Identifying factors that regenerate injured hepatocytes using CRISPR screens
We perform CRISPR screens to identify reprogramming factors ameliorating disease-associated transcriptional circuits in human hepatocytes. We apply this technology to models of lipotoxicity and cholestasis in primary human hepatocytes, iPSC-multi-lineage organoids and human ductal organoids. Among different assays, we harness artificial intelligence-guided microscopy that allows label-free, high-throughput analysis of CRISPR screens. Ultimately, we aim to understand single-cell transcriptional circuits and perturbations in human hepatocytes relevant to chronic liver diseases, e.g., non-alcoholic steatohepatitis (NASH). Importantly, we hope to overcome the limitations of mouse and rat studies.

In vivo Liver Reprogramming
Developing regenerative therapies for chronic liver injuries is demanding because little is known about human hepatocyte transcriptional programs providing resilience and regeneration in vivo. We perform in vivo competitive gene selection screens to identify transcription factors and zonal signals restoring function and tissue regeneration in humanized models of chronic liver injury.

Modeling the human fetal liver with Hepato-hematopoietic Organoids from Pluripotent Stem Cells
The mammalian fetal liver harbors hematopoietic stem and progenitor cells. We lineage-engineer from endoderm and mesoderm human fetal liver organoids that co-develop different syngeneic lineages, e.g., hepatoblasts, stellate cells, hematopoietic progenitor cells and different immune cell lineages, e.g., macrophages and granulocytes. Single-cell multi-omics and bioinformatic analyses help us to understand lineage bifurcations and cell-cell interactions. Ultimately, this human fetal liver organoid platform could serve for the studies of infant leukemias or newborn inflammatory liver diseases.