierdo, Abril G, additional, Chen, Jing, additional, Packer, Richard, additional, Hall, Robert J, additional, Guyatt, Anna L, additional, Batini, Chiara, additional, Thompson, Rebecca J, additional, Pavuluri, Chandan, additional, Malik, Vidhi, additional, Hobbs, Brian D, additional, Moll, Matthew, additional, Kim, Wonji, additional, Tal-Singer, Ruth, additional, Bakke, Per, additional, Fawcett, Katherine A, additional, John, Catherine, additional, Coley, Kayesha, additional, Piga, Noemi Nicole, additional, Pozarickij, Alfred, additional, Lin, Kuang, additional, Millwood, Iona Y, additional, Chen, Zhengming, additional, Li, Liming, additional, Wielscher, Sara RA, additional, Lahousse, Lies, additional, Brusselle, Guy, additional, Uitterlinden, Andre G, additional, Manichaikul, Ani, additional, Oelsner, Elizabeth C, additional, Rich, Stephen S, additional, Barr, R. Graham, additional, Kerr, Shona M, additional, Vitart, Veronique, additional, Brown, Michael R, additional, Wielscher, Matthias, additional, Imboden, Medea, additional, Jeong, Ayoung, additional, Bartz, Traci M, additional, Gharib, Sina A, additional, Flexeder, Claudia, additional, Karrasch, Stefan, additional, Gieger, Christian, additional, Peters, Annette, additional, Stubbe, Beate, additional, Hu, Xiaowei, additional, Ortega, Victor E, additional, Meyers, Deborah A, additional, Bleecker, Eugene R, additional, Gabriel, Stacey B, additional, Gupta, Namrata, additional, Smith, Albert Vernon, additional, Luan, Jian’an, additional, Zhao, Jing-Hua, additional, Hansen, Ailin F, additional, Langhammer, Arnulf, additional, Willer, Cristen, additional, Bhatta, Laxmi, additional, Porteous, David, additional, Smith, Blair H, additional, Campbell, Archie, additional, Sofer, Tamar, additional, Lee, Jiwon, additional, Daviglus, Martha L, additional, Yu, Bing, additional, Lim, Elise, additional, Xu, Hanfei, additional, O’Connor, George T, additional, Thareja, Gaurav, additional, E., Omar M, additional, Mbarek, Hamdi, additional, Suhre, Karsten, additional, Granell, Raquel, additional, Faquih, Tariq O, additional, Hiemstra, Pieter S, additional, Slats, Annelies M, additional, Mullin, Benjamin H, additional, Hui, Jennie, additional, James, Alan, additional, Beilby, John, additional, Patasova, Karina, additional, Hysi, Pirro, additional, Koskela, Jukka T, additional, Wyss, Annah B, additional, Jin, Jianping, additional, Sikdar, Sinjini, additional, Lee, Mikyeong, additional, May-Wilson, Sebastian, additional, Pirastu, Nicola, additional, Kentistou, Katherine A, additional, Joshi, Peter K, additional, Timmers, Paul RHJ, additional, Williams, Alexander T, additional, Free, Robert C, additional, Wang, Xueyang, additional, Morrison, John L, additional, Gilliland, Frank D, additional, Chen, Zhanghua, additional, Wang, Carol A, additional, Foong, Rachel E, additional, Harris, Sarah E, additional, Taylor, Adele, additional, Redmond, Paul, additional, Cook, James P, additional, Mahajan, Anubha, additional, Lind, Lars, additional, Palviainen, Teemu, additional, Lehtimäki, Terho, additional, Raitakari, Olli T, additional, Kaprio, Jaakko, additional, Rantanen, Taina, additional, Pietiläinen, Kirsi H, additional, Cox, Simon R, additional, Pennell, Craig E, additional, Hall, Graham L, additional, Gauderman, W. James, additional, Brightling, Chris, additional, Wilson, James F, additional, Vasankari, Tuula, additional, Laitinen, Tarja, additional, Salomaa, Veikko, additional, Mook-Kanamori, Dennis O, additional, Timpson, Nicholas J, additional, Zeggini, Eleftheria, additional, Dupuis, Josée, additional, Hayward, Caroline, additional, Brumpton, Ben, additional, Langenberg, Claudia, additional, Weiss, Stefan, additional, Homuth, Georg, additional, Schmidt, Carsten Oliver, additional, Probst-Hensch, Nicole, additional, Jarvelin, Marjo-Riitta, additional, Morrison, Alanna C, additional, Polasek, Ozren, additional, Rudan, Igor, additional, Lee, Joo-Hyeon, additional, Sayers, Ian, additional, Rawlins, Emma L, additional, Dudbridge, Frank, additional, Silverman, Edwin K, additional, Strachan, David P, additional, Walters, Robin G, additional, Morris, Andrew P, additional, London, Stephanie J, additional, Cho, Michael H, additional, Wain, Louise V, additional, Hall, Ian P, additional, and Tobin, Martin D, additional

