Bio


Dr. David Paik is an instructor at the Stanford Cardiovascular Institute. At Stanford, his focus is to utilize single-cell omics to elucidate patient-specific mechanisms of various cardiovascular diseases, characterize embryonic heart development, and optimize differentiation of iPSCs to subtypes of cardiovascular cells. Dr. Paik received his BA in Biochemistry and Molecular Biology at Boston University (2010) and PhD in Cell and Developmental Biology at Vanderbilt University (2015). During his PhD training, Dr. Paik investigated the endogenous cardiac repair mechanisms in the adult heart following ischemic injury such as myocardial infarction, with focus on the role of Wnt signaling pathway on coronary vessel formation and plasticity of endothelial cells during cardiac tissue repair. At this time Dr. Paik completed HHMI/VUMC Certificate Program in Molecular Medicine, where he was supervised by his clinical mentor Dr. Douglas Sawyer to interact with congestive heart failure patients and to bridge clinical sciences with basic and translational cardiovascular research. Since 2016 he has been mentored by Dr. Joseph Wu at the Stanford Cardiovascular Institute. Dr. Paik is currently supported by the NIH NHLBI K99/R00 Pathway to Independence Award.

Honors & Awards


  • Career Development Award, American Heart Association (2022-)
  • K99/R00 Pathway to Independence Award, NIH NHLBI (02/2020-01/2025)
  • Early Career Blogger, American Heart Association (2019-2020)
  • CVI Manuscript Award, Stanford Cardiovascular Institute (05/2019)
  • Best Manuscript Award, Editorial Board of Circulation Research (11/2018)
  • Travel Award, Stanford Cardiovascular Institute (12/2017)
  • T32 Postdoctoral Fellowship, NIH NIBIB (11/2016-10/2018)
  • T32 Predoctoral Fellowship, NIH NHLBI (07/2013-06/2015)
  • Certificate Program in Molecular Medicine, Vanderbilt University (2015)
  • Mark W. Riemen Research Prize, Boston University (2009)

All Publications


  • Adverse effects of air pollution-derived fine particulate matter on cardiovascular homeostasis and disease. Trends in cardiovascular medicine Bae, H. R., Chandy, M., Aguilera, J., Smith, E. M., Nadeau, K. C., Wu, J. C., Paik, D. T. 2021

    Abstract

    Air pollution is a rapidly growing major health concern around the world. Atmospheric particulate matter that has a diameter of less than 2.5 m (PM2.5) refers to an air pollutant composed of particles and chemical compounds that originate from various sources. While epidemiological studies have established the association between PM2.5 exposure and cardiovascular diseases, the precise cellular and molecular mechanisms by which PM2.5 promotes cardiovascular complications are yet to be fully elucidated. In this review, we summarize the various sources of PM2.5, its components, and the concentrations of ambient PM2.5 in various settings. We discuss the experimental findings to date that evaluate the potential adverse effects of PM2.5 on cardiovascular homeostasis and function, and the possible therapeutic options that may alleviate PM2.5-driven cardiovascular damage.

    View details for DOI 10.1016/j.tcm.2021.09.010

    View details for PubMedID 34619335

  • Endocardial/endothelial angiocrines regulate cardiomyocyte development and maturation and induce features of ventricular non-compaction. European heart journal Rhee, S., Paik, D. T., Yang, J. Y., Nagelberg, D., Williams, I., Tian, L., Roth, R., Chandy, M., Ban, J., Belbachir, N., Kim, S., Zhang, H., Phansalkar, R., Wong, K. M., King, D. A., Valdez, C., Winn, V. D., Morrison, A. J., Wu, J. C., Red-Horse, K. 2021

    Abstract

    AIMS: Non-compaction cardiomyopathy is a devastating genetic disease caused by insufficient consolidation of ventricular wall muscle that can result in inadequate cardiac performance. Despite being the third most common cardiomyopathy, the mechanisms underlying the disease, including the cell types involved, are poorly understood. We have previously shown that endothelial cell-specific deletion of the chromatin remodeller gene Ino80 results in defective coronary vessel development that leads to ventricular non-compaction in embryonic mouse hearts. We aimed to identify candidate angiocrines expressed by endocardial and ECs inwildtype and LVNC conditions in Tie2Cre;Ino80fl/fl transgenic embryonic mouse hearts, and test the effect of these candidates on cardiomyocyte proliferation and maturation.METHODS AND RESULTS: We used single-cell RNA-sequencing to characterize endothelial and endocardial defects in Ino80-deficient hearts. We observed a pathological endocardial cell population in the non-compacted hearts and identified multiple dysregulated angiocrine factors that dramatically affected cardiomyocyte behaviour. We identified Col15A1 as a coronary vessel-secreted angiocrine factor, downregulated by Ino80-deficiency, that functioned to promote cardiomyocyte proliferation. Furthermore, mutant endocardial and endothelial cells (ECs) up-regulated expression of secreted factors, such as Tgfbi, Igfbp3, Isg15, and Adm, which decreased cardiomyocyte proliferation and increased maturation.CONCLUSIONS: These findings support a model where coronary ECs normally promote myocardial compaction through secreted factors, but that endocardial and ECs can secrete factors that contribute to non-compaction under pathological conditions.

