Christin S Kuo

All Publications

• Interleukin(IL)-1/IL-6-inhibitor-associated drug reaction with eosinophilia and systemic symptoms (DReSS) in systemic inflammatory illnesses. The journal of allergy and clinical immunology. In practice Saper, V. E., Tian, L., Verstegen, R. H., Conrad, C. K., Cidon, M., Hopper, R. K., Kuo, C. S., Osoegawa, K., Baszis, K., Bingham, C. A., Ferguson, I., Hahn, T., Horne, A., Isupova, E. A., Jones, J. T., Kasapcopur, Ö., Klein-Gitelman, M. S., Kostik, M. M., Ozen, S., Phadke, O., Prahalad, S., Randell, R. L., Sener, S., Stingl, C., Abdul-Aziz, R., Akoghlanian, S., Al Julandani, D., Alvarez, M. B., Bader-Meunier, B., Balay-Dustrude, E. E., Balboni, I., Baxter, S. K., Berard, R. A., Bhattad, S., Bolaria, R., Boneparth, A., Cassidy, E. A., Co, D. O., Collins, K. P., Dancey, P., Dickinson, A. M., Edelheit, B. S., Espada, G., Flanagan, E. R., Imundo, L. F., Jindal, A. K., Kim, H. A., Klaus, G., Lake, C., Lapin, W. B., Lawson, E. F., Marmor, I., Mombourquette, J., Ogunjimi, B., Olveda, R., Ombrello, M. J., Onel, K., Poholek, C., Ramanan, A. V., Ravelli, A., Reinhardt, A., Robinson, A. D., Rouster-Stevens, K., Saad, N., Schneider, R., Selmanovic, V., Pasic, I. S., Shenoi, S., Shilo, N. R., Soep, J. B., Sura, A., Taber, S. F., Tesher, M., Tibaldi, J., Torok, K. S., Tsin, C. M., Vasquez-Canizares, N., Villacis Nunez, D. S., Way, E. E., Whitehead, B., Zemel, L. S., Sharma, S., Fernández-Viña, M. A., Mellins, E. D. 2024

  Abstract

  After introducing interleukin(IL)-1/IL-6 inhibitors, some Still and Still-like patients developed unusual often fatal pulmonary disease. This complication was associated with scoring as DReSS (drug reaction with eosinophilia and systemic symptoms) implicating these inhibitors, although DReSS can be difficult to recognize in the setting of systemic inflammatory disease.We sought to facilitate recognition of IL-1/IL-6 inhibitor-DReSS in systemic inflammatory illnesses (Still/Still-like) by looking at timing and reaction-associated features. We evaluated outcomes of stopping or not-stopping IL-1/IL-6-inhibitors after DReSS reaction began.In an international study collaborating primarily with pediatric specialists, we characterized features of 89 drug-reaction cases versus 773 drug-exposed controls and compared outcomes of 52 cases stopping IL-1/IL-6-inhibitors to 37 cases not-stopping these drugs.Before reaction began, drug-reaction cases and controls were clinically comparable, except for younger disease onset age for reaction cases with pre-existing cardiothoracic comorbidities. After reaction began, increased rates of pulmonary complications and macrophage activation syndrome (MAS), differentiated drug-reaction cases from drug-tolerant controls (p=4.7x10-35; p=1.1x10-24, respectively). Initial DReSS feature was typically reported 2-8 weeks after initiating IL-1/IL-6-inhibition. In drug-reaction cases stopping versus not-stopping IL-1/IL-6-inhibitor treatment, reaction related features were indistinguishable, including pulmonary complication rates [75%(39/52] versus [76%(28/37)]. Those stopping subsequently required fewer medications for treatment of systemic inflammation, had decreased rates of MAS, and improved survival (p=0.005, multivariate regression). Resolution of pulmonary complications occurred in 67%(26/39) of drug-reaction cases who stopped and in none who continued inhibitors.In systemic inflammatory illnesses, recognition of IL-1/IL-6-inhibitor-associated reactions followed by avoidance of IL-1/IL-6-inhibitors significantly improved outcomes.

  View details for DOI 10.1016/j.jaip.2024.07.002

  View details for PubMedID 39002722

• Interstitial macrophages are a focus of viral takeover and inflammation in COVID-19 initiation in human lung. The Journal of experimental medicine Wu, T. T., Travaglini, K. J., Rustagi, A., Xu, D., Zhang, Y., Andronov, L., Jang, S., Gillich, A., Dehghannasiri, R., Martinez-Colon, G. J., Beck, A., Liu, D. D., Wilk, A. J., Morri, M., Trope, W. L., Bierman, R., Weissman, I. L., Shrager, J. B., Quake, S. R., Kuo, C. S., Salzman, J., Moerner, W. E., Kim, P. S., Blish, C. A., Krasnow, M. A. 2024; 221 (6)

  Abstract

  Early stages of deadly respiratory diseases including COVID-19 are challenging to elucidate in humans. Here, we define cellular tropism and transcriptomic effects of SARS-CoV-2 virus by productively infecting healthy human lung tissue and using scRNA-seq to reconstruct the transcriptional program in "infection pseudotime" for individual lung cell types. SARS-CoV-2 predominantly infected activated interstitial macrophages (IMs), which can accumulate thousands of viral RNA molecules, taking over 60% of the cell transcriptome and forming dense viral RNA bodies while inducing host profibrotic (TGFB1, SPP1) and inflammatory (early interferon response, CCL2/7/8/13, CXCL10, and IL6/10) programs and destroying host cell architecture. Infected alveolar macrophages (AMs) showed none of these extreme responses. Spike-dependent viral entry into AMs used ACE2 and Sialoadhesin/CD169, whereas IM entry used DC-SIGN/CD209. These results identify activated IMs as a prominent site of viral takeover, the focus of inflammation and fibrosis, and suggest targeting CD209 to prevent early pathology in COVID-19 pneumonia. This approach can be generalized to any human lung infection and to evaluate therapeutics.

