Browsing by Author "Kadur Lakshminarasimha Murthy, Preetish"

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    An integrated cell atlas of the lung in health and disease.
    (Nature medicine, 2023-06) Sikkema, Lisa; Ramírez-Suástegui, Ciro; Strobl, Daniel C; Gillett, Tessa E; Zappia, Luke; Madissoon, Elo; Markov, Nikolay S; Zaragosi, Laure-Emmanuelle; Ji, Yuge; Ansari, Meshal; Arguel, Marie-Jeanne; Apperloo, Leonie; Banchero, Martin; Bécavin, Christophe; Berg, Marijn; Chichelnitskiy, Evgeny; Chung, Mei-I; Collin, Antoine; Gay, Aurore CA; Gote-Schniering, Janine; Hooshiar Kashani, Baharak; Inecik, Kemal; Jain, Manu; Kapellos, Theodore S; Kole, Tessa M; Leroy, Sylvie; Mayr, Christoph H; Oliver, Amanda J; von Papen, Michael; Peter, Lance; Taylor, Chase J; Walzthoeni, Thomas; Xu, Chuan; Bui, Linh T; De Donno, Carlo; Dony, Leander; Faiz, Alen; Guo, Minzhe; Gutierrez, Austin J; Heumos, Lukas; Huang, Ni; Ibarra, Ignacio L; Jackson, Nathan D; Kadur Lakshminarasimha Murthy, Preetish; Lotfollahi, Mohammad; Tabib, Tracy; Talavera-López, Carlos; Travaglini, Kyle J; Wilbrey-Clark, Anna; Worlock, Kaylee B; Yoshida, Masahiro; Lung Biological Network Consortium; van den Berge, Maarten; Bossé, Yohan; Desai, Tushar J; Eickelberg, Oliver; Kaminski, Naftali; Krasnow, Mark A; Lafyatis, Robert; Nikolic, Marko Z; Powell, Joseph E; Rajagopal, Jayaraj; Rojas, Mauricio; Rozenblatt-Rosen, Orit; Seibold, Max A; Sheppard, Dean; Shepherd, Douglas P; Sin, Don D; Timens, Wim; Tsankov, Alexander M; Whitsett, Jeffrey; Xu, Yan; Banovich, Nicholas E; Barbry, Pascal; Duong, Thu Elizabeth; Falk, Christine S; Meyer, Kerstin B; Kropski, Jonathan A; Pe'er, Dana; Schiller, Herbert B; Tata, Purushothama Rao; Schultze, Joachim L; Teichmann, Sara A; Misharin, Alexander V; Nawijn, Martijn C; Luecken, Malte D; Theis, Fabian J
    Single-cell technologies have transformed our understanding of human tissues. Yet, studies typically capture only a limited number of donors and disagree on cell type definitions. Integrating many single-cell datasets can address these limitations of individual studies and capture the variability present in the population. Here we present the integrated Human Lung Cell Atlas (HLCA), combining 49 datasets of the human respiratory system into a single atlas spanning over 2.4 million cells from 486 individuals. The HLCA presents a consensus cell type re-annotation with matching marker genes, including annotations of rare and previously undescribed cell types. Leveraging the number and diversity of individuals in the HLCA, we identify gene modules that are associated with demographic covariates such as age, sex and body mass index, as well as gene modules changing expression along the proximal-to-distal axis of the bronchial tree. Mapping new data to the HLCA enables rapid data annotation and interpretation. Using the HLCA as a reference for the study of disease, we identify shared cell states across multiple lung diseases, including SPP1+ profibrotic monocyte-derived macrophages in COVID-19, pulmonary fibrosis and lung carcinoma. Overall, the HLCA serves as an example for the development and use of large-scale, cross-dataset organ atlases within the Human Cell Atlas.
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    Epigenetic basis of oncogenic-Kras-mediated epithelial-cellular proliferation and plasticity.