    View details for DOI 10.1093/eurheartj/ehab298

    View details for PubMedID 34279605

  • Genetic and non-genetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium. Genome medicine Kasela, S., Ortega, V. E., Martorella, M., Garudadri, S., Nguyen, J., Ampleford, E., Pasanen, A., Nerella, S., Buschur, K. L., Barjaktarevic, I. Z., Barr, R. G., Bleecker, E. R., Bowler, R. P., Comellas, A. P., Cooper, C. B., Couper, D. J., Criner, G. J., Curtis, J. L., Han, M. K., Hansel, N. N., Hoffman, E. A., Kaner, R. J., Krishnan, J. A., Martinez, F. J., McDonald, M. N., Meyers, D. A., Paine, R. 3., Peters, S. P., Castro, M., Denlinger, L. C., Erzurum, S. C., Fahy, J. V., Israel, E., Jarjour, N. N., Levy, B. D., Li, X., Moore, W. C., Wenzel, S. E., Zein, J., NHLBI SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS), NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Langelier, C., Woodruff, P. G., Lappalainen, T., Christenson, S. A., Alexis, N. E., Anderson, W. H., Arjomandi, M., Barjaktarevic, I., Barr, R. G., Basta, P., Bateman, L. A., Bhatt, S. P., Bleecker, E. R., Boucher, R. C., Bowler, R. P., Christenson, S. A., Comellas, A. P., Cooper, C. B., Couper, D. J., Criner, G. J., Crystal, R. G., Curtis, J. L., Doerschuk, C. M., Dransfield, M. T., Drummond, B., Freeman, C. M., Galban, C., Han, M. L., Hansel, N. N., Hastie, A. T., Hoffman, E. A., Huang, Y., Kaner, R. J., Kanner, R. E., Kleerup, E. C., Krishnan, J. A., LaVange, L. M., Lazarus, S. C., Martinez, F. J., Meyers, D. A., Moore, W. C., Newell, J. D., Paine, R. 3., Paulin, L., Peters, S. P., Pirozzi, C., Putcha, N., Oelsner, E. C., O'Neal, W. K., Ortega, V. E., Raman, S., Rennard, S. I., Tashkin, D. P., Wells, J. M., Wise, R. A., Woodruff, P. G., Abe, N., Abecasis, G., Aguet, F., Albert, C., Almasy, L., Alonso, A., Ament, S., Anderson, P., Anugu, P., Applebaum-Bowden, D., Ardlie, K., Arking, D., Arnett, D. K., Ashley-Koch, A., Aslibekyan, S., Assimes, T., Auer, P., Avramopoulos, D., Barnard, J., Barnes, K., Barr, R. G., Barron-Casella, E., Barwick, L., Beaty, T., Beck, G., Becker, D., Becker, L., Beer, R., Beitelshees, A., Benjamin, E., Benos, T., Bezerra, M., Bielak, L., Bis, J., Blackwell, T., Blangero, J., Boerwinkle, E., Bowden, D. W., Bowler, R., Brody, J., Broeckel, U., Broome, J., Bunting, K., Burchard, E., Bustamante, C., Buth, E., Cade, B., Cardwell, J., Carey, V., Carty, C., Casaburi, R., Casella, J., Castaldi, P., Chaffin, M., Chang, C., Chang, Y., Chasman, D., Chavan, S., Chen, B., Chen, W., Chen, Y. I., Cho, M., Choi, S. H., Chuang, L., Chung, M., Chung, R., Clish, C., Comhair, S., Conomos, M., Cornell, E., Correa, A., Crandall, C., Crapo, J., Cupples, L. A., Curran, J., Curtis, J., Custer, B., Damcott, C., Darbar, D., Das, S., David, S., Davis, C., Daya, M., de Andrade, M., de Las Fuentes, L., DeBaun, M., Deka, R., DeMeo, D., Devine, S., Duan, Q., Duggirala, R., Durda, J. P., Dutcher, S., Eaton, C., Ekunwe, L., Boueiz, A. E., Ellinor, P., Emery, L., Erzurum, S., Farber, C., Fingerlin, T., Flickinger, M., Fornage, M., Franceschini, N., Frazar, C., Fu, M., Fullerton, S. M., Fulton, L., Gabriel, S., Gan, W., Gao, S., Gao, Y., Gass, M., Gelb, B., Geng, X. P., Geraci, M., Germer, S., Gerszten, R., Ghosh, A., Gibbs, R., Gignoux, C., Gladwin, M., Glahn, D., Gogarten, S., Gong, D., Goring, H., Graw, S., Grine, D., Gu, C. C., Guan, Y., Guo, X., Gupta, N., Haessler, J., Hall, M., Harris, D., Hawley, N. L., He, J., Heavner, B., Heckbert, S., Hernandez, R., Herrington, D., Hersh, C., Hidalgo, B., Hixson, J., Hobbs, B., Hokanson, J., Hong, E., Hoth, K., Hsiung, C. A., Hung, Y., Huston, H., Hwu, C. M., Irvin, M. R., Jackson, R., Jain, D., Jaquish, C., Jhun, M. A., Johnsen, J., Johnson, A., Johnson, C., Johnston, R., Jones, K., Kang, H. M., Kaplan, R., Kardia, S., Kathiresan, S., Kelly, S., Kenny, E., Kessler, M., Khan, A., Kim, W., Kinney, G., Konkle, B., Kooperberg, C., Kramer, H., Lange, C., Lange, E., Lange, L., Laurie, C., Laurie, C., LeBoff, M., Lee, J., Lee, S. S., Lee, W., LeFaive, J., Levine, D., Levy, D., Lewis, J., Li, X., Li, Y., Lin, H., Lin, H., Lin, K. H., Lin, X., Liu, S., Liu, Y., Liu, Y., Loos, R. J., Lubitz, S., Lunetta, K., Luo, J., Mahaney, M., Make, B., Manichaikul, A., Manson, J. A., Margolin, L., Martin, L., Mathai, S., Mathias, R., May, S., McArdle, P., McDonald, M., McFarland, S., McGarvey, S., McGoldrick, D., McHugh, C., Mei, H., Mestroni, L., Meyers, D. A., Mikulla, J., Min, N., Minear, M., Minster, R. L., Mitchell, B. D., Moll, M., Montasser, M. E., Montgomery, C., Moscati, A., Musani, S., Mwasongwe, S., Mychaleckyj, J. C., Nadkarni, G., Naik, R., Naseri, T., Natarajan, P., Nekhai, S., Nelson, S. C., Neltner, B., Nickerson, D., North, K., O'Connell, J., O'Connor, T., Ochs-Balcom, H., Paik, D., Palmer, N., Pankow, J., Papanicolaou, G., Parsa, A., Peralta, J. M., Perez, M., Perry, J., Peters, U., Peyser, P., Phillips, L. S., Pollin, T., Post, W., Becker, J. P., Boorgula, M. P., Preuss, M., Psaty, B., Qasba, P., Qiao, D., Qin, Z., Rafaels, N., Raffield, L., Ramachandran, V. S., Rao, D. C., Rasmussen-Torvik, L., Ratan, A., Redline, S., Reed, R., Regan, E., Reiner, A., Reupena, M. S., Rice, K., Rich, S., Roden, D., Roselli, C., Rotter, J., Ruczinski, I., Russell, P., Ruuska, S., Ryan, K., Sabino, E. C., Saleheen, D., Salimi, S., Salzberg, S., Sandow, K., Sankaran, V. G., Scheller, C., Schmidt, E., Schwander, K., Schwartz, D., Sciurba, F., Seidman, C., Seidman, J., Sheehan, V., Sherman, S. L., Shetty, A., Shetty, A., Sheu, W. H., Shoemaker, M. B., Silver, B., Silverman, E., Smith, J., Smith, J., Smith, N., Smith, T., Smoller, S., Snively, B., Snyder, M., Sofer, T., Sotoodehnia, N., Stilp, A. M., Storm, G., Streeten, E., Su, J. L., Sung, Y. J., Sylvia, J., Szpiro, A., Sztalryd, C., Taliun, D., Tang, H., Taub, M., Taylor, K. D., Taylor, M., Taylor, S., Telen, M., Thornton, T. A., Threlkeld, M., Tinker, L., Tirschwell, D., Tishkoff, S., Tiwari, H., Tong, C., Tracy, R., Tsai, M., Vaidya, D., Van Den Berg, D., VandeHaar, P., Vrieze, S., Walker, T., Wallace, R., Walts, A., Wang, F. F., Wang, H., Watson, K., Weeks, D. E., Weir, B., Weiss, S., Weng, L. C., Wessel, J., Willer, C., Williams, K., Williams, L. K., Wilson, C., Wilson, J., Wong, Q., Wu, J., Xu, H., Yanek, L., Yang, I., Yang, R., Zaghloul, N., Zekavat, M., Zhang, Y., Zhao, S. X., Zhao, W., Zhi, D., Zhou, X., Zhu, X., Zody, M., Zoellner, S. 2021; 13 (1): 66

    Abstract

    BACKGROUND: The large airway epithelial barrier provides one of the first lines of defense against respiratory viruses, including SARS-CoV-2 that causes COVID-19. Substantial inter-individual variability in individual disease courses is hypothesized to be partially mediated by the differential regulation of the genes that interact with the SARS-CoV-2 virus or are involved in the subsequent host response. Here, we comprehensively investigated non-genetic and genetic factors influencing COVID-19-relevant bronchial epithelial gene expression.METHODS: We analyzed RNA-sequencing data from bronchial epithelial brushings obtained from uninfected individuals. We related ACE2 gene expression to host and environmental factors in the SPIROMICS cohort of smokers with and without chronic obstructive pulmonary disease (COPD) and replicated these associations in two asthma cohorts, SARP and MAST. To identify airway biology beyond ACE2 binding that may contribute to increased susceptibility, we used gene set enrichment analyses to determine if gene expression changes indicative of a suppressed airway immune response observed early in SARS-CoV-2 infection are also observed in association with host factors. To identify host genetic variants affecting COVID-19 susceptibility in SPIROMICS, we performed expression quantitative trait (eQTL) mapping and investigated the phenotypic associations of the eQTL variants.RESULTS: We found that ACE2 expression was higher in relation to active smoking, obesity, and hypertension that are known risk factors of COVID-19 severity, while an association with interferon-related inflammation was driven by the truncated, non-binding ACE2 isoform. We discovered that expression patterns of a suppressed airway immune response to early SARS-CoV-2 infection, compared to other viruses, are similar to patterns associated with obesity, hypertension, and cardiovascular disease, which may thus contribute to a COVID-19-susceptible airway environment. eQTL mapping identified regulatory variants for genes implicated in COVID-19, some of which had pheWAS evidence for their potential role in respiratory infections.CONCLUSIONS: These data provide evidence that clinically relevant variation in the expression of COVID-19-related genes is associated with host factors, environmental exposures, and likely host genetic variation.

    View details for DOI 10.1186/s13073-021-00866-2

    View details for PubMedID 33883027

  • Unraveling intricacies of cardiovascular disease at the single-cell resolution. Trends in cardiovascular medicine Zhang, J. X., Chey, Y., Paik, D. T. 2021