  View details for DOI 10.1084/jem.20232192

  View details for PubMedID 38597954

• An organism-wide atlas of hormonal signaling based on the mouse lemur single-cell transcriptome. Nature communications Liu, S., Ezran, C., Wang, M. F., Li, Z., Awayan, K., Long, J. Z., De Vlaminck, I., Wang, S., Epelbaum, J., Kuo, C. S., Terrien, J., Krasnow, M. A., Ferrell, J. E. 2024; 15 (1): 2188

  Abstract

  Hormones mediate long-range cell communication and play vital roles in physiology, metabolism, and health. Traditionally, endocrinologists have focused on one hormone or organ system at a time. Yet, hormone signaling by its very nature connects cells of different organs and involves crosstalk of different hormones. Here, we leverage the organism-wide single cell transcriptional atlas of a non-human primate, the mouse lemur (Microcebus murinus), to systematically map source and target cells for 84 classes of hormones. This work uncovers previously-uncharacterized sites of hormone regulation, and shows that the hormonal signaling network is densely connected, decentralized, and rich in feedback loops. Evolutionary comparisons of hormonal genes and their expression patterns show that mouse lemur better models human hormonal signaling than mouse, at both the genomic and transcriptomic levels, and reveal primate-specific rewiring of hormone-producing/target cells. This work complements the scale and resolution of classical endocrine studies and sheds light on primate hormone regulation.

  View details for DOI 10.1038/s41467-024-46070-9

  View details for PubMedID 38467625

  View details for PubMedCentralID 1540572

• Neuroendocrinology of the lung revealed by single-cell RNA sequencing. eLife Kuo, C. S., Darmanis, S., Diaz de Arce, A., Liu, Y., Almanzar, N., Wu, T. T., Quake, S. R., Krasnow, M. A. 2022; 11

  Abstract

  Pulmonary neuroendocrine cells (PNECs) are sensory epithelial cells that transmit airway status to the brain via sensory neurons and locally via calcitonin gene-related peptide (CGRP) and γ- aminobutyric acid (GABA). Several other neuropeptides and neurotransmitters have been detected in various species, but the number, targets, functions, and conservation of PNEC signals are largely unknown. We used scRNAseq to profile hundreds of the rare mouse and human PNECs. This revealed over 40 PNEC neuropeptide and peptide hormone genes, most cells expressing unique combinations of 5-18 genes. Peptides are packaged in separate vesicles, their release presumably regulated by the distinct, multimodal combinations of sensors we show are expressed by each PNEC. Expression of the peptide receptors predicts an array of local cell targets, and we show the new PNEC signal angiotensin directly activates one subtype of innervating sensory neuron. Many signals lack lung targets so may have endocrine activity like those of PNEC-derived carcinoid tumors. PNECs are an extraordinarily rich and diverse signaling hub rivaling the enteroendocrine system.

  View details for DOI 10.7554/eLife.78216

  View details for PubMedID 36469459

• The Tabula Sapiens: A multiple-organ, single-cell transcriptomic atlas of humans. Science (New York, N.Y.) Jones, R. C., Karkanias, J., Krasnow, M. A., Pisco, A. O., Quake, S. R., Salzman, J., Yosef, N., Bulthaup, B., Brown, P., Harper, W., Hemenez, M., Ponnusamy, R., Salehi, A., Sanagavarapu, B. A., Spallino, E., Aaron, K. A., Concepcion, W., Gardner, J. M., Kelly, B., Neidlinger, N., Wang, Z., Crasta, S., Kolluru, S., Morri, M., Pisco, A. O., Tan, S. Y., Travaglini, K. J., Xu, C., Alcántara-Hernández, M., Almanzar, N., Antony, J., Beyersdorf, B., Burhan, D., Calcuttawala, K., Carter, M. M., Chan, C. K., Chang, C. A., Chang, S., Colville, A., Crasta, S., Culver, R. N., Cvijović, I., D'Amato, G., Ezran, C., Galdos, F. X., Gillich, A., Goodyer, W. R., Hang, Y., Hayashi, A., Houshdaran, S., Huang, X., Irwin, J. C., Jang, S., Juanico, J. V., Kershner, A. M., Kim, S., Kiss, B., Kolluru, S., Kong, W., Kumar, M. E., Kuo, A. H., Leylek, R., Li, B., Loeb, G. B., Lu, W. J., Mantri, S., Markovic, M., McAlpine, P. L., de Morree, A., Morri, M., Mrouj, K., Mukherjee, S., Muser, T., Neuhöfer, P., Nguyen, T. D., Perez, K., Phansalkar, R., Pisco, A. O., Puluca, N., Qi, Z., Rao, P., Raquer-McKay, H., Schaum, N., Scott, B., Seddighzadeh, B., Segal, J., Sen, S., Sikandar, S., Spencer, S. P., Steffes, L. C., Subramaniam, V. R., Swarup, A., Swift, M., Travaglini, K. J., Van Treuren, W., Trimm, E., Veizades, S., Vijayakumar, S., Vo, K. C., Vorperian, S. K., Wang, W., Weinstein, H. N., Winkler, J., Wu, T. T., Xie, J., Yung, A. R., Zhang, Y., Detweiler, A. M., Mekonen, H., Neff, N. F., Sit, R. V., Tan, M., Yan, J., Bean, G. R., Charu, V., Forgó, E., Martin, B. A., Ozawa, M. G., Silva, O., Tan, S. Y., Toland, A., Vemuri, V. N., Afik, S., Awayan, K., Botvinnik, O. B., Byrne, A., Chen, M., Dehghannasiri, R., Detweiler, A. M., Gayoso, A., Granados, A. A., Li, Q., Mahmoudabadi, G., McGeever, A., de Morree, A., Olivieri, J. E., Park, M., Pisco, A. O., Ravikumar, N., Salzman, J., Stanley, G., Swift, M., Tan, M., Tan, W., Tarashansky, A. J., Vanheusden, R., Vorperian, S. K., Wang, P., Wang, S., Xing, G., Xu, C., Yosef, N., Alcántara-Hernández, M., Antony, J., Chan, C. K., Chang, C. A., Colville, A., Crasta, S., Culver, R., Dethlefsen, L., Ezran, C., Gillich, A., Hang, Y., Ho, P. Y., Irwin, J. C., Jang, S., Kershner, A. M., Kong, W., Kumar, M. E., Kuo, A. H., Leylek, R., Liu, S., Loeb, G. B., Lu, W. J., Maltzman, J. S., Metzger, R. J., de Morree, A., Neuhöfer, P., Perez, K., Phansalkar, R., Qi, Z., Rao, P., Raquer-McKay, H., Sasagawa, K., Scott, B., Sinha, R., Song, H., Spencer, S. P., Swarup, A., Swift, M., Travaglini, K. J., Trimm, E., Veizades, S., Vijayakumar, S., Wang, B., Wang, W., Winkler, J., Xie, J., Yung, A. R., Artandi, S. E., Beachy, P. A., Clarke, M. F., Giudice, L. C., Huang, F. W., Huang, K. C., Idoyaga, J., Kim, S. K., Krasnow, M., Kuo, C. S., Nguyen, P., Quake, S. R., Rando, T. A., Red-Horse, K., Reiter, J., Relman, D. A., Sonnenburg, J. L., Wang, B., Wu, A., Wu, S. M., Wyss-Coray, T. 2022; 376 (6594): eabl4896

