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1. Cell types of origin of the cell-free transcriptome

Author

Jones, Robert C, Karkanias, Jim, Krasnow, Mark, Pisco, Angela Oliveira, Quake, Stephen R, Salzman, Julia, Yosef, Nir, Bulthaup, Bryan, Brown, Phillip, Harper, William, Hemenez, Marisa, Ponnusamy, Ravikumar, Salehi, Ahmad, Sanagavarapu, Bhavani A, Spallino, Eileen, Aaron, Ksenia A, Concepcion, Waldo, Gardner, James M, Kelly, Burnett, Neidlinger, Nikole, Wang, Zifa, Crasta, Sheela, Kolluru, Saroja, Morri, Maurizio, Tan, Serena Y, Travaglini, Kyle J, Xu, Chenling, Alcántara-Hernández, Marcela, Almanzar, Nicole, Antony, Jane, Beyersdorf, Benjamin, Burhan, Deviana, Calcuttawala, Kruti, Carter, Matthew M, Chan, Charles KF, Chang, Charles A, Chang, Stephen, Colville, Alex, Culver, Rebecca N, Cvijović, Ivana, D’Amato, Gaetano, Ezran, Camille, Galdos, Francisco X, Gillich, Astrid, Goodyer, William R, Hang, Yan, Hayashi, Alyssa, Houshdaran, Sahar, Huang, Xianxi, Irwin, Juan C, Jang, SoRi, Juanico, Julia Vallve, Kershner, Aaron M, Kim, Soochi, Kiss, Bernhard, Kong, William, Kumar, Maya E, Kuo, Angera H, Leylek, Rebecca, Li, Baoxiang, Loeb, Gabriel B, Lu, Wan-Jin, Mantri, Sruthi, Markovic, Maxim, McAlpine, Patrick L, de Morree, Antoine, Mrouj, Karim, Mukherjee, Shravani, Muser, Tyler, Neuhöfer, Patrick, Nguyen, Thi D, Perez, Kimberly, Phansalkar, Ragini, Puluca, Nazan, Qi, Zhen, Rao, Poorvi, Raquer-McKay, Hayley, Schaum, Nicholas, Scott, Bronwyn, Seddighzadeh, Bobak, Segal, Joe, Sen, Sushmita, Sikandar, Shaheen, Spencer, Sean P, Steffes, Lea, Subramaniam, Varun R, Swarup, Aditi, Swift, Michael, Van Treuren, Will, Trimm, Emily, Veizades, Stefan, Vijayakumar, Sivakamasundari, Vo, Kim Chi, Vorperian, Sevahn K, Wang, Wanxin, Weinstein, Hannah NW, Winkler, Juliane, Wu, Timothy TH, Xie, Jamie, and Yung, Andrea R

Subjects
Human Genome, Genetics, Cell-Free Nucleic Acids, Humans, Transcriptome, Tabula Sapiens Consortium
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.

Published
2022

2. The Tabula Sapiens: A multiple-organ, single-cell transcriptomic atlas of humans

Author

Jones, Robert C, Karkanias, Jim, Krasnow, Mark A, Pisco, Angela Oliveira, Quake, Stephen R, Salzman, Julia, Yosef, Nir, Bulthaup, Bryan, Brown, Phillip, Harper, William, Hemenez, Marisa, Ponnusamy, Ravikumar, Salehi, Ahmad, Sanagavarapu, Bhavani A, Spallino, Eileen, Aaron, Ksenia A, Concepcion, Waldo, Gardner, James M, Kelly, Burnett, Neidlinger, Nikole, Wang, Zifa, Crasta, Sheela, Kolluru, Saroja, Morri, Maurizio, Tan, Serena Y, Travaglini, Kyle J, Xu, Chenling, Alcántara-Hernández, Marcela, Almanzar, Nicole, Antony, Jane, Beyersdorf, Benjamin, Burhan, Deviana, Calcuttawala, Kruti, Carter, Matthew M, Chan, Charles KF, Chang, Charles A, Chang, Stephen, Colville, Alex, Culver, Rebecca N, Cvijović, Ivana, D'Amato, Gaetano, Ezran, Camille, Galdos, Francisco X, Gillich, Astrid, Goodyer, William R, Hang, Yan, Hayashi, Alyssa, Houshdaran, Sahar, Huang, Xianxi, Irwin, Juan C, Jang, SoRi, Juanico, Julia Vallve, Kershner, Aaron M, Kim, Soochi, Kiss, Bernhard, Kong, William, Kumar, Maya E, Kuo, Angera H, Li, Baoxiang, Loeb, Gabriel B, Lu, Wan-Jin, Mantri, Sruthi, Markovic, Maxim, McAlpine, Patrick L, de Morree, Antoine, Mrouj, Karim, Mukherjee, Shravani, Muser, Tyler, Neuhöfer, Patrick, Nguyen, Thi D, Perez, Kimberly, Puluca, Nazan, Qi, Zhen, Rao, Poorvi, Raquer-McKay, Hayley, Schaum, Nicholas, Scott, Bronwyn, Seddighzadeh, Bobak, Segal, Joe, Sen, Sushmita, Sikandar, Shaheen, Spencer, Sean P, Steffes, Lea C, Subramaniam, Varun R, Swarup, Aditi, Swift, Michael, Van Treuren, Will, Trimm, Emily, Veizades, Stefan, Vijayakumar, Sivakamasundari, Vo, Kim Chi, Vorperian, Sevahn K, Wang, Wanxin, Weinstein, Hannah NW, Winkler, Juliane, Wu, Timothy TH, Xie, Jamie, Yung, Andrea R, Zhang, Yue, and Detweiler, Angela M

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Human Genome, 2.1 Biological and endogenous factors, Generic health relevance, Atlases as Topic, B-Lymphocytes, Cells, Humans, Organ Specificity, RNA Splicing, Single-Cell Analysis, T-Lymphocytes, Transcriptome, Tabula Sapiens Consortium*, General Science & Technology
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.