    View details for DOI 10.1016/j.tcm.2021.03.006

    View details for PubMedID 33812976

  • Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program. Nature Taliun, D., Harris, D. N., Kessler, M. D., Carlson, J., Szpiech, Z. A., Torres, R., Taliun, S. A., Corvelo, A., Gogarten, S. M., Kang, H. M., Pitsillides, A. N., LeFaive, J., Lee, S., Tian, X., Browning, B. L., Das, S., Emde, A., Clarke, W. E., Loesch, D. P., Shetty, A. C., Blackwell, T. W., Smith, A. V., Wong, Q., Liu, X., Conomos, M. P., Bobo, D. M., Aguet, F., Albert, C., Alonso, A., Ardlie, K. G., Arking, D. E., Aslibekyan, S., Auer, P. L., Barnard, J., Barr, R. G., Barwick, L., Becker, L. C., Beer, R. L., Benjamin, E. J., Bielak, L. F., Blangero, J., Boehnke, M., Bowden, D. W., Brody, J. A., Burchard, E. G., Cade, B. E., Casella, J. F., Chalazan, B., Chasman, D. I., Chen, Y. I., Cho, M. H., Choi, S. H., Chung, M. K., Clish, C. B., Correa, A., Curran, J. E., Custer, B., Darbar, D., Daya, M., de Andrade, M., DeMeo, D. L., Dutcher, S. K., Ellinor, P. T., Emery, L. S., Eng, C., Fatkin, D., Fingerlin, T., Forer, L., Fornage, M., Franceschini, N., Fuchsberger, C., Fullerton, S. M., Germer, S., Gladwin, M. T., Gottlieb, D. J., Guo, X., Hall, M. E., He, J., Heard-Costa, N. L., Heckbert, S. R., Irvin, M. R., Johnsen, J. M., Johnson, A. D., Kaplan, R., Kardia, S. L., Kelly, T., Kelly, S., Kenny, E. E., Kiel, D. P., Klemmer, R., Konkle, B. A., Kooperberg, C., Kottgen, A., Lange, L. A., Lasky-Su, J., Levy, D., Lin, X., Lin, K., Liu, C., Loos, R. J., Garman, L., Gerszten, R., Lubitz, S. A., Lunetta, K. L., Mak, A. C., Manichaikul, A., Manning, A. K., Mathias, R. A., McManus, D. D., McGarvey, S. T., Meigs, J. B., Meyers, D. A., Mikulla, J. L., Minear, M. A., Mitchell, B. D., Mohanty, S., Montasser, M. E., Montgomery, C., Morrison, A. C., Murabito, J. M., Natale, A., Natarajan, P., Nelson, S. C., North, K. E., O'Connell, J. R., Palmer, N. D., Pankratz, N., Peloso, G. M., Peyser, P. A., Pleiness, J., Post, W. S., Psaty, B. M., Rao, D. C., Redline, S., Reiner, A. P., Roden, D., Rotter, J. I., Ruczinski, I., Sarnowski, C., Schoenherr, S., Schwartz, D. A., Seo, J., Seshadri, S., Sheehan, V. A., Sheu, W. H., Shoemaker, M. B., Smith, N. L., Smith, J. A., Sotoodehnia, N., Stilp, A. M., Tang, W., Taylor, K. D., Telen, M., Thornton, T. A., Tracy, R. P., Van Den Berg, D. J., Vasan, R. S., Viaud-Martinez, K. A., Vrieze, S., Weeks, D. E., Weir, B. S., Weiss, S. T., Weng, L., Willer, C. J., Zhang, Y., Zhao, X., Arnett, D. K., Ashley-Koch, A. E., Barnes, K. C., Boerwinkle, E., Gabriel, S., Gibbs, R., Rice, K. M., Rich, S. S., Silverman, E. K., Qasba, P., Gan, W., NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Papanicolaou, G. J., Nickerson, D. A., Browning, S. R., Zody, M. C., Zollner, S., Wilson, J. G., Cupples, L. A., Laurie, C. C., Jaquish, C. E., Hernandez, R. D., O'Connor, T. D., Abecasis, G. R., Abe, N., Almasy, L., Ament, S., Anderson, P., Anugu, P., Applebaum-Bowden, D., Assimes, T., Avramopoulos, D., Barron-Casella, E., Beaty, T., Beck, G., Becker, D., Beitelshees, A., Benos, T., Bezerra, M., Bis, J., Bowler, R., Broeckel, U., Broome, J., Bunting, K., Bustamante, C., Buth, E., Cardwell, J., Carey, V., Carty, C., Casaburi, R., Castaldi, P., Chaffin, M., Chang, C., Chang, Y., Chavan, S., Chen, B., Chen, W., Chuang, L., Chung, R., Comhair, S., Cornell, E., Crandall, C., Crapo, J., Curtis, J., Damcott, C., David, S., Davis, C., Fuentes, L. d., DeBaun, M., Deka, R., Devine, S., Duan, Q., Duggirala, R., Durda, J. P., Eaton, C., Ekunwe, L., El Boueiz, A., Erzurum, S., Farber, C., Flickinger, M., Fornage, M., Frazar, C., Fu, M., Fulton, L., Gao, S., Gao, Y., Gass, M., Gelb, B., Geng, X. P., Geraci, M., Ghosh, A., Gignoux, C., Glahn, D., Gong, D., Goring, H., Graw, S., Grine, D., Gu, C. C., Guan, Y., Gupta, N., Haessler, J., Hawley, N. L., Heavner, B., Herrington, D., Hersh, C., Hidalgo, B., Hixson, J., Hobbs, B., Hokanson, J., Hong, E., Hoth, K., Hsiung, C. A., Hung, Y., Huston, H., Hwu, C. M., Jackson, R., Jain, D., Jhun, M. A., Johnson, C., Johnston, R., Jones, K., Kathiresan, S., Khan, A., Kim, W., Kinney, G., Kramer, H., Lange, C., Lange, E., Lange, L., Laurie, C., LeBoff, M., Lee, J., Lee, S. S., Lee, W., Levine, D., Lewis, J., Li, X., Li, Y., Lin, H., Lin, H., Lin, K. H., Liu, S., Liu, Y., Liu, Y., Luo, J., Mahaney, M., Make, B., Manson, J., Margolin, L., Martin, L., Mathai, S., May, S., McArdle, P., McDonald, M., McFarland, S., McGoldrick, D., McHugh, C., Mei, H., Mestroni, L., Min, N., Minster, R. L., Moll, M., Moscati, A., Musani, S., Mwasongwe, S., Mychaleckyj, J. C., Nadkarni, G., Naik, R., Naseri, T., Nekhai, S., Neltner, B., Ochs-Balcom, H., Paik, D., Pankow, J., Parsa, A., Peralta, J. M., Perez, M., Perry, J., Peters, U., Phillips, L. S., Pollin, T., Becker, J. P., Boorgula, M. P., Preuss, M., Qiao, D., Qin, Z., Rafaels, N., Raffield, L., Rasmussen-Torvik, L., Ratan, A., Reed, R., Regan, E., Reupena, M. S., Roselli, C., Russell, P., Ruuska, S., Ryan, K., Sabino, E. C., Saleheen, D., Salimi, S., Salzberg, S., Sandow, K., Sankaran, V. G., Scheller, C., Schmidt, E., Schwander, K., Sciurba, F., Seidman, C., Seidman, J., Sherman, S. L., Shetty, A., Sheu, W. H., Silver, B., Smith, J., Smith, T., Smoller, S., Snively, B., Snyder, M., Sofer, T., Storm, G., Streeten, E., Sung, Y. J., Sylvia, J., Szpiro, A., Sztalryd, C., Tang, H., Taub, M., Taylor, M., Taylor, S., Threlkeld, M., Tinker, L., Tirschwell, D., Tishkoff, S., Tiwari, H., Tong, C., Tsai, M., Vaidya, D., VandeHaar, P., Walker, T., Wallace, R., Walts, A., Wang, F. F., Wang, H., Watson, K., Wessel, J., Williams, K., Williams, L. K., Wilson, C., Wu, J., Xu, H., Yanek, L., Yang, I., Yang, R., Zaghloul, N., Zekavat, M., Zhao, S. X., Zhao, W., Zhi, D., Zhou, X., Zhu, X. 2021; 590 (7845): 290–99

    Abstract

    The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes)1. In the first 53,831 TOPMed samples, we detected more than 400million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.

    View details for DOI 10.1038/s41586-021-03205-y

    View details for PubMedID 33568819

  • Endothelial-Myocardial Angiocrine Signaling in Heart Development. Frontiers in cell and developmental biology Kim, H., Wang, M., Paik, D. T. 2021; 9: 697130

    Abstract

    Vascular endothelial cells are a multifunctional cell type with organotypic specificity in their function and structure. In this review, we discuss various subpopulations of endothelial cells in the mammalian heart, which spatiotemporally regulate critical cellular and molecular processes of heart development via unique sets of angiocrine signaling pathways. In particular, elucidation of intercellular communication among the functional cell types in the developing heart has recently been accelerated by the use of single-cell sequencing. Specifically, we overview the heterogeneic nature of cardiac endothelial cells and their contribution to heart tube and chamber formation, myocardial trabeculation and compaction, and endocardial cushion and valve formation via angiocrine pathways.