  Abstract

  Molecular characterization of cell types using single-cell transcriptome sequencing is revolutionizing cell biology and enabling new insights into the physiology of human organs. We created a human reference atlas comprising nearly 500,000 cells from 24 different tissues and organs, many from the same donor. This atlas enabled molecular characterization of more than 400 cell types, their distribution across tissues, and tissue-specific variation in gene expression. Using multiple tissues from a single donor enabled identification of the clonal distribution of T cells between tissues, identification of the tissue-specific mutation rate in B cells, and analysis of the cell cycle state and proliferative potential of shared cell types across tissues. Cell type-specific RNA splicing was discovered and analyzed across tissues within an individual.

  View details for DOI 10.1126/science.abl4896

  View details for PubMedID 35549404

• Cell types of origin of the cell-free transcriptome. Nature biotechnology Vorperian, S. K., Moufarrej, M. N., Tabula Sapiens Consortium, Quake, S. R., Jones, R. C., Karkanias, J., Krasnow, M., Pisco, A. O., Quake, S. R., Salzman, J., Yosef, N., Bulthaup, B., Brown, P., Harper, W., Hemenez, M., Ponnusamy, R., Salehi, A., Sanagavarapu, B. A., Spallino, E., Aaron, K. A., Concepcion, W., Gardner, J. M., Kelly, B., Neidlinger, N., Wang, Z., Crasta, S., Kolluru, S., Morri, M., Tan, S. Y., Travaglini, K. J., Xu, C., Alcantara-Hernandez, M., Almanzar, N., Antony, J., Beyersdorf, B., Burhan, D., Calcuttawala, K., Carter, M. M., Chan, C. K., Chang, C. A., Chang, S., Colville, A., Culver, R. N., Cvijovic, I., D'Amato, G., Ezran, C., Galdos, F. X., Gillich, A., Goodyer, W. R., Hang, Y., Hayashi, A., Houshdaran, S., Huang, X., Irwin, J. C., Jang, S., Juanico, J. V., Kershner, A. M., Kim, S., Kiss, B., Kong, W., Kumar, M. E., Kuo, A. H., Leylek, R., Li, B., Loeb, G. B., Lu, W., Mantri, S., Markovic, M., McAlpine, P. L., de Morree, A., Mrouj, K., Mukherjee, S., Muser, T., Neuhofer, P., Nguyen, T. D., Perez, K., Phansalkar, R., Puluca, N., Qi, Z., Rao, P., Raquer-McKay, H., Schaum, N., Scott, B., Seddighzadeh, B., Segal, J., Sen, S., Sikandar, S., Spencer, S. P., Steffes, L., Subramaniam, V. R., Swarup, A., Swift, M., Van Treuren, W., Trimm, E., Veizades, S., Vijayakumar, S., Vo, K. C., Vorperian, S. K., Wang, W., Weinstein, H. N., Winkler, J., Wu, T. T., Xie, J., Yung, A. R., Zhang, Y., Detweiler, A. M., Mekonen, H., Neff, N. F., Sit, R. V., Tan, M., Yan, J., Bean, G. R., Charu, V., Forgo, E., Martin, B. A., Ozawa, M. G., Silva, O., Toland, A., Vemuri, V. N., Afik, S., Awayan, K., Bierman, R., Botvinnik, O. B., Byrne, A., Chen, M., Dehghannasiri, R., Gayoso, A., Granados, A. A., Li, Q., Mahmoudabadi, G., McGeever, A., Olivieri, J. E., Park, M., Ravikumar, N., Stanley, G., Tan, W., Tarashansky, A. J., Vanheusden, R., Wang, P., Wang, S., Xing, G., Xu, C., Yosef, N., Culver, R., Dethlefsen, L., Ho, P., Liu, S., Maltzman, J. S., Metzger, R. J., Sasagawa, K., Sinha, R., Song, H., Wang, B., Artandi, S. E., Beachy, P. A., Clarke, M. F., Giudice, L. C., Huang, F. W., Huang, K. C., Idoyaga, J., Kim, S. K., Kuo, C. S., Nguyen, P., Rando, T. A., Red-Horse, K., Reiter, J., Relman, D. A., Sonnenburg, J. L., Wu, A., Wu, S. M., Wyss-Coray, T. 2022

  Abstract

  Cell-free RNA from liquid biopsies can be analyzed to determine disease tissue of origin. We extend this concept to identify cell types of origin using the Tabula Sapiens transcriptomic cell atlas as well as individual tissue transcriptomic cell atlases in combination with the Human Protein Atlas RNA consensus dataset. We define cell type signature scores, which allow the inference of cell types that contribute to cell-free RNA for a variety of diseases.