Published
2022
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23. Chronic lung diseases are associated with gene expression programs favoring SARS-CoV-2 entry and severity

Author

Massachusetts Institute of Technology. Institute for Medical Engineering & Science, Ragon Institute of MGH, MIT and Harvard, Massachusetts Institute of Technology. Department of Biology, Howard Hughes Medical Institute, Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology. Department of Chemistry, Bui, Linh T., Winters, Nichelle I., Chung, Mei-I, Joseph, Chitra, Gutierrez, Austin J., Habermann, Arun C., Adams, Taylor S., Schupp, Jonas C., Poli, Sergio, Peter, Lance M., Taylor, Chase J., Blackburn, Jessica B., Richmond, Bradley W., Nicholson, Andrew G., Rassl, Doris, Wallace, William A., Rosas, Ivan O., Jenkins, R. Gisli, Kaminski, Naftali, Kropski, Jonathan A., Banovich, Nicholas E., Misharin, Alexander V., Tsankov, Alexander M., Spira, Avrum, Barbry, Pascal, Brazma, Alvis, Samakovlis, Christos, Shepherd, Douglas P., Rawlins, Emma L., Theis, Fabian J., Griffonnet, Jennifer, Lee, Haeock, Schiller, Herbert B., Hofman, Paul, Powell, Joseph E., Schultze, Joachim L., Whitsett, Jeffrey, Choi, Jiyeon, Lundeberg, Joakim, Ordovas-Montanes, Jose, Rajagopal, Jayaraj, Meyer, Kerstin B., Krasnow, Mark A., Saeb‐Parsy, Kourosh, Zhang, Kun, Lafyatis, Robert, Leroy, Sylvie, Haniffa, Muzlifah, Nawijn, Martijn C., Nikolić, Marko Z., van den Berge, Maarten, Kuhnemund, Malte, Marquette, Charles-Hugo, Von Papen, Michael, Eickelberg, Oliver, Rosenblatt-Rosen, Orit, Reyfman, Paul A., Pe’er, Dana, Horvath, Peter, Tata, Purushothama Rao, Regev, Aviv, Rojas, Mauricio, Seibold, Max A., Shalek, Alex K., Spence, Jason R., Teichmann, Sarah A., Quake, Stephen, Duong, Thu Elizabeth, Biancalani, Tommaso, Desai, Tushar, Sun, Xin, Zaragosi, Laure Emmanuelle, Massachusetts Institute of Technology. Institute for Medical Engineering & Science, Ragon Institute of MGH, MIT and Harvard, Massachusetts Institute of Technology. Department of Biology, Howard Hughes Medical Institute, Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology. Department of Chemistry, Bui, Linh T., Winters, Nichelle I., Chung, Mei-I, Joseph, Chitra, Gutierrez, Austin J., Habermann, Arun C., Adams, Taylor S., Schupp, Jonas C., Poli, Sergio, Peter, Lance M., Taylor, Chase J., Blackburn, Jessica B., Richmond, Bradley W., Nicholson, Andrew G., Rassl, Doris, Wallace, William A., Rosas, Ivan O., Jenkins, R. Gisli, Kaminski, Naftali, Kropski, Jonathan A., Banovich, Nicholas E., Misharin, Alexander V., Tsankov, Alexander M., Spira, Avrum, Barbry, Pascal, Brazma, Alvis, Samakovlis, Christos, Shepherd, Douglas P., Rawlins, Emma L., Theis, Fabian J., Griffonnet, Jennifer, Lee, Haeock, Schiller, Herbert B., Hofman, Paul, Powell, Joseph E., Schultze, Joachim L., Whitsett, Jeffrey, Choi, Jiyeon, Lundeberg, Joakim, Ordovas-Montanes, Jose, Rajagopal, Jayaraj, Meyer, Kerstin B., Krasnow, Mark A., Saeb‐Parsy, Kourosh, Zhang, Kun, Lafyatis, Robert, Leroy, Sylvie, Haniffa, Muzlifah, Nawijn, Martijn C., Nikolić, Marko Z., van den Berge, Maarten, Kuhnemund, Malte, Marquette, Charles-Hugo, Von Papen, Michael, Eickelberg, Oliver, Rosenblatt-Rosen, Orit, Reyfman, Paul A., Pe’er, Dana, Horvath, Peter, Tata, Purushothama Rao, Regev, Aviv, Rojas, Mauricio, Seibold, Max A., Shalek, Alex K., Spence, Jason R., Teichmann, Sarah A., Quake, Stephen, Duong, Thu Elizabeth, Biancalani, Tommaso, Desai, Tushar, Sun, Xin, and Zaragosi, Laure Emmanuelle