Published
2022

3. Targeting acid ceramidase inhibits YAP/TAZ signaling to reduce fibrosis in mice

Author

Alsamman, Sarah, Christenson, Stephanie A, Yu, Amy, Ayad, Nadia ME, Mooring, Meghan S, Segal, Joe M, Hu, Jimmy Kuang-Hsien, Schaub, Johanna R, Ho, Steve S, Rao, Vikram, Marlow, Megan M, Turner, Scott M, Sedki, Mai, Pantano, Lorena, Ghoshal, Sarani, Ferreira, Diego Dos Santos, Ma, Hsiao-Yen, Duwaerts, Caroline C, Espanol-Suner, Regina, Wei, Lan, Newcomb, Benjamin, Mileva, Izolda, Canals, Daniel, Hannun, Yusuf A, Chung, Raymond T, Mattis, Aras N, Fuchs, Bryan C, Tager, Andrew M, Yimlamai, Dean, Weaver, Valerie M, Mullen, Alan C, Sheppard, Dean, and Chen, Jennifer Y

Subjects
Medical Biotechnology, Biomedical and Clinical Sciences, 2.1 Biological and endogenous factors, Acid Ceramidase, Adaptor Proteins, Signal Transducing, Animals, Fibrosis, Hepatic Stellate Cells, Humans, Mice, Signal Transduction, Biological Sciences, Medical and Health Sciences, Medical biotechnology, Biomedical engineering
Abstract

Hepatic stellate cells (HSCs) drive hepatic fibrosis. Therapies that inactivate HSCs have clinical potential as antifibrotic agents. We previously identified acid ceramidase (aCDase) as an antifibrotic target. We showed that tricyclic antidepressants (TCAs) reduce hepatic fibrosis by inhibiting aCDase and increasing the bioactive sphingolipid ceramide. We now demonstrate that targeting aCDase inhibits YAP/TAZ activity by potentiating its phosphorylation-mediated proteasomal degradation via the ubiquitin ligase adaptor protein β-TrCP. In mouse models of fibrosis, pharmacologic inhibition of aCDase or genetic knockout of aCDase in HSCs reduces fibrosis, stromal stiffness, and YAP/TAZ activity. In patients with advanced fibrosis, aCDase expression in HSCs is increased. Consistently, a signature of the genes most down-regulated by ceramide identifies patients with advanced fibrosis who could benefit from aCDase targeting. The findings implicate ceramide as a critical regulator of YAP/TAZ signaling and HSC activation and highlight aCDase as a therapeutic target for the treatment of fibrosis.

Published
2020

4. A single-cell transcriptomic atlas characterizes ageing tissues in the mouse

Author

Almanzar, Nicole, Antony, Jane, Baghel, Ankit S, Bakerman, Isaac, Bansal, Ishita, Barres, Ben A, Beachy, Philip A, Berdnik, Daniela, Bilen, Biter, Brownfield, Douglas, Cain, Corey, Chan, Charles KF, Chen, Michelle B, Clarke, Michael F, Conley, Stephanie D, Darmanis, Spyros, Demers, Aaron, Demir, Kubilay, de Morree, Antoine, Divita, Tessa, du Bois, Haley, Ebadi, Hamid, Espinoza, F Hernán, Fish, Matt, Gan, Qiang, George, Benson M, Gillich, Astrid, Gòmez-Sjöberg, Rafael, Green, Foad, Genetiano, Geraldine, Gu, Xueying, Gulati, Gunsagar S, Hahn, Oliver, Haney, Michael Seamus, Hang, Yan, Harris, Lincoln, He, Mu, Hosseinzadeh, Shayan, Huang, Albin, Huang, Kerwyn Casey, Iram, Tal, Isobe, Taichi, Ives, Feather, Jones, Robert C, Kao, Kevin S, Karkanias, Jim, Karnam, Guruswamy, Keller, Andreas, Kershner, Aaron M, Khoury, Nathalie, Kim, Seung K, Kiss, Bernhard M, Kong, William, Krasnow, Mark A, Kumar, Maya E, Kuo, Christin S, Lam, Jonathan, Lee, Davis P, Lee, Song E, Lehallier, Benoit, Leventhal, Olivia, Li, Guang, Li, Qingyun, Liu, Ling, Lo, Annie, Lu, Wan-Jin, Lugo-Fagundo, Maria F, Manjunath, Anoop, May, Andrew P, Maynard, Ashley, McGeever, Aaron, McKay, Marina, McNerney, M Windy, Merrill, Bryan, Metzger, Ross J, Mignardi, Marco, Min, Dullei, Nabhan, Ahmad N, Neff, Norma F, Ng, Katharine M, Nguyen, Patricia K, Noh, Joseph, Nusse, Roel, Pálovics, Róbert, Patkar, Rasika, Peng, Weng Chuan, Penland, Lolita, Pisco, Angela Oliveira, Pollard, Katherine, Puccinelli, Robert, Qi, Zhen, Quake, Stephen R, Rando, Thomas A, Rulifson, Eric J, Schaum, Nicholas, Segal, Joe M, Sikandar, Shaheen S, Sinha, Rahul, Sit, Rene V, and Sonnenburg, Justin