  View details for DOI 10.1038/s41587-021-01188-9

  View details for PubMedID 35132263

• RNA splicing programs define tissue compartments and cell types at single-cell resolution ELIFE Olivieri, J., Dehghannasiri, R., Wang, P. L., Jang, S., de Morree, A., Tan, S. Y., Ming, J., Wu, A., Consortium, T., Quake, S. R., Krasnow, M. A., Salzman, J. 2021; 10

  View details for DOI 10.7554/eLife.70692.sa2

  View details for Web of Science ID 000715795700001

• Tissue-specific telomere shortening and degenerative changes in a patient with TINF2 mutation and dyskeratosis congenita. Human pathology (New York) Roake, C. M., Juntilla, M., Agarwal-Hashmi, R., Artandi, S., Kuo, C. S. 2021; 25

  Abstract

  Dyskeratosis congenita is a disease of impaired tissue maintenance downstream of telomere dysfunction. Characteristically, patients present with the clinical triad of nail dystrophy, oral leukoplakia, and skin pigmentation defects, but the disease involves degenerative changes in multiple organs. Mutations in telomere-binding proteins such as TINF2 (TRF1-interacting nuclear factor 2) or in telomerase, the enzyme that counteracts age related telomere shortening, are causative in dyskeratosis congenita. We present a patient who presented with severe hypoxemia at age 13. The patient had a history of myelodysplastic syndrome treated with bone marrow transplant at the age of 5. At age 18 she was hospitalized for an acute pneumonia progressing to respiratory failure, developed renal failure and ultimately, she and her family opted to withdraw support as she was not a candidate for a lung transplant. Sequencing of the patient's TINF2 locus revealed a heterozygous mutation (c.844C > T, Arg282Cys) which has previously been reported in a subset of dyskeratosis congenita patients. Tissue sections from multiple organs showed degenerative changes including disorganized bone remodeling, diffuse alveolar damage and small vessel proliferation in the lung, and hyperkeratosis with hyperpigmentation of the skin. Autopsy samples revealed a bimodal distribution of telomere length, with telomeres from donor hematopoietic tissues being an age-appropriate length and those from patient tissues showing pathogenic shortening, with the shortest telomeres in lung, liver, and kidney. We report for the first time a survey of degenerative changes and telomere lengths in multiple organs in a patient with dyskeratosis congenita.

  View details for DOI 10.1016/j.ehpc.2021.200517

  View details for PubMedID 34522616

• Cell-autonomous immune gene expression is repressed in pulmonary neuroendocrine cells and small cell lung cancer. Communications biology Cai, L., Liu, H., Huang, F., Fujimoto, J., Girard, L., Chen, J., Li, Y., Zhang, Y., Deb, D., Stastny, V., Pozo, K., Kuo, C. S., Jia, G., Yang, C., Zou, W., Alomar, A., Huffman, K., Papari-Zareei, M., Yang, L., Drapkin, B., Akbay, E. A., Shames, D. S., Wistuba, I. I., Wang, T., Johnson, J. E., Xiao, G., DeBerardinis, R. J., Minna, J. D., Xie, Y., Gazdar, A. F. 2021; 4 (1): 314

  Abstract

  Small cell lung cancer (SCLC) is classified as a high-grade neuroendocrine (NE) tumor, but a subset of SCLC has been termed "variant" due to the loss of NE characteristics. In this study, we computed NE scores for patient-derived SCLC cell lines and xenografts, as well as human tumors. We aligned NE properties with transcription factor-defined molecular subtypes. Then we investigated the different immune phenotypes associated with high and low NE scores. We found repression of immune response genes as a shared feature between classic SCLC and pulmonary neuroendocrine cells of the healthy lung. With loss of NE fate, variant SCLC tumors regain cell-autonomous immune gene expression and exhibit higher tumor-immune interactions. Pan-cancer analysis revealed this NE lineage-specific immune phenotype in other cancers. Additionally, we observed MHC I re-expression in SCLC upon development of chemoresistance. These findings may help guide the design of treatment regimens in SCLC.

