(1). For many decades, stem cells and other primitive cells have been known to resist virus infection, particularly retroviruses. Recent studies have made similar observations with a diverse array of viruses and tissue stem cells, suggesting that virus resistance is a general property of stem cells. Such restriction likely evolved to protect these primitive cells because of their critical roles in tissue regeneration and repair. Eukaryotic cells have evolved multiple strategies to protect themselves against pathogens. Stem cells, however, are unique. When exposed to pathogens they do not produce the same robust interferon (IFN) responses that terminally differentiated cells use to combat infection. Therefore, the mechanisms by which stem cells potently block virus infection are poorly understood.
Our recent study revealed that stem cells constitutively express subset of IFN stimulated genes (ISGs), independently of IFNs. This intrinsic ISG expression varies in a cell type-specific manner and ISG expression decreases as cells terminally differentiate at which time cells become responsive to canonical IFN signaling. We also demonstrated that intrinsically expressed ISGs protect stem cells against viral infection in vitro and in vivo. The mechanisms underlying this intrinsic ISG expression in stem cells, however, remain elusive. To this end, we will use comprehensive and less biased approaches (e.g. RNA-seq, ATAC-seq, CRISPR KO screens) to dissect the regulatory mechanisms governing intrinsic ISG expression in stem cells.
(2). Mechanistic insights into human disease may enable the development of treatments that are effective in broad patient populations. Traditionally, human diseases have been modeled in animals, which enable many powerful avenues for research. Recently, the emergence and marriage of ex vitro human pluripotent stem cells (hPSCs, including hESC and iPSCs)-based human tissue engineering technologies and new powerful tools for genomic editing/mutagenesis have offered new opportunities for human disease modeling and deep biological understanding, especially for diseases that are associated with genetic variations, promising the personalized/precise identification of drug targets and biomarkers for improving clinical practice. In this project, we will be focusing on developing multicellular models (organoid culture and 3D Transwell culture) to understand fibrotic liver diseases, including alcoholic and nonalcoholic fatty liver diseases.