Subjects
Biochemistry and Cell Biology, Biological Sciences, Human Genome, Genetics, Aging, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Generic health relevance, Animals, Cellular Senescence, DNA Mutational Analysis, Female, Gene Expression Regulation, Developmental, Genomic Instability, Immunity, Liver, Male, Mice, Models, Animal, Organ Specificity, Single-Cell Analysis, T-Lymphocytes, Transcriptome, Tabula Muris Consortium, General Science & Technology
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.

Published
2020

5. The role of E-cadherin in regulating embryonic stem cell pluripotent states

Author

Segal, Joe, Ward, Christopher, and Bobola, Nicoletta

Subjects
616.02, embryonic stem cells, E-cadherin, naive pluripotency, primed pluripotency, EP300, NCOA3, ESRRB
Abstract

The Ward group have previously demonstrated that E-cadherin regulates the naïve pluripotent state of mouse Embryonic Stem (mES) cells via activation of the LIF/STAT3 pathway. Loss of E-cadherin in mES cells leads to a 'primed' pluripotent phenotype characterized by LIF-independent self-renewal through ACTIVIN/NODAL signalling, similar to mouse Epiblast Stem (EpiS) and human (h)ES cells. However, the exact mechanism of E-cadherin's regulation of pluripotency in both mouse and human ES cells has remained elusive. In this study we describe a novel network modelling approach of transcriptomic analysis using gene expression changes shared between three independently derived E-cadherin negative cell lines (collectively termed ESDeltaEcad cells). Our models predicted regulation of pluripotency pathways via the co-activator protein EP300. We show that E-cadherin regulates the cell localisation and binding of EP300 to NANOG-OCT4-SOX2 DNA clusters. EP300 also functions to phosphorylate SMAD2 in the absence of E-cadherin and to inhibit pluripotency-associated transcripts in Ecad-/- mES cells. Using comparative network analysis of E-cadherin antagonism in mouse and human transcriptomes we have identified that E-cadherin plays a major role in regulating the transcriptional circuitry between naive and primed ES cell states. We show that this is likely to be mediated at least partly by positive activation of NCOA3 and ESRRB. Differential transcript expression in Ecad-/- mES cells correlates with loss of ESRRB protein expression and altered cellular localisation of NCOA3, both regulators of naive pluripotency. We have gone on to show through peptide antagonism that while E-cadherin is an important upstream regulator of genes critical in defining the naïve pluripotent state, this action is not necessarily dependent on the loss of cell-cell contact associated with E-cadherin inhibition. We present the first data that E-cadherin regulates naïve mES cell pluripotency by regulation of EP300, ESRRB and NCOA3 activity. Furthermore we have shown E-cadherin to inhibit the naïve transcriptional phenotype in hES cells. Peptides that target E-cadherin also provide a valuable tool for controlling the transition between naive and pluripotent states in mouse and human ES cells.

Published
2016

9. Single cell analysis of human foetal liver captures the transcriptional profile of hepatobiliary hybrid progenitors

Author

Segal, Joe M., Kent, Deniz, Wesche, Daniel J., Ng, Soon Seng, Serra, Maria, Oulès, Bénédicte, Kar, Gozde, Emerton, Guy, Blackford, Samuel J. I., Darmanis, Spyros, Miquel, Rosa, Luong, Tu Vinh, Yamamoto, Ryo, Bonham, Andrew, Jassem, Wayel, Heaton, Nigel, Vigilante, Alessandra, King, Aileen, Sancho, Rocio, Teichmann, Sarah, Quake, Stephen R., Nakauchi, Hiromitsu, and Rashid, S. Tamir

Published
2019
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10. Molecular hallmarks of heterochronic parabiosis at single-cell resolution