  View details for DOI 10.1038/s42003-021-01842-7

  View details for PubMedID 33750914

• Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics. Nature medicine Muus, C., Luecken, M. D., Eraslan, G., Sikkema, L., Waghray, A., Heimberg, G., Kobayashi, Y., Vaishnav, E. D., Subramanian, A., Smillie, C., Jagadeesh, K. A., Duong, E. T., Fiskin, E., Triglia, E. T., Ansari, M., Cai, P., Lin, B., Buchanan, J., Chen, S., Shu, J., Haber, A. L., Chung, H., Montoro, D. T., Adams, T., Aliee, H., Allon, S. J., Andrusivova, Z., Angelidis, I., Ashenberg, O., Bassler, K., Becavin, C., Benhar, I., Bergenstrahle, J., Bergenstrahle, L., Bolt, L., Braun, E., Bui, L. T., Callori, S., Chaffin, M., Chichelnitskiy, E., Chiou, J., Conlon, T. M., Cuoco, M. S., Cuomo, A. S., Deprez, M., Duclos, G., Fine, D., Fischer, D. S., Ghazanfar, S., Gillich, A., Giotti, B., Gould, J., Guo, M., Gutierrez, A. J., Habermann, A. C., Harvey, T., He, P., Hou, X., Hu, L., Hu, Y., Jaiswal, A., Ji, L., Jiang, P., Kapellos, T. S., Kuo, C. S., Larsson, L., Leney-Greene, M. A., Lim, K., Litvinukova, M., Ludwig, L. S., Lukassen, S., Luo, W., Maatz, H., Madissoon, E., Mamanova, L., Manakongtreecheep, K., Leroy, S., Mayr, C. H., Mbano, I. M., McAdams, A. M., Nabhan, A. N., Nyquist, S. K., Penland, L., Poirion, O. B., Poli, S., Qi, C., Queen, R., Reichart, D., Rosas, I., Schupp, J. C., Shea, C. V., Shi, X., Sinha, R., Sit, R. V., Slowikowski, K., Slyper, M., Smith, N. P., Sountoulidis, A., Strunz, M., Sullivan, T. B., Sun, D., Talavera-Lopez, C., Tan, P., Tantivit, J., Travaglini, K. J., Tucker, N. R., Vernon, K. A., Wadsworth, M. H., Waldman, J., Wang, X., Xu, K., Yan, W., Zhao, W., Ziegler, C. G., NHLBI LungMap Consortium, Human Cell Atlas Lung Biological Network, Deutsch, G. H., Dutra, J., Gaulton, K. J., Holden-Wiltse, J., Huyck, H. L., Mariani, T. J., Misra, R. S., Poole, C., Preissl, S., Pryhuber, G. S., Rogers, L., Sun, X., Wang, A., Whitsett, J. A., Xu, Y., Alladina, J., Banovich, N. E., Barbry, P., Beane, J. E., Bhattacharyya, R. P., Black, K. E., Brazma, A., Campbell, J. D., Cho, J. L., Collin, J., Conrad, C., de Jong, K., Desai, T., Ding, D. Z., Eickelberg, O., Eils, R., Ellinor, P. T., Faiz, A., Falk, C. S., Farzan, M., Gellman, A., Getz, G., Glass, I. A., Greka, A., Haniffa, M., Hariri, L. P., Hennon, M. W., Horvath, P., Hubner, N., Hung, D. T., Huyck, H. L., Janssen, W. J., Juric, D., Kaminski, N., Koenigshoff, M., Koppelman, G. H., Krasnow, M. A., Kropski, J. A., Kuhnemund, M., Lafyatis, R., Lako, M., Lander, E. S., Lee, H., Lenburg, M. E., Marquette, C., Metzger, R. J., Linnarsson, S., Liu, G., Lo, Y. M., Lundeberg, J., Marioni, J. C., Mazzilli, S. A., Medoff, B. D., Meyer, K. B., Miao, Z., Misharin, A. V., Nawijn, M. C., Nikolic, M. Z., Noseda, M., Ordovas-Montanes, J., Oudit, G. Y., Pe'er, D., Powell, J. E., Quake, S. R., Rajagopal, J., Tata, P. R., Rawlins, E. L., Regev, A., Reid, M. E., Reyfman, P. A., Rieger-Christ, K. M., Rojas, M., Rozenblatt-Rosen, O., Saeb-Parsy, K., Samakovlis, C., Sanes, J. R., Schiller, H. B., Schultze, J. L., Schwarz, R. F., Segre, A. V., Seibold, M. A., Seidman, C. E., Seidman, J. G., Shalek, A. K., Shepherd, D. P., Sinha, R., Spence, J. R., Spira, A., Sun, X., Sundstrom, E., Teichmann, S. A., Theis, F. J., Tsankov, A. M., Vallier, L., van den Berge, M., Van Zyl, T. A., Villani, A., Weins, A., Xavier, R. J., Yildirim, A. O., Zaragosi, L., Zerti, D., Zhang, H., Zhang, K., Zhang, X. 2021

  Abstract

  Angiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body. We assessed the cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues. ACE2, TMPRSS2 and CTSL are coexpressed in specific subsets of respiratory epithelial cells in the nasal passages, airways and alveoli, and in cells from other organs associated with coronavirus disease 2019 (COVID-19) transmission or pathology. We performed a meta-analysis of 31 lung single-cell RNA-sequencing studies with 1,320,896 cells from 377 nasal, airway and lung parenchyma samples from 228 individuals. This revealed cell-type-specific associations of age, sex and smoking with expression levels of ACE2, TMPRSS2 and CTSL. Expression of entry factors increased with age and in males, including in airway secretory cells and alveolar type 2 cells. Expression programs shared by ACE2+TMPRSS2+ cells in nasal, lung and gut tissues included genes that may mediate viral entry, key immune functions and epithelial-macrophage cross-talk, such as genes involved in the interleukin-6, interleukin-1, tumor necrosis factor and complement pathways. Cell-type-specific expression patterns may contribute to the pathogenesis of COVID-19, and our work highlights putative molecular pathways for therapeutic intervention.

  View details for DOI 10.1038/s41591-020-01227-z

  View details for PubMedID 33654293

• A molecular cell atlas of the human lung from single-cell RNA sequencing. Nature Travaglini, K. J., Nabhan, A. N., Penland, L., Sinha, R., Gillich, A., Sit, R. V., Chang, S., Conley, S. D., Mori, Y., Seita, J., Berry, G. J., Shrager, J. B., Metzger, R. J., Kuo, C. S., Neff, N., Weissman, I. L., Quake, S. R., Krasnow, M. A. 2020

  Abstract

  Although single-cell RNA sequencing studies have begun to provide compendia of cell expression profiles1-9, it has been difficult to systematically identify and localize all molecularcell types in individual organs to create a full molecular cell atlas. Here, using droplet- and plate-based single-cell RNA sequencing of approximately 75,000 human cells across all lung tissue compartments and circulating blood, combined with a multi-pronged cell annotation approach, we create an extensive cell atlas of the human lung. We define the gene expression profiles and anatomical locations of 58 cell populations in the human lung, including 41 out of 45 previously known cell types and 14 previously unknown ones. This comprehensive molecular atlas identifies the biochemical functions of lung cells and the transcription factors and markers for making and monitoring them; defines the cell targets of circulating hormones and predicts local signalling interactions and immune cell homing; and identifies cell types that are directly affected by lung disease genes and respiratory viruses. By comparing human and mouse data, we identified 17 molecular cell types that have been gained or lost during lung evolution and others with substantially altered expression profiles, revealing extensive plasticity of cell types and cell-type-specific gene expression during organ evolution including expression switches between cell types. This atlas provides the molecular foundation for investigating how lung cell identities, functions and interactions are achieved in development and tissue engineering and altered in disease and evolution.

