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.
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)
Bachelor of Arts, Boston University (2010)
Doctor of Philosophy, Vanderbilt University (2015)
Joseph Wu, Postdoctoral Faculty Sponsor
- Single-Cell RNA Sequencing of Human Embryonic Stem Cell Differentiation Delineates Adverse Effects of Nicotine on Embryonic Development STEM CELL REPORTS 2019; 12 (4): 772–86
- Marked Vascular Dysfunction in a Case of Peripartum Cardiomyopathy JOURNAL OF VASCULAR RESEARCH 2019; 56 (1): 11–15
Systems-Wide Approaches in Induced Pluripotent Stem Cell Models.
Annual review of pathology
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.
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.
2018; 9 (1): 368
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
2018; 22 (3): 428–44.e5
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
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
2017; 26 (9): 678-693
View details for DOI 10.1089/scd.2016.0226
- Simply derived epicardial cells. Nature biomedical engineering 2017; 1
Origin of Matrix-Producing Cells That Contribute to Aortic Fibrosis in Hypertension
2016; 67 (2): 461-468
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
2015; 117 (9): 804-816
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
2014; 8 (1): 229-241
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