    View details for DOI 10.3389/fcell.2021.697130

    View details for PubMedID 34277641

  • Inherited causes of clonal haematopoiesis in 97,691 whole genomes. Nature Bick, A. G., Weinstock, J. S., Nandakumar, S. K., Fulco, C. P., Bao, E. L., Zekavat, S. M., Szeto, M. D., Liao, X., Leventhal, M. J., Nasser, J., Chang, K., Laurie, C., Burugula, B. B., Gibson, C. J., Lin, A. E., Taub, M. A., Aguet, F., Ardlie, K., Mitchell, B. D., Barnes, K. C., Moscati, A., Fornage, M., Redline, S., Psaty, B. M., Silverman, E. K., Weiss, S. T., Palmer, N. D., Vasan, R. S., Burchard, E. G., Kardia, S. L., He, J., Kaplan, R. C., Smith, N. L., Arnett, D. K., Schwartz, D. A., Correa, A., de Andrade, M., Guo, X., Konkle, B. A., Custer, B., Peralta, J. M., Gui, H., Meyers, D. A., McGarvey, S. T., Chen, I. Y., Shoemaker, M. B., Peyser, P. A., Broome, J. G., Gogarten, S. M., Wang, F. F., Wong, Q., Montasser, M. E., Daya, M., Kenny, E. E., North, K. E., Launer, L. J., Cade, B. E., Bis, J. C., Cho, M. H., Lasky-Su, J., Bowden, D. W., Cupples, L. A., Mak, A. C., Becker, L. C., Smith, J. A., Kelly, T. N., Aslibekyan, S., Heckbert, S. R., Tiwari, H. K., Yang, I. V., Heit, J. A., Lubitz, S. A., Johnsen, J. M., Curran, J. E., Wenzel, S. E., Weeks, D. E., Rao, D. C., Darbar, D., Moon, J., Tracy, R. P., Buth, E. J., Rafaels, N., Loos, R. J., Durda, P., Liu, Y., Hou, L., Lee, J., Kachroo, P., Freedman, B. I., Levy, D., Bielak, L. F., Hixson, J. E., Floyd, J. S., Whitsel, E. A., Ellinor, P. T., Irvin, M. R., Fingerlin, T. E., Raffield, L. M., Armasu, S. M., Wheeler, M. M., Sabino, E. C., Blangero, J., Williams, L. K., Levy, B. D., Sheu, W. H., Roden, D. M., Boerwinkle, E., Manson, J. E., Mathias, R. A., Desai, P., Taylor, K. D., Johnson, A. D., NHLBI Trans-Omics for Precision Medicine Consortium, Auer, P. L., Kooperberg, C., Laurie, C. C., Blackwell, T. W., Smith, A. V., Zhao, H., Lange, E., Lange, L., Rich, S. S., Rotter, J. I., Wilson, J. G., Scheet, P., Kitzman, J. O., Lander, E. S., Engreitz, J. M., Ebert, B. L., Reiner, A. P., Jaiswal, S., Abecasis, G., Sankaran, V. G., Kathiresan, S., Natarajan, P., Abe, N., Albert, C., Almasy, L., Alonso, A., Ament, S., Anderson, P., Anugu, P., Applebaum-Bowden, D., Arking, D., Ashley-Koch, A., Aslibekyan, S., Assimes, T., Avramopoulos, D., Barnard, J., Barr, R. G., Barron-Casella, E., Barwick, L., Beaty, T., Beck, G., Becker, D., Beer, R., Beitelshees, A., Benjamin, E., Benos, P., Bezerra, M., Bielak, L., Bowler, R., Brody, J., Broeckel, U., Bunting, K., Bustamante, C., Cardwell, J., Carey, V., Carty, C., Casaburi, R., Casella, J., Castaldi, P., Chaffin, M., Chang, C., Chang, Y., Chasman, D., Chavan, S., Chen, B., Chen, W., Choi, S. H., Chuang, L., Chung, M., Chung, R., Clish, C., Comhair, S., Cornell, E., Crandall, C., Crapo, J., Curtis, J., Damcott, C., Das, S., David, S., Davis, C., DeBaun, M., Deka, R., DeMeo, D., Devine, S., Duan, Q., Duggirala, R., Dutcher, S., Eaton, C., Ekunwe, L., Boueiz, A. E., Emery, L., Erzurum, S., Farber, C., Flickinger, M., Franceschini, N., Frazar, C., Fu, M., Fullerton, S. M., Fulton, L., Gabriel, S., Gan, W., Gao, S., Gao, Y., Gass, M., Gelb, B., Priscilla Geng, X., Geraci, M., Germer, S., Gerszten, R., Ghosh, A., Gibbs, R., Gignoux, C., Gladwin, M., Glahn, D., Gong, D., Goring, H., Graw, S., Grine, D., Gu, C. C., Guan, Y., Gupta, N., Haessler, J., Hall, M., Harris, D., Hawley, N. L., Heavner, B., Hernandez, R., Herrington, D., Hersh, C., Hidalgo, B., Hobbs, B., Hokanson, J., Hong, E., Hoth, K., Agnes Hsiung, C., Hung, Y., Huston, H., Hwu, C. M., Jackson, R., Jain, D., Jaquish, C., Jhun, M. A., Johnson, C., Johnston, R., Jones, K., Kang, H. M., Kelly, S., Kessler, M., Khan, A., Kim, W., Kinney, G., Kramer, H., Lange, C., LeBoff, M., Lee, S. S., Lee, W., LeFaive, J., Levine, D., Lewis, J., Li, X., Li, Y., Lin, H., Lin, H., Lin, K. H., Lin, X., Liu, S., Liu, Y., Lunetta, K., Luo, J., Mahaney, M., Make, B., Manichaikul, A., Margolin, L., Martin, L., Mathai, S., May, S., McArdle, P., McDonald, M., McFarland, S., McGoldrick, D., McHugh, C., Mei, H., Mestroni, L., Mikulla, J., Min, N., Minear, M., Minster, R. L., Moll, M., Montgomery, C., Musani, S., Mwasongwe, S., Mychaleckyj, J. C., Nadkarni, G., Naik, R., Naseri, T., Nekhai, S., Nelson, S. C., Neltner, B., Nickerson, D., O'Connell, J., O'Connor, T., Ochs-Balcom, H., Paik, D., Pankow, J., Papanicolaou, G., Parsa, A., Perez, M., Perry, J., Peters, U., Peyser, P., Phillips, L. S., Pollin, T., Post, W., Becker, J. P., Boorgula, M. P., Preuss, M., Qasba, P., Qiao, D., Qin, Z., Rasmussen-Torvik, L., Ratan, A., Reed, R., Regan, E., Sefuiva Reupena, M., Rice, K., Roselli, C., Ruczinski, I., Russell, P., Ruuska, S., Ryan, K., Saleheen, D., Salimi, S., Salzberg, S., Sandow, K., Scheller, C., Schmidt, E., Schwander, K., Sciurba, F., Seidman, C., Seidman, J., Sheehan, V., Sherman, S. L., Shetty, A., Shetty, A., Silver, B., Smith, J., Smith, T., Smoller, S., Snively, B., Snyder, M., Sofer, T., Sotoodehnia, N., Stilp, A. M., Storm, G., Streeten, E., Su, J. L., Sung, Y. J., Sylvia, J., Szpiro, A., Sztalryd, C., Taliun, D., Tang, H., Taylor, M., Taylor, S., Telen, M., Thornton, T. A., Threlkeld, M., Tinker, L., Tirschwell, D., Tishkoff, S., Tiwari, H., Tong, C., Tsai, M., Vaidya, D., Berg, D. V., VandeHaar, P., Vrieze, S., Walker, T., Wallace, R., Walts, A., Wang, H., Watson, K., Weir, B., Weng, L., Wessel, J., Willer, C., Williams, K., Wilson, C., Wu, J., Xu, H., Yanek, L., Yang, R., Zaghloul, N., Zhang, Y., Zhao, S. X., Zhao, W., Zhi, D., Zhou, X., Zhu, X., Zody, M., Zoellner, S. 2020

    Abstract

    Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown1. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer2-4 and coronary heart disease5-this phenomenon istermed clonal haematopoiesis of indeterminate potential (CHIP)6. Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIPdriver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.

    View details for DOI 10.1038/s41586-020-2819-2

    View details for PubMedID 33057201

  • Single-Cell RNA-seq Unveils Unique Transcriptomic Signatures of Organ-Specific Endothelial Cells. Circulation Paik, D. T., Tian, L., Williams, I. M., Rhee, S., Zhang, H., Liu, C., Mishra, R., Wu, S. M., Red-Horse, K., Wu, J. C. 2020

    Abstract

    Background: Endothelial cells (ECs) display considerable functional heterogeneity depending on the vessel and tissue in which they are located. While these functional differences are presumably imprinted in the transcriptome, the pathways and networks which sustain EC heterogeneity have not been fully delineated. Methods: To investigate the transcriptomic basis of EC specificity, we analyzed single-cell RNA-sequencing (scRNA-seq) data from tissue-specific mouse ECs generated by the Tabula Muris consortium. We employed a number of bioinformatics tools to uncover markers and sources of EC heterogeneity from scRNA-seq data. Results: We found a strong correlation between tissue-specific EC transcriptomic measurements generated by either scRNA-seq or bulk RNA-seq, thus validating the approach. Using a graph-based clustering algorithm, we found that certain tissue-specific ECs cluster strongly by tissue (e.g. liver, brain) whereas others (i.e. adipose, heart) have considerable transcriptomic overlap with ECs from other tissues. We identified novel markers of tissue-specific ECs and signaling pathways that may be involved in maintaining their identity. Sex was a considerable source of heterogeneity in the endothelial transcriptome and we discovered Lars2 to be a gene that is highly enriched in ECs from male mice. In addition, we found that markers of heart and lung ECs in mice were conserved in human fetal heart and lung ECs. Finally, we identified potential angiocrine interactions between tissue-specific ECs and other cell types by analyzing ligand and receptor expression patterns. Conclusions: In summary, we use scRNA-seq data generated by the Tabula Muris consortium to uncover transcriptional networks that maintain tissue-specific EC identity and to identify novel angiocrine and functional relationships between tissue-specific ECs.

    View details for DOI 10.1161/CIRCULATIONAHA.119.041433

    View details for PubMedID 32929989

  • High-throughput Preparation of DNA, RNA, and Protein from Cryopreserved Human iPSCs for Multi-omics Analysis. Current protocols in stem cell biology Zhang, J. X., Lau, E., Paik, D. T., Zhuge, Y., Wu, J. C. 2020; 54 (1): e114

    Abstract

    We describe the procedure to isolate genomic DNA, RNA, and protein directly from cryopreserved induced pluripotent stem cell (iPSC) vials using commercially available solid-phase extraction kits, and we report the relationship between macromolecule yields and experimental and storage factors. Sufficient quantities of DNA, RNA, and protein are recoverable from as low as 1 million cryopreserved cells across 728 distinct iPSC lines suitable for whole-genome sequencing, RNA sequencing, and mass spectrometry experiments. Nucleic acids extracted from iPSC stocks cryopreserved up to 4 years maintain sufficient quantity and integrity for downstream analysis with minimal genomic DNA fragmentation. An expected positive correlation exists between cell count and DNA or RNA yield, with comparable yields recovered between cells across different cryostorage timespans. This article provides an effective way to simultaneously isolate iPSC biomolecules for multi-omics investigations. © 2020 Wiley Periodicals LLC. Basic Protocol 1: QIAshredder and AllPrep DNA/RNA/protein mini kit extraction and subsequent DNA quantification and quality analysis Basic Protocol 2: Broad-range RNA quantification and quality assay using QuBit 4 Fluorometer and associated kits.