Author

Pálovics, Róbert, Keller, Andreas, Schaum, Nicholas, Tan, Weilun, Fehlmann, Tobias, Borja, Michael, Kern, Fabian, Bonanno, Liana, Calcuttawala, Kruti, Webber, James, McGeever, Aaron, Almanzar, Nicole, Antony, Jane, Baghel, Ankit S., Bakerman, Isaac, Bansal, Ishita, Barres, Ben A., Beachy, Philip A., Berdnik, Daniela, Bilen, Biter, Brownfield, Douglas, Cain, Corey, Chan, Charles K. F., Chen, Michelle B., Clarke, Michael F., Conley, Stephanie D., Demers, Aaron, Demir, Kubilay, de Morree, Antoine, Divita, Tessa, du Bois, Haley, Ebadi, Hamid, Espinoza, F. Hernán, Fish, Matt, Gan, Qiang, George, Benson M., Gillich, Astrid, Gòmez-Sjöberg, Rafael, Green, Foad, Genetiano, Geraldine, Gu, Xueying, Gulati, Gunsagar S., Hahn, Oliver, Haney, Michael Seamus, Hang, Yan, Harris, Lincoln, He, Mu, Hosseinzadeh, Shayan, Huang, Albin, Huang, Kerwyn Casey, Iram, Tal, Isobe, Taichi, Ives, Feather, Jones, Robert C., Kao, Kevin S., Karnam, Guruswamy, Kershner, Aaron M., Khoury, Nathalie, Kim, Seung K., Kiss, Bernhard M., Kong, William, Krasnow, Mark A., Kumar, Maya E., Kuo, Christin S., Lam, Jonathan, Lee, Davis P., Lee, Song E., Lehallier, Benoit, Leventhal, Olivia, Li, Guang, Li, Qingyun, Liu, Ling, Lo, Annie, Lu, Wan-Jin, Lugo-Fagundo, Maria F., Manjunath, Anoop, May, Andrew P., Maynard, Ashley, McKay, Marina, McNerney, M. Windy, Merrill, Bryan, Metzger, Ross J., Mignardi, Marco, Min, Dullei, Nabhan, Ahmad N., Ng, Katharine M., Nguyen, Patricia K., Noh, Joseph, Nusse, Roel, Patkar, Rasika, Peng, Weng Chuan, Penland, Lolita, Pollard, Katherine, Puccinelli, Robert, Qi, Zhen, Rando, Thomas A., Rulifson, Eric J., Segal, Joe M., Sikandar, Shaheen S., Sinha, Rahul, Sit, Rene V., Sonnenburg, Justin, Staehli, Daniel, Szade, Krzysztof, Tan, Michelle, Tato, Cristina, Tellez, Krissie, Torrez Dulgeroff, Laughing Bear, Travaglini, Kyle J., Tropini, Carolina, Tsui, Margaret, Waldburger, Lucas, Wang, Bruce M., van Weele, Linda J., Weinberg, Kenneth, Weissman, Irving L., Wosczyna, Michael N., Wu, Sean M., Xiang, Jinyi, Xue, Soso, Yamauchi, Kevin A., Yang, Andrew C., Yerra, Lakshmi P., Youngyunpipatkul, Justin, Yu, Brian, Zanini, Fabio, Zardeneta, Macy E., Zee, Alexander, Zhao, Chunyu, Zhang, Fan, Zhang, Hui, Zhang, Martin Jinye, Zhou, Lu, Zou, James, Luo, Jian, Pisco, Angela Oliveira, Karkanias, Jim, Neff, Norma F., Darmanis, Spyros, Quake, Stephen R., and Wyss-Coray, Tony

Subjects
Aging, Multidisciplinary, Parabiosis, Mesenchymal Stem Cells, Hematopoietic Stem Cells, Article, Organ Specificity/genetics, Mitochondria, Electron Transport, Electron Transport/genetics, Organ Specificity, Aging/genetics, Adipocytes, Hepatocytes, Rejuvenation, RNA-Seq, Single-Cell Analysis
Abstract

The ability to slow or reverse biological ageing would have major implications for mitigating disease risk and maintaining vitality1. Although an increasing number of interventions show promise for rejuvenation2, their effectiveness on disparate cell types across the body and the molecular pathways susceptible to rejuvenation remain largely unexplored. Here we performed single-cell RNA sequencing on 20 organs to reveal cell-type-specific responses to young and aged blood in heterochronic parabiosis. Adipose mesenchymal stromal cells, haematopoietic stem cells and hepatocytes are among those cell types that are especially responsive. On the pathway level, young blood invokes new gene sets in addition to reversing established ageing patterns, with the global rescue of genes encoding electron transport chain subunits pinpointing a prominent role of mitochondrial function in parabiosis-mediated rejuvenation. We observed an almost universal loss of gene expression with age that is largely mimicked by parabiosis: aged blood reduces global gene expression, and young blood restores it in select cell types. Together, these data lay the groundwork for a systemic understanding of the interplay between blood-borne factors and cellular integrity.

Published
2022
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11. The Tabula Sapiens: A multiple-organ, single-cell transcriptomic atlas of humans

Author

Tabula Sapiens Consortium, Jones, Robert C, Karkanias, Jim, Krasnow, Mark A, Pisco, Angela Oliveira, Quake, Stephen R, Salzman, Julia, Yosef, Nir, Bulthaup, Bryan, Brown, Phillip, Harper, William, Hemenez, Marisa, Ponnusamy, Ravikumar, Salehi, Ahmad, Sanagavarapu, Bhavani A, Spallino, Eileen, Aaron, Ksenia A, Concepcion, Waldo, Gardner, James M, Kelly, Burnett, Neidlinger, Nikole, Wang, Zifa, Crasta, Sheela, Kolluru, Saroja, Morri, Maurizio, Tan, Serena Y, Travaglini, Kyle J, Xu, Chenling, Alcántara-Hernández, Marcela, Almanzar, Nicole, Antony, Jane, Beyersdorf, Benjamin, Burhan, Deviana, Calcuttawala, Kruti, Carter, Matthew M, Chan, Charles KF, Chang, Charles A, Chang, Stephen, Colville, Alex, Culver, Rebecca N, Cvijović, Ivana, D'Amato, Gaetano, Ezran, Camille, Galdos, Francisco X, Gillich, Astrid, Goodyer, William R, Hang, Yan, Hayashi, Alyssa, Houshdaran, Sahar, Huang, Xianxi, Irwin, Juan C, Jang, SoRi, Juanico, Julia Vallve, Kershner, Aaron M, Kim, Soochi, Kiss, Bernhard, Kong, William, Kumar, Maya E, Kuo, Angera H, Leylek, Rebecca, Li, Baoxiang, Loeb, Gabriel B, Lu, Wan-Jin, Mantri, Sruthi, Markovic, Maxim, McAlpine, Patrick L, de Morree, Antoine, Mrouj, Karim, Mukherjee, Shravani, Muser, Tyler, Neuhöfer, Patrick, Nguyen, Thi D, Perez, Kimberly, Phansalkar, Ragini, Puluca, Nazan, Qi, Zhen, Rao, Poorvi, Raquer-McKay, Hayley, Schaum, Nicholas, Scott, Bronwyn, Seddighzadeh, Bobak, Segal, Joe, Sen, Sushmita, Sikandar, Shaheen, Spencer, Sean P, Steffes, Lea C, Subramaniam, Varun R, Swarup, Aditi, Swift, Michael, Van Treuren, Will, Trimm, Emily, Veizades, Stefan, Vijayakumar, Sivakamasundari, and Vo, Kim Chi