Abstract

AbstractPatients with chronic lung disease (CLD) have an increased risk for severe coronavirus disease-19 (COVID-19) and poor outcomes. Here, we analyze the transcriptomes of 611,398 single cells isolated from healthy and CLD lungs to identify molecular characteristics of lung cells that may account for worse COVID-19 outcomes in patients with chronic lung diseases. We observe a similar cellular distribution and relative expression of SARS-CoV-2 entry factors in control and CLD lungs. CLD AT2 cells express higher levels of genes linked directly to the efficiency of viral replication and the innate immune response. Additionally, we identify basal differences in inflammatory gene expression programs that highlight how CLD alters the inflammatory microenvironment encountered upon viral exposure to the peripheral lung. Our study indicates that CLD is accompanied by changes in cell-type-specific gene expression programs that prime the lung epithelium for and influence the innate and adaptive immune responses to SARS-CoV-2 infection.

Published
2022

27. An organoid CRISPRi screen revealed that SOX9 primes human fetal lung tip progenitors to receive WNT and RTK signals

Author

Sun, Dawei, primary, Batlle, Oriol Llora, additional, van den Ameele, Jelle, additional, Thomas, John C., additional, He, Peng, additional, Lim, Kyungtae, additional, Tang, Walfred, additional, Xu, Chufan, additional, Meyer, Kerstin B., additional, Teichmann, Sarah A., additional, Marioni, John C., additional, Jackson, Stephen P., additional, Brand, Andrea H., additional, and Rawlins, Emma L., additional

Published
2022
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32. Ciliated epithelial cell lifespan in the mouse trachea and lung

Author

Rawlins, Emma L. and Hogan, Brigid L.M.

Subjects
Epithelial cells -- Physiological aspects, Epithelial cells -- Genetic aspects, Lungs -- Physiological aspects, Trachea -- Physiological aspects, Biological sciences
Abstract

The steady-state turnover of epithelial cells in the lung and trachea is highly relevant to investigators who are studying endogenous stem cells, manipulating gene expression in vivo, or using viral vectors for gene therapy. However, the average lifetime of different airway epithelial cell types has not previously been assessed using currently available genetic techniques. Here, we use Cre/loxP genetic technology to indelibly label a random fraction of ciliated cells throughout the airways of a cohort of mice and follow them in vivo for up to 18 mo. We demonstrate that ciliated airway epithelial cells are a terminally differentiated population. Moreover, their average half-life of 6 mo in the trachea and 17 mo in the lung is much longer than previously available estimates, with significant numbers of labeled cells still present after 18 mo. Cre recombinase; Rosa26R-eYFP; stem cell

Published
2008

33. Organoid Easytag: an efficient workflow for gene targeting in human organoids

Author

Sun, Dawei, Evans, Lewis D., and Rawlins, Emma L.

Abstract

Human organoid systems recapitulate key features of organs offering platforms for modelling human developmental biology and disease. However, tissue-derived organoids suffer from low efficiency of genetic manipulations, especially CRISPR/Cas9-mediated knock-ins. We have systematically optimised and developed an “Organoid Easytag” pipeline for efficient (40-65%) and accurate gene targeting to facilitate generation of reporter lines and gene knock-outs in organoid based research.

Published
2020
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34. Distinct populations of crypt-associated fibroblasts act as signaling hubs to control colon homeostasis

Author

Rawlins, Emma, Rawlins, E ( Emma ), Brügger, Michael David; https://orcid.org/0000-0001-8792-2187, Valenta, Tomas; https://orcid.org/0000-0002-3043-1835, Fazilaty, Hassan; https://orcid.org/0000-0002-9387-0413, Hausmann, George; https://orcid.org/0000-0002-2146-6665, Basler, Konrad; https://orcid.org/0000-0003-3534-1529, Rawlins, Emma, Rawlins, E ( Emma ), Brügger, Michael David; https://orcid.org/0000-0001-8792-2187, Valenta, Tomas; https://orcid.org/0000-0002-3043-1835, Fazilaty, Hassan; https://orcid.org/0000-0002-9387-0413, Hausmann, George; https://orcid.org/0000-0002-2146-6665, and Basler, Konrad; https://orcid.org/0000-0003-3534-1529