  View details for DOI 10.1038/s41586-020-2922-4

  View details for PubMedID 33208946

• A single-cell transcriptomic atlas characterizes ageing tissues in the mouse. Nature 2020

  Abstract

  Ageing is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death1. Despite rapid advances over recent years, many of the molecular and cellular processes that underlie the progressive loss of healthy physiology are poorly understood2. To gain a better insight into these processes, here we generate a single-cell transcriptomic atlas across the lifespan of Mus musculus that includes data from 23 tissues and organs. We found cell-specific changes occurring across multiple cell types and organs, as well as age-related changes in the cellular composition of different organs. Using single-cell transcriptomic data, we assessed cell-type-specific manifestations of different hallmarks of ageing-such as senescence3, genomic instability4 and changes in the immune system2. This transcriptomic atlas-which we denote Tabula Muris Senis, or 'Mouse Ageing Cell Atlas'-provides molecular information about how the most important hallmarks of ageing are reflected in a broad range of tissues and cell types.

  View details for DOI 10.1038/s41586-020-2496-1

  View details for PubMedID 32669714

• Ageing hallmarks exhibit organ-specific temporal signatures. Nature Schaum, N. n., Lehallier, B. n., Hahn, O. n., Pálovics, R. n., Hosseinzadeh, S. n., Lee, S. E., Sit, R. n., Lee, D. P., Losada, P. M., Zardeneta, M. E., Fehlmann, T. n., Webber, J. T., McGeever, A. n., Calcuttawala, K. n., Zhang, H. n., Berdnik, D. n., Mathur, V. n., Tan, W. n., Zee, A. n., Tan, M. n., Pisco, A. O., Karkanias, J. n., Neff, N. F., Keller, A. n., Darmanis, S. n., Quake, S. R., Wyss-Coray, T. n. 2020

  Abstract

  Ageing is the single greatest cause of disease and death worldwide, and understanding the associated processes could vastly improve quality of life. Although major categories of ageing damage have been identified-such as altered intercellular communication, loss of proteostasis and eroded mitochondrial function1-these deleterious processes interact with extraordinary complexity within and between organs, and a comprehensive, whole-organism analysis of ageing dynamics has been lacking. Here we performed bulk RNA sequencing of 17 organs and plasma proteomics at 10 ages across the lifespan of Mus musculus, and integrated these findings with data from the accompanying Tabula Muris Senis2-or 'Mouse Ageing Cell Atlas'-which follows on from the original Tabula Muris3. We reveal linear and nonlinear shifts in gene expression during ageing, with the associated genes clustered in consistent trajectory groups with coherent biological functions-including extracellular matrix regulation, unfolded protein binding, mitochondrial function, and inflammatory and immune response. Notably, these gene sets show similar expression across tissues, differing only in the amplitude and the age of onset of expression. Widespread activation of immune cells is especially pronounced, and is first detectable in white adipose depots during middle age. Single-cell RNA sequencing confirms the accumulation of T cells and B cells in adipose tissue-including plasma cells that express immunoglobulin J-which also accrue concurrently across diverse organs. Finally, we show how gene expression shifts in distinct tissues are highly correlated with corresponding protein levels in plasma, thus potentially contributing to the ageing of the systemic circulation. Together, these data demonstrate a similar yet asynchronous inter- and intra-organ progression of ageing, providing a foundation from which to track systemic sources of declining health at old age.

  View details for DOI 10.1038/s41586-020-2499-y

  View details for PubMedID 32669715

• Axon-like protrusions promote small cell lung cancer migration and metastasis. eLife Yang, D., Qu, F., Cai, H., Chuang, C., Lim, J. S., Jahchan, N., Gruner, B. M., S Kuo, C., Kong, C., Oudin, M. J., Winslow, M. M., Sage, J. 2019; 8

  Abstract

  Metastasis is the main cause of death in cancer patients but remains a poorly understood process. Small cell lung cancer (SCLC) is one of the most lethal and most metastatic cancer types. SCLC cells normally express neuroendocrine and neuronal gene programs but accumulating evidence indicates that these cancer cells become relatively more neuronal and less neuroendocrine as they gain the ability to metastasize. Here we show that mouse and human SCLC cells in culture and in vivo can grow cellular protrusions that resemble axons. The formation of these protrusions is controlled by multiple neuronal factors implicated in axonogenesis, axon guidance, and neuroblast migration. Disruption of these axon-like protrusions impairs cell migration in culture and inhibits metastatic ability in vivo. The co-option of developmental neuronal programs is a novel molecular and cellular mechanism that contributes to the high metastatic ability of SCLC.

  View details for DOI 10.7554/eLife.50616

  View details for PubMedID 31833833

• Rare Pulmonary Neuroendocrine Cells Are Stem Cells Regulated by Rb, p53, and Notch. Cell Ouadah, Y. n., Rojas, E. R., Riordan, D. P., Capostagno, S. n., Kuo, C. S., Krasnow, M. A. 2019; 179 (2): 403–16.e23

  Abstract

  Pulmonary neuroendocrine (NE) cells are neurosensory cells sparsely distributed throughout the bronchial epithelium, many in innervated clusters of 20-30 cells. Following lung injury, NE cells proliferate and generate other cell types to promote epithelial repair. Here, we show that only rare NE cells, typically 2-4 per cluster, function as stem cells. These fully differentiated cells display features of classical stem cells. Most proliferate (self-renew) following injury, and some migrate into the injured area. A week later, individual cells, often just one per cluster, lose NE identity (deprogram), transit amplify, and reprogram to other fates, creating large clonal repair patches. Small cell lung cancer (SCLC) tumor suppressors regulate the stem cells: Rb and p53 suppress self-renewal, whereas Notch marks the stem cells and initiates deprogramming and transit amplification. We propose that NE stem cells give rise to SCLC, and transformation results from constitutive activation of stem cell renewal and inhibition of deprogramming.