Subjects
B-Lymphocytes, General Science & Technology, Cells, T-Lymphocytes, RNA Splicing, Human Genome, Tabula Sapiens Consortium, Atlases as Topic, Organ Specificity, Genetics, Humans, Generic health relevance, Single-Cell Analysis, Transcriptome, Biotechnology
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.

Published
2022

12. The Tabula Sapiens: A multiple-organ, single-cell transcriptomic atlas of humans.

Author

Tabula Sapiens Consortium*, Tabula Sapiens Consortium*, Jones, Robert C, Karkanias, Jim, Krasnow, Mark A, Pisco, Angela Oliveira, Quake, Stephen R, Salzman, Julia, Yosef, Nir, Bulthaup, Bryan, Brown, Phillip, Harper, William, Hemenez, Marisa, Ponnusamy, Ravikumar, Salehi, Ahmad, Sanagavarapu, Bhavani A, Spallino, Eileen, Aaron, Ksenia A, Concepcion, Waldo, Gardner, James M, Kelly, Burnett, Neidlinger, Nikole, Wang, Zifa, Crasta, Sheela, Kolluru, Saroja, Morri, Maurizio, Tan, Serena Y, Travaglini, Kyle J, Xu, Chenling, Alcántara-Hernández, Marcela, Almanzar, Nicole, Antony, Jane, Beyersdorf, Benjamin, Burhan, Deviana, Calcuttawala, Kruti, Carter, Matthew M, Chan, Charles KF, Chang, Charles A, Chang, Stephen, Colville, Alex, Culver, Rebecca N, Cvijović, Ivana, D'Amato, Gaetano, Ezran, Camille, Galdos, Francisco X, Gillich, Astrid, Goodyer, William R, Hang, Yan, Hayashi, Alyssa, Houshdaran, Sahar, Huang, Xianxi, Irwin, Juan C, Jang, SoRi, Juanico, Julia Vallve, Kershner, Aaron M, Kim, Soochi, Kiss, Bernhard, Kong, William, Kumar, Maya E, Kuo, Angera H, Leylek, Rebecca, Li, Baoxiang, Loeb, Gabriel B, Lu, Wan-Jin, Mantri, Sruthi, Markovic, Maxim, McAlpine, Patrick L, de Morree, Antoine, Mrouj, Karim, Mukherjee, Shravani, Muser, Tyler, Neuhöfer, Patrick, Nguyen, Thi D, Perez, Kimberly, Phansalkar, Ragini, Puluca, Nazan, Qi, Zhen, Rao, Poorvi, Raquer-McKay, Hayley, Schaum, Nicholas, Scott, Bronwyn, Seddighzadeh, Bobak, Segal, Joe, Sen, Sushmita, Sikandar, Shaheen, Spencer, Sean P, Steffes, Lea C, Subramaniam, Varun R, Swarup, Aditi, Swift, Michael, Van Treuren, Will, Trimm, Emily, Veizades, Stefan, Vijayakumar, Sivakamasundari, Vo, Kim Chi, Tabula Sapiens Consortium*, Tabula Sapiens Consortium*, Jones, Robert C, Karkanias, Jim, Krasnow, Mark A, Pisco, Angela Oliveira, Quake, Stephen R, Salzman, Julia, Yosef, Nir, Bulthaup, Bryan, Brown, Phillip, Harper, William, Hemenez, Marisa, Ponnusamy, Ravikumar, Salehi, Ahmad, Sanagavarapu, Bhavani A, Spallino, Eileen, Aaron, Ksenia A, Concepcion, Waldo, Gardner, James M, Kelly, Burnett, Neidlinger, Nikole, Wang, Zifa, Crasta, Sheela, Kolluru, Saroja, Morri, Maurizio, Tan, Serena Y, Travaglini, Kyle J, Xu, Chenling, Alcántara-Hernández, Marcela, Almanzar, Nicole, Antony, Jane, Beyersdorf, Benjamin, Burhan, Deviana, Calcuttawala, Kruti, Carter, Matthew M, Chan, Charles KF, Chang, Charles A, Chang, Stephen, Colville, Alex, Culver, Rebecca N, Cvijović, Ivana, D'Amato, Gaetano, Ezran, Camille, Galdos, Francisco X, Gillich, Astrid, Goodyer, William R, Hang, Yan, Hayashi, Alyssa, Houshdaran, Sahar, Huang, Xianxi, Irwin, Juan C, Jang, SoRi, Juanico, Julia Vallve, Kershner, Aaron M, Kim, Soochi, Kiss, Bernhard, Kong, William, Kumar, Maya E, Kuo, Angera H, Leylek, Rebecca, Li, Baoxiang, Loeb, Gabriel B, Lu, Wan-Jin, Mantri, Sruthi, Markovic, Maxim, McAlpine, Patrick L, de Morree, Antoine, Mrouj, Karim, Mukherjee, Shravani, Muser, Tyler, Neuhöfer, Patrick, Nguyen, Thi D, Perez, Kimberly, Phansalkar, Ragini, Puluca, Nazan, Qi, Zhen, Rao, Poorvi, Raquer-McKay, Hayley, Schaum, Nicholas, Scott, Bronwyn, Seddighzadeh, Bobak, Segal, Joe, Sen, Sushmita, Sikandar, Shaheen, Spencer, Sean P, Steffes, Lea C, Subramaniam, Varun R, Swarup, Aditi, Swift, Michael, Van Treuren, Will, Trimm, Emily, Veizades, Stefan, Vijayakumar, Sivakamasundari, and Vo, Kim Chi