    View details for DOI 10.1002/cpsc.114

    View details for PubMedID 32584494

  • Dynamic incorporation of multiple in silico functional annotations empowers rare variant association analysis of large whole-genome sequencing studies at scale. Nature genetics Li, X., Li, Z., Zhou, H., Gaynor, S. M., Liu, Y., Chen, H., Sun, R., Dey, R., Arnett, D. K., Aslibekyan, S., Ballantyne, C. M., Bielak, L. F., Blangero, J., Boerwinkle, E., Bowden, D. W., Broome, J. G., Conomos, M. P., Correa, A., Cupples, L. A., Curran, J. E., Freedman, B. I., Guo, X., Hindy, G., Irvin, M. R., Kardia, S. L., Kathiresan, S., Khan, A. T., Kooperberg, C. L., Laurie, C. C., Liu, X. S., Mahaney, M. C., Manichaikul, A. W., Martin, L. W., Mathias, R. A., McGarvey, S. T., Mitchell, B. D., Montasser, M. E., Moore, J. E., Morrison, A. C., O'Connell, J. R., Palmer, N. D., Pampana, A., Peralta, J. M., Peyser, P. A., Psaty, B. M., Redline, S., Rice, K. M., Rich, S. S., Smith, J. A., Tiwari, H. K., Tsai, M. Y., Vasan, R. S., Wang, F. F., Weeks, D. E., Weng, Z., Wilson, J. G., Yanek, L. R., NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Lipids Working Group, Neale, B. M., Sunyaev, S. R., Abecasis, G. R., Rotter, J. I., Willer, C. J., Peloso, G. M., Natarajan, P., Lin, X., Abe, N., Abecasis, G. R., Aguet, F., Albert, C., Almasy, L., Alonso, A., Ament, S., Anderson, P., Anugu, P., Applebaum-Bowden, D., Ardlie, K., Arking, D., Arnett, D. K., Ashley-Koch, A., Aslibekyan, S., Assimes, T., Auer, P., Avramopoulos, D., Barnard, J., Barnes, K., Barr, R. G., Barron-Casella, E., Barwick, L., Beaty, T., Beck, G., Becker, D., Becker, L., Beer, R., Beitelshees, A., Benjamin, E., Benos, T., Bezerra, M., Bielak, L. F., Bis, J., Blackwell, T., Blangero, J., Boerwinkle, E., Bowden, D. W., Bowler, R., Brody, J., Broeckel, U., Broome, J. G., Bunting, K., Burchard, E., Bustamante, C., Buth, E., Cade, B., Cardwell, J., Carey, V., Carty, C., Casaburi, R., Casella, J., Castaldi, P., Chaffin, M., Chang, C., Chang, Y., Chasman, D., Chavan, S., Chen, B., Chen, W., Chen, Y. I., Cho, M., Choi, S. H., Chuang, L., Chung, M., Chung, R., Clish, C., Comhair, S., Conomos, M. P., Cornell, E., Correa, A., Crandall, C., Crapo, J., Cupples, L. A., Curran, J. E., Curtis, J., Custer, B., Damcott, C., Darbar, D., Das, S., David, S., Davis, C., Daya, M., de Andrade, M., Fuentes, L. d., DeBaun, M., Deka, R., DeMeo, D., Devine, S., Duan, Q., Duggirala, R., Durda, J. P., Dutcher, S., Eaton, C., Ekunwe, L., El Boueiz, A., Ellinor, P., Emery, L., Erzurum, S., Farber, C., Fingerlin, T., Flickinger, M., Fornage, M., Franceschini, N., Frazar, C., Fu, M., Fullerton, S. M., Fulton, L., Gabriel, S., Gan, W., Gao, S., Gao, Y., Gass, M., Gelb, B., Geng, X. P., Geraci, M., Germer, S., Gerszten, R., Ghosh, A., Gibbs, R., Gignoux, C., Gladwin, M., Glahn, D., Gogarten, S., Gong, D., Goring, H., Graw, S., Grine, D., Gu, C. C., Guan, Y., Guo, X., Gupta, N., Haessler, J., Hall, M., Harris, D., Hawley, N. L., He, J., Heckbert, S., Hernandez, R., Herrington, D., Hersh, C., Hidalgo, B., Hixson, J., Hobbs, B., Hokanson, J., Hong, E., Hoth, K., Hsiung, C. A., Hung, Y., Huston, H., Hwu, C. M., Irvin, M. R., Jackson, R., Jain, D., Jaquish, C., Jhun, M. A., Johnsen, J., Johnson, A., Johnson, C., Johnston, R., Jones, K., Kang, H. M., Kaplan, R., Kardia, S. L., Kathiresan, S., Kelly, S., Kenny, E., Kessler, M., Khan, A. T., Kim, W., Kinney, G., Konkle, B., Kooperberg, C. L., Kramer, H., Lange, C., Lange, E., Lange, L., Laurie, C. C., Laurie, C., LeBoff, M., Lee, J., Lee, S. S., Lee, W., LeFaive, J., Levine, D., Levy, D., Lewis, J., Li, X., Li, Y., Lin, H., Lin, H., Lin, K. H., Lin, X., Liu, S., Liu, Y., Liu, Y., Loos, R. J., Lubitz, S., Lunetta, K., Luo, J., Mahaney, M. C., Make, B., Manichaikul, A. W., Manson, J., Margolin, L., Martin, L. W., Mathai, S., Mathias, R. A., May, S., McArdle, P., McDonald, M., McFarland, S., McGarvey, S. T., McGoldrick, D., McHugh, C., Mei, H., Mestroni, L., Meyers, D. A., Mikulla, J., Min, N., Minear, M., Minster, R. L., Mitchell, B. D., Moll, M., Montasser, M. E., Montgomery, C., Moscati, A., Musani, S., Mwasongwe, S., Mychaleckyj, J. C., Nadkarni, G., Naik, R., Naseri, T., Natarajan, P., Nekhai, S., Nelson, S. C., Neltner, B., Nickerson, D., North, K., O'Connell, J. R., O'Connor, T., Ochs-Balcom, H., Paik, D., Palmer, N. D., Pankow, J., Papanicolaou, G., Parsa, A., Peralta, J. M., Perez, M., Perry, J., Peters, U., Peyser, P. A., Phillips, L. S., Pollin, T., Post, W., Becker, J. P., Boorgula, M. P., Preuss, M., Psaty, B. M., Qasba, P., Qiao, D., Qin, Z., Rafaels, N., Raffield, L., Vasan, R. S., Rao, D. C., Rasmussen-Torvik, L., Ratan, A., Redline, S., Reed, R., Regan, E., Reiner, A., Reupena, M. S., Rice, K. M., Rich, S. S., Roden, D., Roselli, C., Rotter, J. I., Ruczinski, I., Russell, P., Ruuska, S., Ryan, K., Sabino, E. C., Saleheen, D., Salimi, S., Salzberg, S., Sandow, K., Sankaran, V. G., Scheller, C., Schmidt, E., Schwander, K., Schwartz, D., Sciurba, F., Seidman, C., Seidman, J., Sheehan, V., Sherman, S. L., Shetty, A., Shetty, A., Sheu, W. H., Shoemaker, M. B., Silver, B., Silverman, E., Smith, J. A., Smith, J., Smith, N., Smith, T., Smoller, S., Snively, B., Snyder, M., Sofer, T., Sotoodehnia, N., Stilp, A. M., Storm, G., Streeten, E., Su, J. L., Sung, Y. J., Sylvia, J., Szpiro, A., Sztalryd, C., Taliun, D., Tang, H., Taub, M., Taylor, K. D., Taylor, M., Taylor, S., Telen, M., Thornton, T. A., Threlkeld, M., Tinker, L., Tirschwell, D., Tishkoff, S., Tiwari, H. K., Tong, C., Tracy, R., Tsai, M. Y., Vaidya, D., Van Den Berg, D., VandeHaar, P., Vrieze, S., Walker, T., Wallace, R., Walts, A., Wang, F. F., Wang, H., Watson, K., Weeks, D. E., Weir, B., Weiss, S., Weng, L., Wessel, J., Willer, C. J., Williams, K., Williams, L. K., Wilson, C., Wilson, J. G., Wong, Q., Wu, J., Xu, H., Yanek, L. R., Yang, I., Yang, R., Zaghloul, N., Zekavat, M., Zhang, Y., Zhao, S. X., Zhao, W., Zhi, D., Zhou, X., Zhu, X., Zody, M., Zoellner, S., Abdalla, M., Abecasis, G. R., Arnett, D. K., Aslibekyan, S., Assimes, T., Atkinson, E., Ballantyne, C. M., Beitelshees, A., Bielak, L. F., Bis, J., Bodea, C., Boerwinkle, E., Bowden, D. W., Brody, J., Cade, B., Carlson, J., Chang, I., Chen, Y. I., Chun, S., Chung, R., Conomos, M. P., Correa, A., Cupples, L. A., Damcott, C., de Vries, P., Do, R., Elliott, A., Fu, M., Ganna, A., Gong, D., Graham, S., Haas, M., Haring, B., He, J., Heckbert, S., Himes, B., Hixson, J., Irvin, M. R., Jain, D., Jarvik, G., Jhun, M. A., Jiang, J., Jun, G., Kalyani, R., Kardia, S. L., Kathiresan, S., Khera, A., Klarin, D., Kooperberg, C. L., Kral, B., Lange, L., Laurie, C. C., Laurie, C., Lemaitre, R., Li, Z., Li, X., Lin, X., Mahaney, M. C., Manichaikul, A. W., Martin, L. W., Mathias, R. A., Mathur, R., McGarvey, S. T., McHugh, C., McLenithan, J., Mikulla, J., Mitchell, B. D., Montasser, M. E., Moran, A., Morrison, A. C., Nakao, T., Natarajan, P., Nickerson, D., North, K., O'Connell, J. R., O'Donnell, C., Palmer, N. D., Pampana, A., Patel, A., Peloso, G. M., Perry, J., Peters, U., Peyser, P. A., Pirruccello, J., Pollin, T., Preuss, M., Psaty, B. M., Rao, D. C., Redline, S., Reed, R., Reiner, A., Rich, S. S., Rosenthal, S., Rotter, J. I., Schoenberg, J., Selvaraj, M. S., Sheu, W. H., Smith, J. A., Sofer, T., Stilp, A. M., Sunyaev, S. R., Surakka, I., Sztalryd, C., Tang, H., Taylor, K. D., Tsai, M. Y., Uddin, M. M., Urbut, S., Verbanck, M., Von Holle, A., Wang, H., Wang, F. F., Wiggins, K., Willer, C. J., Wilson, J. G., Wolford, B., Xu, H., Yanek, L. R., Zaghloul, N., Zekavat, M., Zhang, J. 2020