Abstract

Despite recent progress in recognizing the importance of mesenchymal cells for the homeostasis of the intestinal system, the current picture of how these cells communicate with the associated epithelial layer remains unclear. To describe the relevant cell populations in an unbiased manner, we carried out a single-cell transcriptome analysis of the adult murine colon, producing a high-quality atlas of matched colonic epithelium and mesenchyme. We identify two crypt-associated colonic fibroblast populations that are demarcated by different strengths of platelet-derived growth factor receptor A (Pdgfra) expression. Crypt-bottom fibroblasts (CBFs), close to the intestinal stem cells, express low levels of Pdgfra and secrete canonical Wnt ligands, Wnt potentiators, and bone morphogenetic protein (Bmp) inhibitors. Crypt-top fibroblasts (CTFs) exhibit high Pdgfra levels and secrete noncanonical Wnts and Bmp ligands. While the Pdgfralow cells maintain intestinal stem cell proliferation, the Pdgfrahigh cells induce differentiation of the epithelial cells. Our findings enhance our understanding of the crosstalk between various colonic epithelial cells and their associated mesenchymal signaling hubs along the crypt axis—placing differential Pdgfra expression levels in the spotlight of intestinal fibroblast identity.

Published
2020

35. Longitudinal Multi-omics Analyses Identify Responses of Megakaryocytes, Erythroid Cells, and Plasmablasts as Hallmarks of Severe COVID-19

Author

Bernardes, Joana P., primary, Mishra, Neha, additional, Tran, Florian, additional, Bahmer, Thomas, additional, Best, Lena, additional, Blase, Johanna I., additional, Bordoni, Dora, additional, Franzenburg, Jeanette, additional, Geisen, Ulf, additional, Josephs-Spaulding, Jonathan, additional, Köhler, Philipp, additional, Künstner, Axel, additional, Rosati, Elisa, additional, Aschenbrenner, Anna C., additional, Bacher, Petra, additional, Baran, Nathan, additional, Boysen, Teide, additional, Brandt, Burkhard, additional, Bruse, Niklas, additional, Dörr, Jonathan, additional, Dräger, Andreas, additional, Elke, Gunnar, additional, Ellinghaus, David, additional, Fischer, Julia, additional, Forster, Michael, additional, Franke, Andre, additional, Franzenburg, Sören, additional, Frey, Norbert, additional, Friedrichs, Anette, additional, Fuß, Janina, additional, Glück, Andreas, additional, Hamm, Jacob, additional, Hinrichsen, Finn, additional, Hoeppner, Marc P., additional, Imm, Simon, additional, Junker, Ralf, additional, Kaiser, Sina, additional, Kan, Ying H., additional, Knoll, Rainer, additional, Lange, Christoph, additional, Laue, Georg, additional, Lier, Clemens, additional, Lindner, Matthias, additional, Marinos, Georgios, additional, Markewitz, Robert, additional, Nattermann, Jacob, additional, Noth, Rainer, additional, Pickkers, Peter, additional, Rabe, Klaus F., additional, Renz, Alina, additional, Röcken, Christoph, additional, Rupp, Jan, additional, Schaffarzyk, Annika, additional, Scheffold, Alexander, additional, Schulte-Schrepping, Jonas, additional, Schunk, Domagoj, additional, Skowasch, Dirk, additional, Ulas, Thomas, additional, Wandinger, Klaus-Peter, additional, Wittig, Michael, additional, Zimmermann, Johannes, additional, Busch, Hauke, additional, Hoyer, Bimba F., additional, Kaleta, Christoph, additional, Heyckendorf, Jan, additional, Kox, Matthijs, additional, Rybniker, Jan, additional, Schreiber, Stefan, additional, Schultze, Joachim L., additional, Rosenstiel, Philip, additional, Banovich, Nicholas E., additional, Desai, Tushar, additional, Eickelberg, Oliver, additional, Haniffa, Muzlifa, additional, Horvath, Peter, additional, Kropski, Jonathan A., additional, Lafyatis, Robert, additional, Lundeberg, Joakim, additional, Meyer, Kerstin, additional, Nawijn, Martijn C., additional, Nikolic, Marko, additional, Ordovas Montanes, Jose, additional, Pe’er, Dana, additional, Tata, Purushothama Rao, additional, Rawlins, Emma, additional, Regev, Aviv, additional, Reyfman, Paul, additional, Samakovlis, Christos, additional, Schultze, Joachim, additional, Shalek, Alex, additional, Shepherd, Douglas, additional, Spence, Jason, additional, Teichmann, Sarah, additional, Theis, Fabian, additional, Tsankov, Alexander, additional, van den Berge, Maarten, additional, von Papen, Michael, additional, Whitsett, Jeffrey, additional, Zaragosi, Laure Emmanuelle, additional, Angelov, Angel, additional, Bals, Robert, additional, Bartholomäus, Alexander, additional, Becker, Anke, additional, Bezdan, Daniela, additional, Bonifacio, Ezio, additional, Bork, Peer, additional, Clavel, Thomas, additional, Colme-Tatche, Maria, additional, Diefenbach, Andreas, additional, Dilthey, Alexander, additional, Fischer, Nicole, additional, Förstner, Konrad, additional, Frick, Julia-Stefanie, additional, Gagneur, Julien, additional, Goesmann, Alexander, additional, Hain, Torsten, additional, Hummel, Michael, additional, Janssen, Stefan, additional, Kalinowski, Jörn, additional, Kallies, René, additional, Kehr, Birte, additional, Keller, Andreas, additional, Kim-Hellmuth, Sarah, additional, Klein, Christoph, additional, Kohlbacher, Oliver, additional, Korbel, Jan O., additional, Kurth, Ingo, additional, Landthaler, Markus, additional, Li, Yang, additional, Ludwig, Kerstin, additional, Makarewicz, Oliwia, additional, Marz, Manja, additional, McHardy, Alice, additional, Mertes, Christian, additional, Nöthen, Markus, additional, Nürnberg, Peter, additional, Ohler, Uwe, additional, Ossowski, Stephan, additional, Overmann, Jörg, additional, Peter, Silke, additional, Pfeffer, Klaus, additional, Poetsch, Anna R., additional, Pühler, Alfred, additional, Rajewsky, Niklaus, additional, Ralser, Markus, additional, Rieß, Olaf, additional, Ripke, Stephan, additional, Nunes da Rocha, Ulisses, additional, Saliba, Antoine-Emmanuel, additional, Sander, Leif Erik, additional, Sawitzki, Birgit, additional, Schiffer, Philipp, additional, Schulte, Eva-Christina, additional, Sczyrba, Alexander, additional, Stegle, Oliver, additional, Stoye, Jens, additional, Vehreschild, Janne, additional, Vogel, Jörg, additional, von Kleist, Max, additional, Walker, Andreas, additional, Walter, Jörn, additional, Wieczorek, Dagmar, additional, and Ziebuhr, John, additional