  View details for DOI 10.1016/j.cell.2019.09.010

  View details for PubMedID 31585080

• A national registry for childhood interstitial and diffuse lung diseases in the United States. Young, L., Nevel, R., Casey, A., Fishman, M., Welsh, S., Liptzin, D., Hagood, J., Kurland, G., Craven, D., Fiorino, E., Taylor, J., Goldfarb, S., Conrad, C., Kuo, C., Deutsch, G., De, A., Powers, M., Deterding, R. EUROPEAN RESPIRATORY SOC JOURNALS LTD. 2018

  View details for DOI 10.1183/13993003.congress-2018.OA3786

  View details for Web of Science ID 000455567100338

• Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris. Nature 2018; 562 (7727): 367–72

  Abstract

  Here we present a compendium of single-cell transcriptomic data from the model organism Mus musculus that comprises more than 100,000 cells from 20 organs and tissues. These data represent a new resource for cell biology, reveal gene expression in poorly characterized cell populations and enable the direct and controlled comparison of gene expression in cell types that are shared between tissues, such as T lymphocytes and endothelial cells from different anatomical locations. Two distinct technical approaches were used for most organs: one approach, microfluidic droplet-based 3'-end counting, enabled the survey of thousands of cells at relatively low coverage, whereas the other, full-length transcript analysis based on fluorescence-activated cell sorting, enabled the characterization of cell types with high sensitivity and coverage. The cumulative data provide the foundation for an atlas of transcriptomic cell biology.

  View details for DOI 10.1038/s41586-018-0590-4

  View details for PubMedID 30283141

• Pulmonary arteriovenous malformations: an uncharacterised phenotype of dyskeratosis congenita and related telomere biology disorders EUROPEAN RESPIRATORY JOURNAL Khincha, P. P., Bertuch, A. A., Agarwal, S., Townsley, D. M., Young, N. S., Keel, S., Shimamura, A., Boulad, F., Simoneau, T., Justino, H., Kuo, C., Artandi, S., McCaslin, C., Cox, D. W., Chaffee, S., Collins, B. F., Giri, N., Alter, B. P., Raghu, G., Savage, S. A. 2017; 49 (1)

  View details for PubMedID 27824607

  View details for PubMedCentralID PMC5841586

• Respiratory System Involvement in Costello Syndrome AMERICAN JOURNAL OF MEDICAL GENETICS PART A Gomez-Ospina, N., Kuo, C., Ananth, A. L., Myers, A., Brennan, M., Stevenson, D. A., Bernstein, J. A., Hudgins, L. 2016; 170 (7): 1849-1857

  Abstract

  Costello syndrome (CS) is a multisystem disorder caused by heterozygous germline mutations in the HRAS proto-oncogene. Respiratory system complications have been reported in individuals with CS, but a comprehensive description of the full spectrum and incidence of respiratory symptoms in these patients is not available. Here, we report the clinical course of four CS patients with respiratory complications as a major cause of morbidity. Review of the literature identified 56 CS patients with descriptions of their neonatal course and 17 patients in childhood/adulthood. We found that in the neonatal period, respiratory complications are seen in approximately 78% of patients with transient respiratory distress reported in 45% of neonates. Other more specific respiratory diagnoses were reported in 62% of patients, the majority of which comprised disorders of the upper and lower respiratory tract. Symptoms of upper airway obstruction were reported in CS neonates but were more commonly diagnosed in childhood/adulthood (71%). Analysis of HRAS mutations and their respiratory phenotype revealed that the common p.Gly12Ser mutation is more often associated with transient respiratory distress and other respiratory diagnoses. Respiratory failure and dependence on mechanical ventilation occurs almost exclusively with rare mutations. In cases of prenatally diagnosed CS, the high incidence of respiratory complications in the neonatal period should prompt anticipatory guidance and development of a postnatal management plan. This may be important in cases involving rarer mutations. Furthermore, the high frequency of airway obstruction in CS patients suggests that otorhinolaryngological evaluation and sleep studies should be considered. © 2016 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ajmg.a.37655

  View details for PubMedID 27102959

• Formation of a Neurosensory Organ by Epithelial Cell Slithering CELL Kuo, C. S., Krasnow, M. A. 2015; 163 (2): 394-405

  Abstract

  Epithelial cells are normally stably anchored, maintaining their relative positions and association with the basement membrane. Developmental rearrangements occur through cell intercalation, and cells can delaminate during epithelial-mesenchymal transitions and metastasis. We mapped the formation of lung neuroepithelial bodies (NEBs), innervated clusters of neuroendocrine/neurosensory cells within the bronchial epithelium, revealing a targeted mode of cell migration that we named "slithering," in which cells transiently lose epithelial character but remain associated with the membrane while traversing neighboring epithelial cells to reach cluster sites. Immunostaining, lineage tracing, clonal analysis, and live imaging showed that NEB progenitors, initially distributed randomly, downregulate adhesion and polarity proteins, crawling over and between neighboring cells to converge at diametrically opposed positions at bronchial branchpoints, where they reestablish epithelial structure and express neuroendocrine genes. There is little accompanying progenitor proliferation or apoptosis. Activation of the slithering program may explain why lung cancers arising from neuroendocrine cells are highly metastatic.

  View details for DOI 10.1016/j.cell.2015.09.021

  View details for Web of Science ID 000362952700016

  View details for PubMedID 26435104

  View details for PubMedCentralID PMC4597318

• Cellular mechanisms of alveolar pathology in childhood interstitial lung diseases: current insights from mouse genetics CURRENT OPINION IN PEDIATRICS Kuo, C. S., Desai, T. J. 2015; 27 (3): 341-347

  Abstract

  Childhood interstitial lung diseases (ILDs) are a diverse class of disorders affecting the alveolar gas exchange region that lack specific treatments and are usually fatal. Here, we integrate recent insights into alveolar cell biology with histopathology from well characterized mutations of surfactant-associated genes. We take a reductionist approach by parsing discrete histological features and correlating each to perturbation of a particular function of the alveolar epithelial type II (AT2) cell, the central driver of disease, to generate a working model for the cellular mechanisms of disease pathogenesis.The application of genetically modified mice and single cell genomics has yielded new insights into lung biology, including the identification of a bipotent alveolar progenitor in development, mapping of adult AT2 stem cells in vivo, and demonstration that latent cooperative interactions with fibroblasts can be pathologically activated by targeted injury of the AT2 cell.As we learn more about individual and cooperative roles for alveolar cells in health, we can dissect how perturbations of specific cellular functions contribute to disease in childhood ILDs. We hope our updated model centered around the AT2 cell as the initiator of disease provides a cellular framework that researchers can build upon and revise as they identify the specific molecular signals within and between alveolar cells that mediate the diverse pathologic features, so that targeted pharmacologic and cell-based treatments for patients can ultimately be engineered.