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.

Published
2022

13. Small molecule screen employing patient-derived iPSC hepatocytes identifies LRRK2 as a novel therapeutic target for Alpha1 Antitrypsin Deficiency

Author

Kent, Deniz, primary, Ng, Soon Seng, additional, Khoshkenar, Payam, additional, Syanda, Adam, additional, Li, Chao Zheng, additional, Zieger, Marina, additional, Hatch, Stephanie, additional, Segal, Joe, additional, Blackford, Samuel, additional, Le, Kaixing, additional, Chowdary, Vivek, additional, Ismaili, Taylor, additional, Danovi, Davide, additional, Lewis, Patrick, additional, Sahdeo, Sunil, additional, Ebner, Daniel, additional, Mueller, Christian, additional, and Rashid, S. Tamir, additional

Published
2022
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14. Small molecule screen employing patient-derived iPS hepatocytes identifies LRRK2 as a novel therapeutic target for Alpha1 Antitrypsin Deficiency

Author

Kent, Deniz, primary, Ng, Soon Seng, additional, Khoshkenar, Payam, additional, Syanda, Adam M., additional, Chao Zheng, Li, additional, Zieger, Marina, additional, Greer, Cindy, additional, Hatch, Stephanie B, additional, Segal, Joe M, additional, Blackford, Samuel J.I., additional, Chowdary, Vivek, additional, Ismali, Taylor, additional, Danovi, Davide, additional, Sahdeo, Sunil, additional, Ebner, Daniel, additional, Mueller, Christian, additional, and Rashid, S. Tamir, additional

Published
2021
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15. Differential Expression of Insulin-Like Growth Factor 1 and Wnt Family Member 4 Correlates With Functional Heterogeneity of Human Dermal Fibroblasts

Author

Culley, Oliver J., primary, Louis, Blaise, additional, Philippeos, Christina, additional, Oulès, Bénédicte, additional, Tihy, Matthieu, additional, Segal, Joe M., additional, Hyliands, Della, additional, Jenkins, Gail, additional, Bhogal, Ranjit K., additional, Siow, Richard C., additional, and Watt, Fiona M., additional

Published
2021
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16. Ageing hallmarks exhibit organ-specific temporal signatures

Author

Schaum, Nicholas, Lehallier, Benoit, Hahn, Oliver, Pálovics, Róbert, Hosseinzadeh, Shayan, Lee, Song E., Sit, Rene, Lee, Davis P., Losada, Patricia Morán, Zardeneta, Macy E., Fehlmann, Tobias, Webber, James T., McGeever, Aaron, Calcuttawala, Kruti, Zhang, Hui, Berdnik, Daniela, Mathur, Vidhu, Tan, Weilun, Zee, Alexander, Tan, Michelle, Almanzar, Nicole, Antony, Jane, Baghel, Ankit S., Bakerman, Isaac, Bansal, Ishita, Barres, Ben A., Beachy, Philip A., Bilen, Biter, Brownfield, Douglas, Cain, Corey, Chan, Charles K. F., Chen, Michelle B., Clarke, Michael F., Conley, Stephanie D., Darmanis, Spyros, Demers, Aaron, Demir, Kubilay, de Morree, Antoine, Divita, Tessa, du Bois, Haley, Ebadi, Hamid, Espinoza, F. Hernán, Fish, Matt, Gan, Qiang, George, Benson M., Gillich, Astrid, Gòmez-Sjöberg, Rafael, Green, Foad, Genetiano, Geraldine, Gu, Xueying, Gulati, Gunsagar S., Haney, Michael Seamus, Hang, Yan, Harris, Lincoln, He, Mu, Huang, Albin, Huang, Kerwyn Casey, Iram, Tal, Isobe, Taichi, Ives, Feather, Jones, Robert, Kao, Kevin S., Karkanias, Jim, Karnam, Guruswamy, Keller, Andreas, Kershner, Aaron M., Khoury, Nathalie, Kim, Seung K., Kiss, Bernhard M., Kong, William, Krasnow, Mark A., Kumar, Maya E., Kuo, Christin S., Lam, Jonathan Y., Leventhal, Olivia, Li, Guang, Li, Qingyun, Liu, Ling, Lo, Annie, Lu, Wan-Jin, Lugo-Fagundo, Maria F., Manjunath, Anoop, May, Andrew P., Maynard, Ashley, McKay, Marina, McNerney, M. Windy, Merrill, Bryan, Metzger, Ross J., Mignardi, Marco, Min, Dullei, Nabhan, Ahmad N., Neff, Norma F., Ng, Katharine M., Nguyen, Patricia K., Noh, Joseph, Nusse, Roel, Patkar, Rasika, Peng, Weng Chuan, Penland, Lolita, Pisco, Angela Oliveira, Pollard, Katherine, Puccinelli, Robert, Qi, Zhen, Quake, Stephen R., Rando, Thomas A., Rulifson, Eric J., Segal, Joe M., Sikandar, Shaheen S., Sinha, Rahul, Sonnenburg, Justin, Staehli, Daniel, Szade, Krzysztof, Tato, Cristina, Tellez, Krissie, Torrez Dulgeroff, Laughing Bear, Travaglini, Kyle J., Tropini, Carolina, Tsui, Margaret, Waldburger, Lucas, Wang, Bruce M., van Weele, Linda J., Weinberg, Kenneth, Weissman, Irving L., Wosczyna, Michael N., Wu, Sean M., Wyss-Coray, Tony, Xiang, Jinyi, Xue, Soso, Yamauchi, Kevin A., Yang, Andrew C., Yerra, Lakshmi P., Youngyunpipatkul, Justin, Yu, Brian, Zanini, Fabio, Zhao, Chunyu, Zhang, Fan, Zhang, Martin Jinye, Zhou, Lu, and Zou, James