    Abstract

    Large-scale whole-genome sequencing studies have enabled the analysis of rare variants (RVs) associated with complex phenotypes. Commonly used RV association tests have limited scope to leverage variant functions. We propose STAAR (variant-set test for association using annotation information), a scalable and powerful RV association test method that effectively incorporates both variant categories and multiple complementary annotations using a dynamic weighting scheme. For the latter, we introduce 'annotation principal components', multidimensional summaries of in silico variant annotations. STAAR accounts for population structure and relatedness and is scalable for analyzing very large cohort and biobank whole-genome sequencing studies of continuous and dichotomous traits. We applied STAAR to identify RVs associated with four lipid traits in 12,316 discovery and 17,822 replication samples from the Trans-Omics for Precision Medicine Program. We discovered and replicated new RV associations, including disruptive missense RVs of NPC1L1 and an intergenic region near APOC1P1 associated with low-density lipoprotein cholesterol.

    View details for DOI 10.1038/s41588-020-0676-4

    View details for PubMedID 32839606

  • An extracellular matrix paradox in myocardial scar formation. Signal transduction and targeted therapy Cho, S., Paik, D. T., Wu, J. C. 2020; 5 (1): 151

    View details for DOI 10.1038/s41392-020-00270-z

    View details for PubMedID 32788685

  • Single-cell RNA sequencing in cardiovascular development, disease and medicine. Nature reviews. Cardiology Paik, D. T., Cho, S., Tian, L., Chang, H. Y., Wu, J. C. 2020

    Abstract

    Advances in single-cell RNA sequencing (scRNA-seq) technologies in the past 10 years have had a transformative effect on biomedical research, enabling the profiling and analysis of the transcriptomes of single cells at unprecedented resolution and throughput. Specifically, scRNA-seq has facilitated the identification of novel or rare cell types, the analysis of single-cell trajectory construction and stem or progenitor cell differentiation, and the comparison of healthy and disease-related tissues at single-cell resolution. These applications have been critical in advances in cardiovascular research in the past decade as evidenced by the generation of cell atlases of mammalian heart and blood vessels and the elucidation of mechanisms involved in cardiovascular development and stem or progenitor cell differentiation. In this Review, we summarize the currently available scRNA-seq technologies and analytical tools and discuss the latest findings using scRNA-seq that have substantially improved our knowledge on the development of the cardiovascular system and the mechanisms underlying cardiovascular diseases. Furthermore, we examine emerging strategies that integrate multimodal single-cell platforms, focusing on future applications in cardiovascular precision medicine that use single-cell omics approaches to characterize cell-specific responses to drugs or environmental stimuli and to develop effective patient-specific therapeutics.

    View details for DOI 10.1038/s41569-020-0359-y

    View details for PubMedID 32231331

  • Patient and Disease-Specific Induced Pluripotent Stem Cells for Discovery of Personalized Cardiovascular Drugs and Therapeutics. Pharmacological reviews Paik, D. T., Chandy, M. n., Wu, J. C. 2020; 72 (1): 320–42

    Abstract

    Human induced pluripotent stem cells (iPSCs) have emerged as an effective platform for regenerative therapy, disease modeling, and drug discovery. iPSCs allow for the production of limitless supply of patient-specific somatic cells that enable advancement in cardiovascular precision medicine. Over the past decade, researchers have developed protocols to differentiate iPSCs to multiple cardiovascular lineages, as well as to enhance the maturity and functionality of these cells. Despite significant advances, drug therapy and discovery for cardiovascular disease have lagged behind other fields such as oncology. We speculate that this paucity of drug discovery is due to a previous lack of efficient, reproducible, and translational model systems. Notably, existing drug discovery and testing platforms rely on animal studies and clinical trials, but investigations in animal models have inherent limitations due to interspecies differences. Moreover, clinical trials are inherently flawed by assuming that all individuals with a disease will respond identically to a therapy, ignoring the genetic and epigenomic variations that define our individuality. With ever-improving differentiation and phenotyping methods, patient-specific iPSC-derived cardiovascular cells allow unprecedented opportunities to discover new drug targets and screen compounds for cardiovascular disease. Imbued with the genetic information of an individual, iPSCs will vastly improve our ability to test drugs efficiently, as well as tailor and titrate drug therapy for each patient.

    View details for DOI 10.1124/pr.116.013003

    View details for PubMedID 31871214

  • Wnt Activation and Reduced Cell-Cell Contact Synergistically Induce Massive Expansion of Functional Human iPSC-Derived Cardiomyocytes. Cell stem cell Buikema, J. W., Lee, S. n., Goodyer, W. R., Maas, R. G., Chirikian, O. n., Li, G. n., Miao, Y. n., Paige, S. L., Lee, D. n., Wu, H. n., Paik, D. T., Rhee, S. n., Tian, L. n., Galdos, F. X., Puluca, N. n., Beyersdorf, B. n., Hu, J. n., Beck, A. n., Venkamatran, S. n., Swami, S. n., Wijnker, P. n., Schuldt, M. n., Dorsch, L. M., van Mil, A. n., Red-Horse, K. n., Wu, J. Y., Geisen, C. n., Hesse, M. n., Serpooshan, V. n., Jovinge, S. n., Fleischmann, B. K., Doevendans, P. A., van der Velden, J. n., Garcia, K. C., Wu, J. C., Sluijter, J. P., Wu, S. M. 2020; 27 (1): 50–63.e5

    Abstract

    Modulating signaling pathways including Wnt and Hippo can induce cardiomyocyte proliferation in vivo. Applying these signaling modulators to human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in vitro can expand CMs modestly (<5-fold). Here, we demonstrate massive expansion of hiPSC-CMs in vitro (i.e., 100- to 250-fold) by glycogen synthase kinase-3β (GSK-3β) inhibition using CHIR99021 and concurrent removal of cell-cell contact. We show that GSK-3β inhibition suppresses CM maturation, while contact removal prevents CMs from cell cycle exit. Remarkably, contact removal enabled 10 to 25 times greater expansion beyond GSK-3β inhibition alone. Mechanistically, persistent CM proliferation required both LEF/TCF activity and AKT phosphorylation but was independent from yes-associated protein (YAP) signaling. Engineered heart tissues from expanded hiPSC-CMs showed comparable contractility to those from unexpanded hiPSC-CMs, demonstrating uncompromised cellular functionality after expansion. In summary, we uncovered a molecular interplay that enables massive hiPSC-CM expansion for large-scale drug screening and tissue engineering applications.

    View details for DOI 10.1016/j.stem.2020.06.001

    View details for PubMedID 32619518

  • Modeling Secondary Iron Overload Cardiomyopathy with Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes. Cell reports Rhee, J. W., Yi, H. n., Thomas, D. n., Lam, C. K., Belbachir, N. n., Tian, L. n., Qin, X. n., Malisa, J. n., Lau, E. n., Paik, D. T., Kim, Y. n., Choi, B. S., Sayed, N. n., Sallam, K. n., Liao, R. n., Wu, J. C. 2020; 32 (2): 107886

    Abstract

    Excessive iron accumulation in the heart causes iron overload cardiomyopathy (IOC), which initially presents as diastolic dysfunction and arrhythmia but progresses to systolic dysfunction and end-stage heart failure when left untreated. However, the mechanisms of iron-related cardiac injury and how iron accumulates in human cardiomyocytes are not well understood. Herein, using human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), we model IOC and screen for drugs to rescue the iron overload phenotypes. Human iPSC-CMs under excess iron exposure recapitulate early-stage IOC, including oxidative stress, arrhythmia, and contractile dysfunction. We find that iron-induced changes in calcium kinetics play a critical role in dysregulation of CM functions. We identify that ebselen, a selective divalent metal transporter 1 (DMT1) inhibitor and antioxidant, could prevent the observed iron overload phenotypes, supporting the role of DMT1 in iron uptake into the human myocardium. These results suggest that ebselen may be a potential preventive and therapeutic agent for treating patients with secondary iron overload.