Published
2020
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39. SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues

Author

Ziegler, Carly G.K., primary, Allon, Samuel J., additional, Nyquist, Sarah K., additional, Mbano, Ian M., additional, Miao, Vincent N., additional, Tzouanas, Constantine N., additional, Cao, Yuming, additional, Yousif, Ashraf S., additional, Bals, Julia, additional, Hauser, Blake M., additional, Feldman, Jared, additional, Muus, Christoph, additional, Wadsworth, Marc H., additional, Kazer, Samuel W., additional, Hughes, Travis K., additional, Doran, Benjamin, additional, Gatter, G. James, additional, Vukovic, Marko, additional, Taliaferro, Faith, additional, Mead, Benjamin E., additional, Guo, Zhiru, additional, Wang, Jennifer P., additional, Gras, Delphine, additional, Plaisant, Magali, additional, Ansari, Meshal, additional, Angelidis, Ilias, additional, Adler, Heiko, additional, Sucre, Jennifer M.S., additional, Taylor, Chase J., additional, Lin, Brian, additional, Waghray, Avinash, additional, Mitsialis, Vanessa, additional, Dwyer, Daniel F., additional, Buchheit, Kathleen M., additional, Boyce, Joshua A., additional, Barrett, Nora A., additional, Laidlaw, Tanya M., additional, Carroll, Shaina L., additional, Colonna, Lucrezia, additional, Tkachev, Victor, additional, Peterson, Christopher W., additional, Yu, Alison, additional, Zheng, Hengqi Betty, additional, Gideon, Hannah P., additional, Winchell, Caylin G., additional, Lin, Philana Ling, additional, Bingle, Colin D., additional, Snapper, Scott B., additional, Kropski, Jonathan A., additional, Theis, Fabian J., additional, Schiller, Herbert B., additional, Zaragosi, Laure-Emmanuelle, additional, Barbry, Pascal, additional, Leslie, Alasdair, additional, Kiem, Hans-Peter, additional, Flynn, JoAnne L., additional, Fortune, Sarah M., additional, Berger, Bonnie, additional, Finberg, Robert W., additional, Kean, Leslie S., additional, Garber, Manuel, additional, Schmidt, Aaron G., additional, Lingwood, Daniel, additional, Shalek, Alex K., additional, Ordovas-Montanes, Jose, additional, Banovich, Nicholas, additional, Brazma, Alvis, additional, Desai, Tushar, additional, Duong, Thu Elizabeth, additional, Eickelberg, Oliver, additional, Falk, Christine, additional, Farzan, Michael, additional, Glass, Ian, additional, Haniffa, Muzlifah, additional, Horvath, Peter, additional, Hung, Deborah, additional, Kaminski, Naftali, additional, Krasnow, Mark, additional, Kuhnemund, Malte, additional, Lafyatis, Robert, additional, Lee, Haeock, additional, Leroy, Sylvie, additional, Linnarson, Sten, additional, Lundeberg, Joakim, additional, Meyer, Kerstin, additional, Misharin, Alexander, additional, Nawijn, Martijn, additional, Nikolic, Marko Z., additional, Pe’er, Dana, additional, Powell, Joseph, additional, Quake, Stephen, additional, Rajagopal, Jay, additional, Tata, Purushothama Rao, additional, Rawlins, Emma L., additional, Regev, Aviv, additional, Reyfman, Paul A., additional, Rojas, Mauricio, additional, Rosen, Orit, additional, Saeb-Parsy, Kourosh, additional, Samakovlis, Christos, additional, Schiller, Herbert, additional, Schultze, Joachim L., additional, Seibold, Max A., additional, Shepherd, Douglas, additional, Spence, Jason, additional, Spira, Avrum, additional, Sun, Xin, additional, Teichmann, Sarah, additional, Theis, Fabian, additional, Tsankov, Alexander, additional, van den Berge, Maarten, additional, von Papen, Michael, additional, Whitsett, Jeffrey, additional, Xavier, Ramnik, additional, Xu, Yan, additional, and Zhang, Kun, additional