Subjects
0301 basic medicine, Male, Aging, Time Factors, T-Lymphocytes, Plasma Cells, RNA-Seq, Biology, Article, Transcriptome, 03 medical and health sciences, Mice, 0302 clinical medicine, Gene expression, Animals, RNA, Messenger, Gene, Regulation of gene expression, Multidisciplinary, Blood Proteins, Cell biology, 030104 developmental biology, Proteostasis, Gene Expression Regulation, Ageing, Organ Specificity, Immunoglobulin J-Chains, Unfolded protein binding, Female, Single-Cell Analysis, 030217 neurology & neurosurgery
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. Bulk RNA sequencing of organs and plasma proteomics at different ages across the mouse lifespan is integrated with data from the Tabula Muris Senis, a transcriptomic atlas of ageing mouse tissues, to describe organ-specific changes in gene expression during ageing.

Published
2020

17. Validation of Current Good Manufacturing Practice Compliant Human Pluripotent Stem Cell-Derived Hepatocytes for Cell-Based Therapy

Author

Blackford, Samuel John Irwin, Ng, Soon Seng, Segal, Joe Monty, King, Aileen, Austin, Amazon Libby Filou, Kent, Deniz Haluk, Moore, Jennifer, Sheldon, Michael, Ilic, Dusko, Dhawan, Anil, Mitry, Ragai, and Rashid, Sheikh Tamir

Subjects
cGMP, iPSC, Pluripotent stem cells, hESC, Liver therapy, Cellular therapy, Hepatocytes, Bioengineering, Hepatocyte differentiation, Cell transplantation
Abstract

Recent advancements in the production of hepatocytes from human pluripotent stem cells (hPSC-Heps) afford tremendous possibilities for treatment of patients with liver disease. Validated current good manufacturing practice (cGMP) lines are an essential prerequisite for such applications but have only recently been established. Whether such cGMP lines are capable of hepatic differentiation is not known. To address this knowledge gap, we examined the proficiency of three recently derived cGMP lines (two hiPSC and one hESC) to differentiate into hepatocytes and their suitability for therapy. hPSC-Heps generated using a chemically defined four-step hepatic differentiation protocol uniformly demonstrated highly reproducible phenotypes and functionality. Seeding into a 3D poly(ethylene glycol)-diacrylate fabricated inverted colloid crystal scaffold converted these immature progenitors into more advanced hepatic tissue structures. Hepatic constructs could also be successfully encapsulated into the immune-privileged material alginate and remained viable as well as functional upon transplantation into immune competent mice. This is the first report we are aware of demonstrating cGMP-compliant hPSCs can generate cells with advanced hepatic function potentially suitable for future therapeutic applications. Stem Cells Translational Medicine 2018.

Published
2019
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18. Imaging-Based Screen Identifies Laminin 411 as a Physiologically Relevant Niche Factor with Importance for i-Hep Applications

Author

Ong, John, Serra, Maria Paola, Segal, Joe, Cujba, Ana-Maria, Ng, Soon Seng, Butler, Richard, Millar, Val, Hatch, Stephanie, Zimri, Salman, Koike, Hiroyuki, Chan, Karen, Bonham, Andrew, Walk, Michelle, Voss, Ty, Heaton, Nigel, Mitry, Ragai, Dhawan, Anil, Ebner, Daniel, Danovi, Davide, Nakauchi, Hiromitsu, and Rashid, S. Tamir

Published
2018
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19. Loss of GATA6 contributes to acne pathogenesis in human skin.