    (Developmental cell, 2022-02) Kadur Lakshminarasimha Murthy, Preetish; Xi, Rui; Arguijo, Diana; Everitt, Jeffrey I; Kocak, Dewran D; Kobayashi, Yoshihiko; Bozec, Aline; Vicent, Silvestre; Ding, Shengli; Crawford, Gregory E; Hsu, David; Tata, Purushothama Rao; Reddy, Timothy; Shen, Xiling
    Oncogenic Kras induces a hyper-proliferative state that permits cells to progress to neoplasms in diverse epithelial tissues. Depending on the cell of origin, this also involves lineage transformation. Although a multitude of downstream factors have been implicated in these processes, the precise chronology of molecular events controlling them remains elusive. Using mouse models, primary human tissues, and cell lines, we show that, in Kras-mutant alveolar type II cells (AEC2), FOSL1-based AP-1 factor guides the mSWI/SNF complex to increase chromatin accessibility at genomic loci controlling the expression of genes necessary for neoplastic transformation. We identified two orthogonal processes in Kras-mutant distal airway club cells. The first promoted their transdifferentiation into an AEC2-like state through NKX2.1, and the second controlled oncogenic transformation through the AP-1 complex. Our results suggest that neoplasms retain an epigenetic memory of their cell of origin through cell-type-specific transcription factors. Our analysis showed that a cross-tissue-conserved AP-1-dependent chromatin remodeling program regulates carcinogenesis.
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    Human distal lung maps and lineage hierarchies reveal a bipotent progenitor.
    (Nature, 2022-04) Kadur Lakshminarasimha Murthy, Preetish; Sontake, Vishwaraj; Tata, Aleksandra; Kobayashi, Yoshihiko; Macadlo, Lauren; Okuda, Kenichi; Conchola, Ansley S; Nakano, Satoko; Gregory, Simon; Miller, Lisa A; Spence, Jason R; Engelhardt, John F; Boucher, Richard C; Rock, Jason R; Randell, Scott H; Tata, Purushothama Rao
    Mapping the spatial distribution and molecular identity of constituent cells is essential for understanding tissue dynamics in health and disease. We lack a comprehensive map of human distal airways, including the terminal and respiratory bronchioles (TRBs), which are implicated in respiratory diseases1-4. Here, using spatial transcriptomics and single-cell profiling of microdissected distal airways, we identify molecularly distinct TRB cell types that have not-to our knowledge-been previously characterized. These include airway-associated LGR5+ fibroblasts and TRB-specific alveolar type-0 (AT0) cells and TRB secretory cells (TRB-SCs). Connectome maps and organoid-based co-cultures reveal that LGR5+ fibroblasts form a signalling hub in the airway niche. AT0 cells and TRB-SCs are conserved in primates and emerge dynamically during human lung development. Using a non-human primate model of lung injury, together with human organoids and tissue specimens, we show that alveolar type-2 cells in regenerating lungs transiently acquire an AT0 state from which they can differentiate into either alveolar type-1 cells or TRB-SCs. This differentiation programme is distinct from that identified in the mouse lung5-7. Our study also reveals mechanisms that drive the differentiation of the bipotent AT0 cell state into normal or pathological states. In sum, our findings revise human lung cell maps and lineage trajectories, and implicate an epithelial transitional state in primate lung regeneration and disease.
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    Multi-apical polarity of alveolar stem cells and their dynamics during lung development and regeneration.
    (iScience, 2022-10) Konkimalla, Arvind; Konishi, Satoshi; Kobayashi, Yoshihiko; Kadur Lakshminarasimha Murthy, Preetish; Macadlo, Lauren; Mukherjee, Ananya; Elmore, Zachary; Kim, So-Jin; Pendergast, Ann Marie; Lee, Patty J; Asokan, Aravind; Knudsen, Lars; Bravo-Cordero, Jose Javier; Tata, Aleksandra; Tata, Purushothama Rao
    Epithelial cells of diverse tissues are characterized by the presence of a single apical domain. In the lung, electron microscopy studies have suggested that alveolar type-2 epithelial cells (AT2s) en face multiple alveolar sacs. However, apical and basolateral organization of the AT2s and their establishment during development and remodeling after injury repair remain unknown. Thick tissue imaging and electron microscopy revealed that a single AT2 can have multiple apical domains that enface multiple alveoli. AT2s gradually establish multi-apical domains post-natally, and they are maintained throughout life. Lineage tracing, live imaging, and selective cell ablation revealed that AT2s dynamically reorganize multi-apical domains during injury repair. Single-cell transcriptome signatures of residual AT2s revealed changes in cytoskeleton and cell migration. Significantly, cigarette smoke and oncogene activation lead to dysregulation of multi-apical domains. We propose that the multi-apical domains of AT2s enable them to be poised to support the regeneration of a large array of alveolar sacs.