1. Cell reprogramming of chronically injured hepatocytes in vivo and in organoids to restore hepatic function and regeneration as novel therapeutic strategy. We model chronic liver diseases–e.g. non-alcoholic fatty liver disease (NAFLD)–in “humanized” mice harboring human liver cells and human, multi-cellular iPSC-derived organoids. While we constantly try to reduce experimental mouse numbers (3R principles), we perform CRISPR screens using transcriptionally-barcoded gRNAs to determine at a molecular level those gene combinations that regenerate liver cells under lipotoxic stress.
2. Generating human fetal liver organoids with hematopoiesis. We develop human fetal liver organoids–as a platform technology–that harbor syngeneic hepatoblasts, and a “hematopoietic niche” that gives rise to progenitors and multiple lineages. Such platform helps to elucidate the interplay between hepatic and hematopoietic ontogeny. Such developmental assay is relevant to studies of infant leukemias, hepatoblastoma and neonatal auto-inflammatory liver diseases. For this project, we collaborate with the Takebe lab in Cincinnati and Tokyo.
3. Modeling autoinflammation and autoimmunity in human organoids. Here, we harness our know-how in human multi-tissue organoid technology to innovate models of autoinflammatory and autoimmune processes as liver organoids harboring syngeneic auto-aggressive immune cell subsets.