Bio

Bio


Dr. David Paik is a postdoctoral fellow working with Dr. Joseph Wu at Stanford Cardiovascular Institute. At Stanford, his focus is to utilize single-cell RNA-sequencing technology 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). At Vanderbilt, Dr. Paik was trained by Dr. Antonis Hatzopoulos to investigate the endogenous cardiac repair mechanisms in the adult heart following ischemic injury such as myocardial infarction. In particular, Dr. Paik focused on the role of Wnt signaling pathway on coronary vessel formation and plasticity of cardiac endothelial cells during cardiac tissue repair. During his PhD training, 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.

Institute Affiliations


  • Member, Maternal & Child Health Research Institute (MCHRI)

Honors & Awards


  • 2018 CVI Manuscript Award, Stanford Cardiovascular Institute (05/2019)
  • 2018 Best Manuscript Award, Circulation Research (11/2018)
  • Stanford CVI Travel Award, Stanford Cardiovascular Institute (12/2017)
  • NIH T32 Postdoctoral Training Grant, Stanford University (11/2016-11/2018)
  • NIH T32 Predoctoral Training Grant, Vanderbilt University (07/2013-06/2015)
  • Certificate Program in Molecular Medicine, Vanderbilt University (2015)
  • Mark W. Riemen Research Prize, Boston University (2009)

Professional Education


  • Bachelor of Arts, Boston University (2010)
  • Doctor of Philosophy, Vanderbilt University (2015)

Stanford Advisors


Publications

All Publications


  • 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

    Abstract

    Rationale: Human induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) have risen as a useful tool in cardiovascular research, offering a wide gamut of translational and clinical applications. However, inefficiency of the currently available iPSC-EC differentiation protocol and underlying heterogeneity of derived iPSC-ECs remain as major limitations of iPSC-EC technology. Objective: Here we performed droplet-based single-cell RNA-sequencing (scRNA-seq) of the human iPSCs following iPSC-EC differentiation. Droplet-based scRNA-seq enables analysis of thousands of cells in parallel, allowing comprehensive analysis of transcriptional heterogeneity. Methods and Results: Bona fide iPSC-EC cluster was identified by scRNA-seq, which expressed high levels of endothelial-specific genes. iPSC-ECs, sorted by CD144 antibody-conjugated magnetic sorting, exhibited standard endothelial morphology and function including tube formation, response to inflammatory signals, and production of nitric oxide. Non-endothelial cell populations resulting from the differentiation protocol were identified, which included immature and atrial-like cardiomyocytes, hepatic-like cells, and vascular smooth muscle cells. Furthermore, scRNA-seq analysis of purified iPSC-ECs revealed transcriptional heterogeneity with four major subpopulations, marked by robust enrichment of CLDN5, APLNR, GJA5, and ESM1 genes respectively. Conclusions: Massively parallel, droplet-based scRNA-seq allowed meticulous analysis of thousands of human iPSCs subjected to iPSC-EC differentiation. Results showed inefficiency of the differentiation technique, which can be improved with further studies based on identification of molecular signatures that inhibit expansion of non-endothelial cell types. Subtypes of bona fide human iPSC-ECs were also identified, allowing us to sort for iPSC-ECs with specific biological function and identity.

    View details for PubMedID 29986945

  • Endothelial deletion of Ino80 disrupts coronary angiogenesis and causes congenital heart disease. Nature communications Rhee, S., Chung, J. I., King, D. A., D'amato, G., Paik, D. T., Duan, A., Chang, A., Nagelberg, D., Sharma, B., Jeong, Y., Diehn, M., Wu, J. C., Morrison, A. J., Red-Horse, K. 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., Shao, N. Y., Paik, D. T., Wu, H., Guo, H., Termglinchan, V., Churko, J. M., Kim, Y., Kitani, T., Zhao, M. T., Zhang, Y., Wilson, K. D., Karakikes, I., 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., de Almeida, P. E., Termglinchan, V., Diecke, S., Shao, N. Y., Wei, T. T., Yi, H., Dey, D., Nelakanti, R., Brouwer, T. P., Paik, D. T., Sagiv-Barfi, I., Han, A., Quax, P. H., Hamming, J. F., Levy, R., 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

  • 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

  • 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

  • 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