  View details for DOI 10.1097/MOP.0000000000000227

  View details for Web of Science ID 000354214800013

  View details for PubMedID 25888154

  View details for PubMedCentralID PMC4466102

• Interstitial lung disease in children. Current opinion in pediatrics Kuo, C. S., Young, L. R. 2014; 26 (3): 320-327

  Abstract

  There has been tremendous progress in the approach to childhood interstitial lung diseases (chILD), with particular recognition that interstitial lung disease (ILD) in infants is often distinct from the forms that occur in older children and adults. Diagnosis is challenging because of the rarity of ILD and the fact that the presenting symptoms of ILD often overlap those of common respiratory disorders. This review summarizes the newly published recommendations for diagnosis and management, and highlights the recent scientific advances in several specific forms of chILD.Clinical practice guidelines emphasize the role for chest computed tomography, genetic testing, and lung biopsy in the diagnostic evaluation of children with suspected ILD. Recent studies have better defined the characteristics and molecular understanding of several different forms of ILD, including neuroendocrine cell hyperplasia of infancy and ILD, due to mutations in genes affecting surfactant production and metabolism. Despite significant progress, definitive therapies are often lacking.chILD encompasses a collection of rare, diffuse lung diseases. Timely recognition of children with suspected ILD and initiation of appropriate diagnostic evaluations will facilitate medical management. Systematic approaches to clinical care and further studies are needed to improve the outcomes of children with these rare disorders.

  View details for DOI 10.1097/MOP.0000000000000094

  View details for PubMedID 24752172

• PML-dependent apoptosis after DNA damage is regulated by the checkpoint kinase hCds1/Chk2 NATURE CELL BIOLOGY Yang, S. T., Kuo, C., Bisi, J. E., Kim, M. K. 2002; 4 (11): 865-870

  Abstract

  The promyelocytic leukaemia (PML) gene is translocated in most acute promyelocytic leukaemias and encodes a tumour suppressor protein. PML is involved in multiple apoptotic pathways and is thought to be pivotal in gamma irradiation-induced apoptosis. The DNA damage checkpoint kinase hCds1/Chk2 is necessary for p53-dependent apoptosis after gamma irradiation. In addition, gamma irradiation-induced apoptosis also occurs through p53-independent mechanisms, although the molecular mechanism remains largely unknown. Here, we report that hCds1/Chk2 mediates gamma irradiation-induced apoptosis in a p53-independent manner through an ataxia telangiectasia-mutated (ATM)-hCds1/Chk2-PML pathway. Our results provide the first evidence of a functional relationship between PML and a checkpoint kinase in gamma irradiation-induced apoptosis.

  View details for DOI 10.1038/ncb869

  View details for Web of Science ID 000179137700015

  View details for PubMedID 12402044

• Localization, dynamics, and protein interactions reveal distinct roles for ER and Golgi SNAREs JOURNAL OF CELL BIOLOGY Hay, J. C., Klumperman, J., Oorschot, V., Steegmaier, M., Kuo, C. S., Scheller, R. H. 1998; 141 (7): 1489-1502

  Abstract

  ER-to-Golgi transport, and perhaps intraGolgi transport involves a set of interacting soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins including syntaxin 5, GOS-28, membrin, rsec22b, and rbet1. By immunoelectron microscopy we find that rsec22b and rbet1 are enriched in COPII-coated vesicles that bud from the ER and presumably fuse with nearby vesicular tubular clusters (VTCs). However, all of the SNAREs were found on both COPII- and COPI-coated membranes, indicating that similar SNARE machinery directs both vesicle pathways. rsec22b and rbet1 do not appear beyond the first Golgi cisterna, whereas syntaxin 5 and membrin penetrate deeply into the Golgi stacks. Temperature shifts reveal that membrin, rsec22b, rbet1, and syntaxin 5 are present together on membranes that rapidly recycle between peripheral and Golgi-centric locations. GOS-28, on the other hand, maintains a fixed localization in the Golgi. By immunoprecipitation analysis, syntaxin 5 exists in at least two major subcomplexes: one containing syntaxin 5 (34-kD isoform) and GOS-28, and another containing syntaxin 5 (41- and 34-kD isoforms), membrin, rsec22b, and rbet1. Both subcomplexes appear to involve direct interactions of each SNARE with syntaxin 5. Our results indicate a central role for complexes among rbet1, rsec22b, membrin, and syntaxin 5 (34 and 41 kD) at two membrane fusion interfaces: the fusion of ER-derived vesicles with VTCs, and the assembly of VTCs to form cis-Golgi elements. The 34-kD syntaxin 5 isoform, membrin, and GOS-28 may function in intraGolgi transport.

  View details for Web of Science ID 000074605300002

  View details for PubMedID 9647643

• Protein interactions regulating vesicle transport between the endoplasmic reticulum and Golgi apparatus in mammalian cells CELL Hay, J. C., Chao, D. S., Kuo, C. S., Scheller, R. H. 1997; 89 (1): 149-158

  Abstract

  The proposed cis-Golgi vesicle receptor syntaxin 5 was found in a complex with Golgi-associated SNARE of 28 kDa (GOS-28), rbet1, rsly1, and two novel proteins characterized herein: rat sec22b and membrin, both cytoplasmically oriented integral membrane proteins. The complex appears to recapitulate vesicle docking interactions of proteins originating from distinct compartments, since syntaxin 5, rbet1, and GOS-28 localize to Golgi membranes, whereas mouse sec22b and membrin accumulate in the endoplasmic reticulum. Protein interactions in the complex are dramatically rearranged by N-ethylmaleimide-sensitive factor. The complex consists of two or more subcomplexes with some members (rat sec22b and syntaxin 5) in common and others (rbet1 and GOS-28) mutually exclusively associated. We propose that these protein interactions determine vesicle docking/fusion fidelity between the endoplasmic reticulum and Golgi.

  View details for Web of Science ID A1997WR68500018

  View details for PubMedID 9094723