Author

Oules, Benedicte, primary, Philippeos, Christina, primary, Segal, Joe, primary, Tihy, Matthieu, primary, A. Grange, Philippe, primary, Deschamps, Lydia, primary, Quist, Sven, primary, Natsuga, Ken, primary, Dupin, Nicolas, primary, Donati, Giacomo, primary, and Watt, Fiona, primary

Published
2019
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20. FRI-048-Faecal calprotectin in PSC-IBD is a prognostic marker of cholangitis associated complications

Author

Pavlidis, Polychronis, primary, El-Sherif, Yasser, additional, Warner, Ben, additional, Gulati, Shraddha, additional, Sarras, Konstantinos, additional, Alberts, Ellie, additional, Segal, Joe, additional, Rashid, Tamir, additional, Harrison, Phil, additional, Devlin, John, additional, Emlyn, Gwion, additional, Arqoub, Hadil Abu, additional, Dubois, Patrick, additional, Sanchez-Fueyo, Alberto, additional, Heneghan, Michael, additional, Joshi, Deepak, additional, Powell, Nick, additional, and Hayee, Bu, additional

Published
2019
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22. Validation of Current Good Manufacturing Practice Compliant Human Pluripotent Stem Cell-Derived Hepatocytes for Cell-Based Therapy

Author

Blackford, Samuel J.I., primary, Ng, Soon Seng, additional, Segal, Joe M., additional, King, Aileen J.F., additional, Austin, Amazon L., additional, Kent, Deniz, additional, Moore, Jennifer, additional, Sheldon, Michael, additional, Ilic, Dusko, additional, Dhawan, Anil, additional, Mitry, Ragai R., additional, and Rashid, S. Tamir, additional

Published
2018
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23. ADTU-04 Faecal calprotectin in PSC-IBD: a novel marker of cholangitis

Author

Pavlidis, Polychronis, primary, El-Sherif, Yasser, additional, Warner, Ben, additional, Gulati, Shraddha, additional, Sarras, Konstantinos, additional, Alberts, Ellie, additional, Segal, Joe, additional, Rashid, Tamir, additional, Harrison, Phil, additional, Devlin, John, additional, Heneghan, Michael, additional, Fueyo, Alberto, additional, Emlyn, Gwion, additional, Arqoub, Hadil Abu, additional, Dubois, Patrick, additional, Joshi, Deepak, additional, Powell, Nick, additional, and Hayee, Bu’, additional

Published
2018
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25. Conversion of iPS derived hepatic progenitors into scalable, functional and developmentally relevant human organoids using an inverted colloidal crystal poly (ethylene glycol) scaffold engineered from collagen-coated pores of defined size

Author

Seng Ng, Soon, primary, Saeb-Parsy, Kourosh, additional, Segal, Joe M, additional, Serra, Maria Paola, additional, Blackford, Samuel J I, additional, Lopez, Marta Horcas, additional, No, Da Yoon, additional, Frank, Curtis W, additional, Cho, Nam Joon, additional, Nakauchi, Hiromitsu, additional, Glenn, Jeffrey S, additional, and Rashid, S Tamir, additional

Published
2018
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26. Single-cell analysis identifies EpCAM+/CDH6+/TROP-2−cells as human liver progenitors

Author

Segal, Joe M, primary, Wesche, Daniel J, additional, Serra, Maria Paola, additional, Oulès, Bénédicte, additional, Kent, Deniz, additional, Ng, Soon Seng, additional, Kar, Gozde, additional, Emerton, Guy, additional, Blackford, Samuel J I, additional, Darmanis, Spyros, additional, Miquel, Rosa, additional, Vinh, Tu, additional, Yamamoto, Ryo, additional, Bonham, Andrew, additional, Vigilante, Alessandra, additional, Teichmann, Sarah, additional, Quake, Stephen R., additional, Nakauchi, Hiromitsu, additional, and Rashid, S Tamir, additional

Published
2018
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27. Loss of GATA6 contributes to acne pathogenesis in human skin.

Author

Segal, Joe

Abstract

Although acne vulgaris is the most common human inflammatory skin disease, its pathogenic mechanisms remain incompletely understood. Here we show that GATA6, which is expressed in the upper pilosebaceous unit of normal human skin, is down- regulated in acne. GATA6 controls keratinocyte proliferation and differentiation to prevent hyperkeratinisation of the epidermal infundibulum, which is the primary pathological event in acne. When overexpressed in immortalised human sebocytes, GATA6 triggers a junctional zone and sebaceous differentiation program whilst limiting lipid production and cell proliferation. It modulates the immunological repertoire of sebocytes, upregulating PDL-1 and IL10, and controlling their ability to respond to Cutibacterium acnes. GATA6 expression contributes to the therapeutic effect of retinoic acid, the main treatment for acne. In a human sebaceous organoid model GATA6-mediated down-regulation of the infundibular differentiation program is mediated by induction of TGFb signalling. We conclude that GATA6 is a key regulator of homeostasis in the upper pilosebaceous unit and an actionable target in the treatment of acne.

Published
2017

33. Index

Author

Scott-Smith, Giles, Romijn, Peter, and Segal, Joes

Published
2012

35. About the Authors

Author

Scott-Smith, Giles, Romijn, Peter, and Segal, Joes

Published
2012

45. Preface

Author

Scott-Smith, Giles, Romijn, Peter, and Segal, Joes

Published
2012

48. Contents

Author

Scott-Smith, Giles, Romijn, Peter, and Segal, Joes

Published
2012

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