Published
2020
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44. Human embryonic lung epithelial tips are multipotent progenitors that can be expanded in vitro as long-term self-renewing organoids

Author

Nikolić, Marko Z, Caritg, Oriol, Jeng, Quitz, Johnson, Jo-Anne, Sun, Dawei, Howell, Kate J, Brady, Jane L, Laresgoiti, Usua, Allen, George, Butler, Richard, Zilbauer, Matthias, Giangreco, Adam, Rawlins, Emma L, Nikolić, Marko Z [0000-0001-6304-6848], Rawlins, Emma L [0000-0001-7426-3792], and Apollo - University of Cambridge Repository

Subjects
medicine, QH301-705.5, Organogenesis, Science, Respiratory Mucosa, developmental biology, Mice, branching, Animals, Humans, human, Biology (General), Child, Human Biology and Medicine, Lung, lung development, Cell Proliferation, Stem Cells, fungi, Organ Development, food and beverages, human biology, alveolar differentiation, tip progenitor, Cell Differentiation, respiratory system, Embryo, Mammalian, respiratory tract diseases, stem cell, Organoids, Developmental Biology and Stem Cells, Insight, Research Article
Abstract

The embryonic mouse lung is a widely used substitute for human lung development. For example, attempts to differentiate human pluripotent stem cells to lung epithelium rely on passing through progenitor states that have only been described in mouse. The tip epithelium of the branching mouse lung is a multipotent progenitor pool that self-renews and produces differentiating descendants. We hypothesized that the human distal tip epithelium is an analogous progenitor population and tested this by examining morphology, gene expression and in vitro self-renewal and differentiation capacity of human tips. These experiments confirm that human and mouse tips are analogous and identify signalling pathways that are sufficient for long-term self-renewal of human tips as differentiation-competent organoids. Moreover, we identify mouse-human differences, including markers that define progenitor states and signalling requirements for long-term self-renewal. Our organoid system provides a genetically-tractable tool that will allow these human-specific features of lung development to be investigated. DOI: http://dx.doi.org/10.7554/eLife.26575.001, eLife digest Degenerative lung disease occurs when the structure of the lungs breaks down, which makes it harder to get enough oxygen into the bloodstream. Most, but not all, cases occur in smokers and ex-smokers or people who have been exposed to a lot of air pollution. Currently, there is no way to reverse the damage, and even slowing the progress of the disease is extremely difficult. Some researchers are looking for ways to treat patients with degenerative lung diseases by regenerating the surface of their lungs. However, it is still not clear what the most effective route towards this long-term goal will be. One approach to lung regeneration is to use findings from developmental biology to understand how embryos normally build the gas exchange surfaces in the lungs. This knowledge may allow scientists to trigger a similar process in an adult lung to renew or replace any diseased tissue. Alternatively, cells could be collected from patients, reprogrammed and then coaxed into becoming a gas exchange surface in the laboratory. Such a “lung-in-a-dish” could be used to understand how degenerative diseases develop, to discover and test new drugs, or even to treat the patient directly via a transplant. To date, the embryonic development of lungs has mostly been studied using mouse lungs as a model system. However, it was not clear if human lungs actually develop in similar ways to mouse lungs, and whether using mice is a valid research strategy. Nikolić et al. compared embryonic lungs from humans and mice and showed that they are indeed very similar in terms of the cell types that they contain and how they mature. However, some key differences were identified that can only be explored in human cells and tissue. Nikolić et al. went on to identify conditions that allowed them to grow cells from human embryonic lungs indefinitely in a dish. These cells can now be used to investigate the aspects of lung development that are specific to humans. Together these findings provide a useful guide to allow scientists to coax human cells growing in a laboratory to become lung cells. Further improvements to this process will make the lungs-in-a-dish more true to the real organs, meaning that they could be used to better understand lung disease and identify new medicines. In the longer term, Nikolić et al. hope to gain enough insight from the human lung-in-a-dish model to eventually be able to regenerate the lungs of patients with degenerative lung disease. However, this possibility is still many years away. DOI: http://dx.doi.org/10.7554/eLife.26575.002