    View details for DOI 10.1016/j.celrep.2020.107886

    View details for PubMedID 32668256

  • Atheroprotective roles of smooth muscle cell phenotypic modulation and the TCF21 disease gene as revealed by single-cell analysis. Nature medicine Wirka, R. C., Wagh, D., Paik, D. T., Pjanic, M., Nguyen, T., Miller, C. L., Kundu, R., Nagao, M., Coller, J., Koyano, T. K., Fong, R., Woo, Y. J., Liu, B., Montgomery, S. B., Wu, J. C., Zhu, K., Chang, R., Alamprese, M., Tallquist, M. D., Kim, J. B., Quertermous, T. 2019

    Abstract

    In response to various stimuli, vascular smooth muscle cells (SMCs) can de-differentiate, proliferate and migrate in a process known as phenotypic modulation. However, the phenotype of modulated SMCs in vivo during atherosclerosis and the influence of this process on coronary artery disease (CAD) risk have not been clearly established. Using single-cell RNA sequencing, we comprehensively characterized the transcriptomic phenotype of modulated SMCs in vivo in atherosclerotic lesions of both mouse and human arteries and found that these cells transform into unique fibroblast-like cells, termed 'fibromyocytes', rather than into a classical macrophage phenotype. SMC-specific knockout of TCF21-a causal CAD gene-markedly inhibited SMC phenotypic modulation in mice, leading to the presence of fewer fibromyocytes within lesions as well as within the protective fibrous cap of the lesions. Moreover, TCF21 expression was strongly associated with SMC phenotypic modulation in diseased human coronary arteries, and higher levels of TCF21 expression were associated with decreased CAD risk in human CAD-relevant tissues. These results establish a protective role for both TCF21 and SMC phenotypic modulation in this disease.

    View details for DOI 10.1038/s41591-019-0512-5

    View details for PubMedID 31359001

  • Generation of Quiescent Cardiac Fibroblasts from Human Induced Pluripotent Stem Cells for In Vitro Modeling of Cardiac Fibrosis. Circulation research Zhang, H., Tian, L., Shen, M., Wu, H., Gu, M., Tu, C., Paik, D. T., Wu, J. C. 2019

    Abstract

    RATIONALE: Activated fibroblasts are the major cell type that secrete excessive extracellular matrix in response to injury, contributing to pathological fibrosis and leading to organ failure. Effective anti-fibrotic therapeutic solutions, however, are not available due to the poorly defined characteristics and unavailability of tissue-specific fibroblasts. Recent advances in single-cell RNA-sequencing (scRNA-seq) fill such gaps of knowledge by enabling delineation of the developmental trajectories and identification of regulatory pathways of tissue-specific fibroblasts among different organs.OBJECTIVE: This study aims to define the transcriptome profiles of tissue-specific fibroblasts using recently reported mouse scRNA-seq atlas, and to develop a robust chemically defined protocol to derive cardiac fibroblasts (CFs) from human induced pluripotent stem cells (iPSCs) for in vitro modeling of cardiac fibrosis and drug screening.METHODS AND RESULTS: By analyzing the single-cell transcriptome profiles of fibroblasts from 10 selected mouse tissues, we identified distinct tissue-specific signature genes, including transcription factors that define the identities of fibroblasts in the heart, lungs, trachea, and bladder. We also determined that CFs in large are of the epicardial lineage. We thus developed a robust chemically-defined protocol that generates CFs from human iPSCs. Functional studies confirmed that iPSC-derived CFs preserved a quiescent phenotype and highly resembled primary CFs at the transcriptional, cellular, and functional levels. We demonstrated that this cell-based platform is sensitive to both pro- and anti-fibrosis drugs. Finally, we showed that crosstalk between cardiomyocytes and CFs via the atrial/brain natriuretic peptide-natriuretic peptide receptor 1 pathway is implicated in suppressing fibrogenesis.CONCLUSIONS: This study uncovers unique gene signatures that define tissue-specific identities of fibroblasts. The bona fide quiescent CFs derived from human iPSCs can serve as a faithful in vitro platform to better understand the underlying mechanisms of cardiac fibrosis and to screen anti-fibrotic drugs.

    View details for DOI 10.1161/CIRCRESAHA.119.315491

    View details for PubMedID 31288631

  • Transcriptomic Profiling of the Developing Cardiac Conduction System at Single-Cell Resolution. Circulation research Goodyer, W. R., Beyersdorf, B., Paik, D. T., Tian, L., Li, G., Buikema, J. W., Chirikian, O., Choi, S., Venkatraman, S., Adams, E. L., Tessier-Lavigne, M., Wu, J. C., Wu, S. M. 2019

    Abstract

    RATIONALE: The cardiac conduction system (CCS) consists of distinct components including the sinoatrial node (SAN), atrioventricular node (AVN), His bundle, bundle branches (BB) and Purkinje fibers (PF). Despite an essential role for the CCS in heart development and function, the CCS has remained challenging to interrogate due to inherent obstacles including small cell numbers, large cell type heterogeneity, complex anatomy and difficulty in isolation. Single-cell RNA-sequencing (scRNA-seq) allows for genome-wide analysis of gene expression at single-cell resolution.OBJECTIVE: Assess the transcriptional landscape of the entire CCS at single-cell resolution by scRNA-seq within the developing mouse heart.METHODS AND RESULTS: Wild-type, embryonic day 16.5 mouse hearts (n=6 per zone) were harvested and three zones of microdissection were isolated, including: Zone I - SAN region; Zone II - AVN/His region; and Zone III - BB/PF region. Tissue was digested into single cell suspensions, isolated, reverse transcribed and barcoded prior to high-throughput sequencing and bioinformatics analyses. scRNA-seq was performed on over 22,000 cells and all major cell types of the murine heart were successfully captured including bona fide clusters of cells consistent with each major component of the CCS. Unsupervised weighted gene co-expression network analysis led to the discovery of a host of novel CCS genes, a subset of which were validated using fluorescent in situ hybridization as well as whole mount immunolabelling with volume imaging (iDISCO+) in three-dimensions on intact mouse hearts. Further, subcluster analysis unveiled isolation of distinct CCS cell subtypes, including the clinically-relevant but poorly characterized "transitional cells" that bridge the CCS and surrounding myocardium.CONCLUSIONS: Our study represents the first comprehensive assessment of the transcriptional profiles from the entire CCS at single-cell resolution and provides a gene atlas for facilitating future efforts in conduction cell identification, isolation and characterization in the context of development and disease.

    View details for DOI 10.1161/CIRCRESAHA.118.314578

    View details for PubMedID 31284824

  • Single-Cell RNA Sequencing of Human Embryonic Stem Cell Differentiation Delineates Adverse Effects of Nicotine on Embryonic Development STEM CELL REPORTS Guo, H., Tian, L., Zhang, J. Z., Kitani, T., Paik, D. T., Lee, W., Wu, J. C. 2019; 12 (4): 772–86
  • Marked Vascular Dysfunction in a Case of Peripartum Cardiomyopathy JOURNAL OF VASCULAR RESEARCH Khanamiri, S., Rhee, J., Paik, D. T., Chen, I. Y., Liu, C., Sayed, N. 2019; 56 (1): 11–15

    View details for DOI 10.1159/000496163

    View details for Web of Science ID 000467678400002

  • Systems-Wide Approaches in Induced Pluripotent Stem Cell Models. Annual review of pathology Lau, E., Paik, D. T., Wu, J. C. 2018

    Abstract

    Human induced pluripotent stem cells (iPSCs) provide a renewable supply of patient-specific and tissue-specific cells for cellular and molecular studies of disease mechanisms. Combined with advances in various omics technologies, iPSC models can be used to profile the expression of genes, transcripts, proteins, and metabolites in relevant tissues. In the past 2 years, large panels of iPSC lines have been derived from hundreds of genetically heterogeneous individuals, further enabling genome-wide mapping to identify coexpression networks and elucidate gene regulatory networks. Here, we review recent developments in omics profiling of various molecular phenotypes and the emergence of human iPSCs as a systems biology model of human diseases. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease Volume 14 is January 24, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    View details for PubMedID 30379619

  • Large-Scale Single-Cell RNA-Seq Reveals Molecular Signatures of Heterogeneous Populations of Human Induced Pluripotent Stem Cell-Derived Endothelial Cells CIRCULATION RESEARCH Paik, D. T., Tian, L., Lee, J., Sayed, N., Chen, I. Y., Rhee, S., Rhee, J., Kim, Y., Wirka, R. C., Buikema, J. W., Wu, S. M., Red-Horse, K., Quertermous, T., Wu, J. C. 2018; 123 (4): 443–50
  • Endothelial deletion of Ino80 disrupts coronary angiogenesis and causes congenital heart disease. Nature communications Rhee, S. n., Chung, J. I., King, D. A., D'amato, G. n., Paik, D. T., Duan, A. n., Chang, A. n., Nagelberg, D. n., Sharma, B. n., Jeong, Y. n., Diehn, M. n., Wu, J. C., Morrison, A. J., Red-Horse, K. n. 2018; 9 (1): 368

    Abstract

    During development, the formation of a mature, well-functioning heart requires transformation of the ventricular wall from a loose trabecular network into a dense compact myocardium at mid-gestation. Failure to compact is associated in humans with congenital diseases such as left ventricular non-compaction (LVNC). The mechanisms regulating myocardial compaction are however still poorly understood. Here, we show that deletion of the Ino80 chromatin remodeler in vascular endothelial cells prevents ventricular compaction in the developing mouse heart. This correlates with defective coronary vascularization, and specific deletion of Ino80 in the two major coronary progenitor tissues-sinus venosus and endocardium-causes intermediate phenotypes. In vitro, endothelial cells promote myocardial expansion independently of blood flow in an Ino80-dependent manner. Ino80 deletion increases the expression of E2F-activated genes and endothelial cell S-phase occupancy. Thus, Ino80 is essential for coronary angiogenesis and allows coronary vessels to support proper compaction of the heart wall.

