Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic has infected more than 20 million people worldwide as of August 2020 and significantly altered our way of life. Despite its relative low case-fatality rate, the new coronavirus disease (COVID-19) can cause serious illness in people with pre-existing conditions like individuals with Down Syndrome (DS). It is projected that SARS-CoV-2 can cause 8.9-fold increased risk of COVID-19 related hospitalization and deaths in DS patients, yet we have limited experimental resource to understand the basic mechanisms underlying differential disease susceptibility and progression. Here we propose to use i) human induced pluripotent stem cells (iPSCs), ii) tissue-like organoids, iii) live SARS-CoV-2 virus and iv) serum collected from COVID-19 patients. We will generate 40 iPSC-derived organoids from DS and non-DS individuals and infect them with SARS-CoV-2. We will focus on two major clinical manifestations commonly observed in COVID-19 patients with critical conditions: viral myocarditis and severe pulmonary inflammation.
For Aim 1, we will generate cardiac organoids composing of iPSC-derived cardiomyocytes, endothelial cells, and cardiac fibroblasts to assess their functional and structural changes after SARS-CoV-2 infection.
For Aim 2, we will generate lung organoids composing of iPSC-derived lung epithelial cells, endothelial cells, alveolar macrophages, and identify an inflammatory signature after SARS-CoV-2 infection. For both Aims, we will perform single cell RNA sequencing to identify differential gene response among different cell types which contribute to phenotypic changes following SARS-CoV-2 infection.

Public Health Relevance

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) can disproportionally infect and kill individuals with Down Syndrome (DS) at a greater rate than individuals without DS. To investigate the underlying health disparity of coronavirus disease (COVID-19), we plan to use organoids derived from human induced pluripotent stem cells (iPSCs) of DS versus non-DS individuals. Using live SARS-CoV-2 virus and serum collected from COVID-19 patients, we will investigate 1) whether the virus causes myocarditis in cardiac organoids and 2) characterize the inflammatory response in lung organoids from DS and non-DS individuals.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Program Officer
Desvigne-Nickens, Patrice
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Stanford University
Schools of Medicine
United States
Zip Code
Chang, Alex C Y; Chang, Andrew C H; Kirillova, Anna et al. (2018) Telomere shortening is a hallmark of genetic cardiomyopathies. Proc Natl Acad Sci U S A 115:9276-9281
Lee, Jaecheol; Shao, Ning-Yi; Paik, David T et al. (2018) SETD7 Drives Cardiac Lineage Commitment through Stage-Specific Transcriptional Activation. Cell Stem Cell 22:428-444.e5
Knowles, Joshua W; Ashley, Euan A (2018) Cardiovascular disease: The rise of the genetic risk score. PLoS Med 15:e1002546
Zhang, Joe Z; Guo, Hongchao; Wu, Joseph C (2018) Applications of genetically engineered human pluripotent stem cell reporters in cardiac stem cell biology. Curr Opin Biotechnol 52:66-73
Rhee, Siyeon; Chung, Jae I; King, Devin A et al. (2018) Endothelial deletion of Ino80 disrupts coronary angiogenesis and causes congenital heart disease. Nat Commun 9:368
Ma, Ning; Zhang, Joe Z; Itzhaki, Ilanit et al. (2018) Determining the Pathogenicity of a Genomic Variant of Uncertain Significance Using CRISPR/Cas9 and Human-Induced Pluripotent Stem Cells. Circulation 138:2666-2681
Liu, Chun; Oikonomopoulos, Angelos; Sayed, Nazish et al. (2018) Modeling human diseases with induced pluripotent stem cells: from 2D to 3D and beyond. Development 145:
Rhee, June-Wha; Wu, Joseph C (2018) Cardiac Cell Cycle Activation as a Strategy to Improve iPSC-Derived Cardiomyocyte Therapy. Circ Res 122:14-16
Karakikes, Ioannis; Termglinchan, Vittavat; Cepeda, Diana A et al. (2017) A Comprehensive TALEN-Based Knockout Library for Generating Human-Induced Pluripotent Stem Cell-Based Models for Cardiovascular Diseases. Circ Res 120:1561-1571
Li, Yingxin; Sallam, Karim; Schwartz, Peter J et al. (2017) Patient-Specific Induced Pluripotent Stem Cell-Based Disease Model for Pathogenesis Studies and Clinical Pharmacotherapy. Circ Arrhythm Electrophysiol 10:

Showing the most recent 10 out of 33 publications