Published
2017
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45. FGFR2 is required for airway basal cell self-renewal and terminal differentiation

Author

Balasooriya, Gayan I., Goschorska, Maja, Piddini, Eugenia, Rawlins, Emma L., Piddini, Eugenia [0000-0003-3901-076X], Rawlins, Emma [0000-0001-7426-3792], and Apollo - University of Cambridge Repository

Subjects
Trachea, Mouse, Cre-Lox, progenitor, trachea, Lung, mouse, Progenitor, lung
Abstract

Airway stem cells slowly self-renew and produce differentiated progeny to maintain homeostasis throughout the lifespan of an individual. Mutations in the molecular regulators of these processes may drive cancer or degenerative disease, but are also potential therapeutic targets. Conditionally deleting one copy of FGF receptor 2 (FGFR2) in adult mouse airway basal cells results in self-renewal and differentiation phenotypes.We show that FGFR2 signalling correlates with maintenance of expression of a key transcription factor for basal cell self-renewal and differentiation: SOX2. This heterozygous phenotype illustrates that subtle changes in receptor tyrosine kinase signalling can have significant effects, perhaps providing an explanation for the numerous changes seen in cancer.

Published
2017

46. Mechanical cell competition kills cells via induction of lethal p53 levels

Author

Wagstaff, Laura, Goschorska, Maja, Kozyrska, Kasia, Duclos, Guillaume, Kucinski, Iwo, Chessel, Anatole, Hampton-O'Neil, Lea, Bradshaw, Charles R, Allen, George E, Rawlins, Emma L, Silberzan, Pascal, Carazo Salas, Rafael E, Piddini, Eugenia, University of Cambridge [UK] (CAM), Physico-Chimie-Curie (PCC), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Chessel, Anatole [0000-0002-1326-6305], Bradshaw, Charles R [0000-0002-3528-458X], Silberzan, Pascal [0000-0002-8554-882X], and Apollo - University of Cambridge Repository

Subjects
rho-Associated Kinases, Science, Membrane Proteins, Apoptosis, Cell Communication, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Article, Biomechanical Phenomena, Madin Darby Canine Kidney Cells, Dogs, Animals, Drosophila Proteins, Drosophila, Tumor Suppressor Protein p53
Abstract

Cell competition is a quality control mechanism that eliminates unfit cells. How cells compete is poorly understood, but it is generally accepted that molecular exchange between cells signals elimination of unfit cells. Here we report an orthogonal mechanism of cell competition, whereby cells compete through mechanical insults. We show that MDCK cells silenced for the polarity gene scribble (scribKD) are hypersensitive to compaction, that interaction with wild-type cells causes their compaction and that crowding is sufficient for scribKD cell elimination. Importantly, we show that elevation of the tumour suppressor p53 is necessary and sufficient for crowding hypersensitivity. Compaction, via activation of Rho-associated kinase (ROCK) and the stress kinase p38, leads to further p53 elevation, causing cell death. Thus, in addition to molecules, cells use mechanical means to compete. Given the involvement of p53, compaction hypersensitivity may be widespread among damaged cells and offers an additional route to eliminate unfit cells., Cell competition is a quality control mechanism to eliminate unfit cells. Here the authors show that physical compaction of less fit cells surrounded by healthy neighbours leads to increased expression of tumour suppressor p53 in the compacted cells, causing cell death.

Published
2016

47. Cancer: Tumours build their niche

Author

Huch, Meritxell and Rawlins, Emma L.

Subjects
Lung cancer -- Research, Adenocarcinoma -- Research, Cancer cells -- Research, Cancer research, Stem cells -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Meritxell Huch (corresponding author) [1]; Emma L. Rawlins (corresponding author) [1] The development of a tumour resembles, in some aspects, the development of a multicellular organism, except that the [...]

Published
2017
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48. A Subpopulation of Foxj1-Expressing, Nonmyelinating Schwann Cells of the Peripheral Nervous System Contribute to Schwann Cell Remyelination in the Central Nervous System

Author

Ma, Dan, Wang, Bowei, Zawadzka, Malgorzata, Gonzalez, Ginez, Wu, Zhaozong, Yu, Bin, Rawlins, Emma L, Franklin, Robin JM, Zhao, Chao, Ma, Dan [0000-0001-8628-8954], Zhao, Chao [0000-0003-1144-1621], and Apollo - University of Cambridge Repository