    View details for PubMedID 29371594

  • SETD7 Drives Cardiac Lineage Commitment through Stage-Specific Transcriptional Activation. Cell stem cell Lee, J. n., Shao, N. Y., Paik, D. T., Wu, H. n., Guo, H. n., Termglinchan, V. n., Churko, J. M., Kim, Y. n., Kitani, T. n., Zhao, M. T., Zhang, Y. n., Wilson, K. D., Karakikes, I. n., Snyder, M. P., Wu, J. C. 2018; 22 (3): 428–44.e5

    Abstract

    Cardiac development requires coordinated and large-scale rearrangements of the epigenome. The roles and precise mechanisms through which specific epigenetic modifying enzymes control cardiac lineage specification, however, remain unclear. Here we show that the H3K4 methyltransferase SETD7 controls cardiac differentiation by reading H3K36 marks independently of its enzymatic activity. Through chromatin immunoprecipitation sequencing (ChIP-seq), we found that SETD7 targets distinct sets of genes to drive their stage-specific expression during cardiomyocyte differentiation. SETD7 associates with different co-factors at these stages, including SWI/SNF chromatin-remodeling factors during mesodermal formation and the transcription factor NKX2.5 in cardiac progenitors to drive their differentiation. Further analyses revealed that SETD7 binds methylated H3K36 in the bodies of its target genes to facilitate RNA polymerase II (Pol II)-dependent transcription. Moreover, abnormal SETD7 expression impairs functional attributes of terminally differentiated cardiomyocytes. Together, these results reveal how SETD7 acts at sequential steps in cardiac lineage commitment, and they provide insights into crosstalk between dynamic epigenetic marks and chromatin-modifying enzymes.

    View details for PubMedID 29499155

  • Autologous iPSC-Based Vaccines Elicit Anti-tumor Responses In Vivo. Cell stem cell Kooreman, N. G., Kim, Y. n., de Almeida, P. E., Termglinchan, V. n., Diecke, S. n., Shao, N. Y., Wei, T. T., Yi, H. n., Dey, D. n., Nelakanti, R. n., Brouwer, T. P., Paik, D. T., Sagiv-Barfi, I. n., Han, A. n., Quax, P. H., Hamming, J. F., Levy, R. n., Davis, M. M., Wu, J. C. 2018

    Abstract

    Cancer cells and embryonic tissues share a number of cellular and molecular properties, suggesting that induced pluripotent stem cells (iPSCs) may be harnessed to elicit anti-tumor responses in cancer vaccines. RNA sequencing revealed that human and murine iPSCs express tumor-associated antigens, and we show here a proof of principle for using irradiated iPSCs in autologous anti-tumor vaccines. In a prophylactic setting, iPSC vaccines prevent tumor growth in syngeneic murine breast cancer, mesothelioma, and melanoma models. As an adjuvant, the iPSC vaccine inhibited melanoma recurrence at the resection site and reduced metastatic tumor load, which was associated with fewer Th17 cells and increased CD11b+GR1himyeloid cells. Adoptive transfer of T cells isolated from vaccine-treated tumor-bearing mice inhibited tumor growth in unvaccinated recipients, indicating that the iPSC vaccine promotes an antigen-specific anti-tumor T cell response. Our data suggest an easy, generalizable strategy for multiple types of cancer that could prove highly valuable in clinical immunotherapy.

    View details for PubMedID 29456158

  • Simply derived epicardial cells. Nature biomedical engineering Paik, D. T., Wu, J. C. 2017; 1

    Abstract

    A chemically defined protocol requiring no animal-derived components allows for the easier derivation and enduring expansion of epicardial cells from human pluripotent stem cells.

    View details for PubMedID 29354320

    View details for PubMedCentralID PMC5772986

  • Coordinated Proliferation and Differentiation of Human-Induced Pluripotent Stem Cell-Derived Cardiac Progenitor Cells Depend on Bone Morphogenetic Protein Signaling Regulation by GREMLIN 2 STEM CELLS AND DEVELOPMENT Bylund, J. B., Trinh, L. T., Awgulewitsch, C. P., Paik, D. T., Jetter, C., Jha, R., Zhang, J., Nolan, K., Xu, C., Thompson, T. B., Kamp, T. J., Hatzopoulos, A. K. 2017; 26 (9): 678-693

    View details for DOI 10.1089/scd.2016.0226

  • Origin of Matrix-Producing Cells That Contribute to Aortic Fibrosis in Hypertension HYPERTENSION Wu, J., Montaniel, K. R., Saleh, M. A., Xiao, L., Chen, W., Owens, G. K., Humphrey, J. D., Majesky, M. W., Paik, D. T., Hatzopoulos, A. K., Madhur, M. S., Harrison, D. G. 2016; 67 (2): 461-468

    Abstract

    Various hypertensive stimuli lead to exuberant adventitial collagen deposition in large arteries, exacerbating blood pressure elevation and end-organ damage. Collagen production is generally attributed to resident fibroblasts; however, other cells, including resident and bone marrow-derived stem cell antigen positive (Sca-1(+)) cells and endothelial and vascular smooth muscle cells, can produce collagen and contribute to vascular stiffening. Using flow cytometry and immunofluorescence, we found that adventitial Sca-1(+) progenitor cells begin to produce collagen and acquire a fibroblast-like phenotype in hypertension. We also found that bone marrow-derived cells represent more than half of the matrix-producing cells in hypertension, and that one-third of these are Sca-1(+). Cell sorting and lineage-tracing studies showed that cells of endothelial origin contribute to no more than one fourth of adventitial collagen I(+) cells, whereas those of vascular smooth muscle lineage do not contribute. Our findings indicate that Sca-1(+) progenitor cells and bone marrow-derived infiltrating fibrocytes are major sources of arterial fibrosis in hypertension. Endothelial to mesenchymal transition likely also contributes, albeit to a lesser extent and pre-existing resident fibroblasts represent a minority of aortic collagen-producing cells in hypertension. This study shows that vascular stiffening represents a complex process involving recruitment and transformation of multiple cells types that ultimately elaborate adventitial extracellular matrix.

    View details for DOI 10.1161/HYPERTENSIONAHA.115.06123

    View details for Web of Science ID 000368454500034

    View details for PubMedID 26693821

  • Wnt10b Gain-of-Function Improves Cardiac Repair by Arteriole Formation and Attenuation of Fibrosis CIRCULATION RESEARCH Paik, D. T., Rai, M., Ryzhov, S., Sanders, L. N., Aisagbonhi, O., Funke, M. J., Feoktistov, I., Hatzopoulos, A. K. 2015; 117 (9): 804-816

    Abstract

    Myocardial infarction causes irreversible tissue damage, leading to heart failure. We recently discovered that canonical Wnt signaling and the Wnt10b ligand are strongly induced in mouse hearts after infarction. Wnt10b regulates cell fate in various organs, but its role in the heart is unknown.To investigate the effect of Wnt10b gain-of-function on cardiac repair mechanisms and to assess its potential to improve ventricular function after injury.Histological and molecular analyses showed that Wnt10b is expressed in cardiomyocytes and localized in the intercalated discs of mouse and human hearts. After coronary artery ligation or cryoinjury in mice, Wnt10b is strongly and transiently induced in peri-infarct cardiomyocytes during granulation tissue formation. To determine the effect of Wnt10b on neovascularization and fibrosis, we generated a mouse line to increase endogenous Wnt10b levels in cardiomyocytes. We found that gain of Wnt10b function orchestrated a recovery phenotype characterized by robust neovascularization of the injury zone, less myofibroblasts, reduced scar size, and improved ventricular function compared with wild-type mice. Wnt10b stimulated expression of vascular endothelial growth factor receptor 2 in endothelial cells and angiopoietin-1 in vascular smooth muscle cells through nuclear factor-κB activation. These effects coordinated endothelial growth and smooth muscle cell recruitment, promoting robust formation of large, coronary-like blood vessels.Wnt10b gain-of-function coordinates arterial formation and attenuates fibrosis in cardiac tissue after injury. Because generation of mature blood vessels is necessary for efficient perfusion, our findings could lead to novel strategies to optimize the inherent repair capacity of the heart and prevent the onset of heart failure.

    View details for DOI 10.1161/CIRCRESAHA.115.306886

    View details for Web of Science ID 000362410300009

    View details for PubMedID 26338900

  • Endothelial Cells Contribute to Generation of Adult Ventricular Myocytes during Cardiac Homeostasis CELL REPORTS Fioret, B. A., Heimfeld, J. D., Paik, D. T., Hatzopoulos, A. K. 2014; 8 (1): 229-241

    Abstract

    Cardiac tissue undergoes renewal with low rates. Although resident stem cell populations have been identified to support cardiomyocyte turnover, the source of the cardiac stem cells and their niche remain elusive. Using Cre/Lox-based cell lineage tracing strategies, we discovered that labeling of endothelial cells in the adult heart yields progeny that have cardiac stem cell characteristics and express Gata4 and Sca1. Endothelial-derived cardiac progenitor cells were localized in the arterial coronary walls with quiescent and proliferative cells in the media and adventitia layers, respectively. Within the myocardium, we identified labeled cardiomyocytes organized in clusters of single-cell origin. Pulse-chase experiments showed that generation of individual clusters was rapid but confined to specific regions of the heart, primarily in the right anterior and left posterior ventricular walls and the junctions between the two ventricles. Our data demonstrate that endothelial cells are an intrinsic component of the cardiac renewal process.

    View details for DOI 10.1016/j.celrep.2014.06.004

    View details for Web of Science ID 000341403000022

    View details for PubMedID 25001281