Subjects
Central Nervous System, Male, integumentary system, Gene Expression, Forkhead Transcription Factors, Mice, Transgenic, Sciatic Nerve, CNS remyelination, Mice, Inbred C57BL, Foxj1, Mice, Remyelination, Spinal Cord, nervous system, peripheral nerve, Peripheral Nervous System, Animals, Schwann cells, Female, Myelin Sheath
Abstract

New myelin sheaths can be restored to demyelinated axons in a spontaneous regenerative process called remyelination. In general, new myelin sheaths are made by oligodendrocytes newly generated from a widespread population of adult CNS progenitors called oligodendrocyte progenitor cells (OPCs). New myelin in CNS remyelination in both experimental models and clinical diseases can also be generated by Schwann cells (SCs), the myelin-forming cells of the PNS. Fate-mapping studies have shown that SCs contributing to remyelination in the CNS are often derived from OPCs and appear not to be derived from myelinating SCs from the PNS. In this study, we address whether CNS remyelinating SCs can also be generated from PNS-derived cells other than myelinating SCs. Using a genetic fate-mapping approach, we have found that a subpopulation of nonmyelinating SCs identified by the expression of the transcription factor Foxj1 also contribute to CNS SC remyelination, as well as to remyelination in the PNS. We also find that the ependymal cells lining the central canal of the spinal cord, which also express Foxj1, do not generate cells that contribute to CNS remyelination. These findings therefore identify a previously unrecognized population of PNS glia that can participate in the regeneration of new myelin sheaths following CNS demyelination.SIGNIFICANCE STATEMENT Remyelination failure in chronic demyelinating diseases such as multiple sclerosis drives the current quest for developing means by which remyelination in CNS can be enhanced therapeutically. Critical to this endeavor is the need to understand the mechanisms of remyelination, including the nature and identity of the cells capable of generating new myelin sheath-forming cells. Here, we report a previously unrecognized subpopulation of nonmyelinating Schwann cells (SCs) in the PNS, identified by the expression of the transcription factor Foxj1, which can give rise to SCs that are capable of remyelinating both PNS and CNS axons. These cells therefore represent a new cellular target for myelin regenerative strategies for the treatment of CNS disorders characterized by persistent demyelination.

Published
2018

49. The Human Lung Cell Atlas: A High-Resolution Reference Map of the Human Lung in Health and Disease

Author

Schiller, Herbert B., primary, Montoro, Daniel T., additional, Simon, Lukas M., additional, Rawlins, Emma L., additional, Meyer, Kerstin B., additional, Strunz, Maximilian, additional, Vieira Braga, Felipe A., additional, Timens, Wim, additional, Koppelman, Gerard H., additional, Budinger, G. R. Scott, additional, Burgess, Janette K., additional, Waghray, Avinash, additional, van den Berge, Maarten, additional, Theis, Fabian J., additional, Regev, Aviv, additional, Kaminski, Naftali, additional, Rajagopal, Jayaraj, additional, Teichmann, Sarah A., additional, Misharin, Alexander V., additional, and Nawijn, Martijn C., additional

Published
2019
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50. Developing obesity prevention interventions among minority ethnic children in schools and places of worship: The DEAL (DiEt and Active Living) study

Author

Anderson Annie, Rawlins Emma, Baker Graham, Maynard Maria J, and Harding Seeromanie

Subjects
Public aspects of medicine, RA1-1270
Abstract

Abstract Background Childhood obesity is a major public health concern with serious implications for the sustainability of healthcare systems. Studies in the US and UK have shown that ethnicity is consistently associated with childhood obesity, with Black African origin girls in particular being more vulnerable to overweight and obesity than their White peers. Little is known, however, about what promotes or hinders engagement with prevention programmes among ethnic minority children. Methods/Design This paper describes the background and design of an exploratory study conducted in London, UK. The aim of the study was to assess the feasibility, efficacy and cultural acceptability of child- and family-based interventions to reduce risk factors for childhood and adolescent obesity among ethnic minorities. It investigated the use of a population approach (in schools) and a targeted approach (in places of worship). We used a mixture of focus group discussions, in-depth interviews and structured questionnaires to explore what children, parents, grandparents, teachers and religious leaders think hinder and promote engagement with healthy eating and active living choices. We assessed the cultural appropriateness of validated measures of physical activity, dietary behaviour and self efficacy, and of potential elements of interventions informed by the data collected. We are also currently assessing the potential for wider community support (local councils, community networks, faith forums etc) of the intervention. Discussion Analysis of the data is ongoing but the emergent findings suggest that while the school setting may be better for the main implementation of healthy lifestyle interventions, places of worship provide valuable opportunities for family and culturally specific support for implementation. Tackling the rise in childhood and adolescent obesity is a policy priority, as reflected in a range of government initiatives. The study will enhance such policy by developing the evidence base about culturally acceptable interventions to reduce the risk of obesity in children.

Published
2009
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