Spatiotemporal liver dynamics shape hepatocellular heterogeneity and impact in vivo gene engineering
Abstract
Background & aims: Hepatocytes are the liver's main functional cells and are key targets for in vivo gene therapy to treat monogenic diseases. Integrating the transgene into the genome is critical for long-term expression from a single early-life dose, which is achievable via integrating vectors or genome editing. To ensure persistence through liver growth and cell turnover, it is also necessary to target the hepatocytes driving these processes. While liver regeneration and homeostasis have been studied extensively, hepatocyte growth and maturation remain less well understood. Here, we investigate how hepatocyte heterogeneity evolves during liver growth and its implications for in vivo gene engineering.
Methods: We performed clonal tracing, as well as single-cell and spatial transcriptomics, on mouse livers of various ages. We evaluated the efficiency, stability, and lobule distribution of lentiviral gene transfer and targeted transgene integration.
Results: We found that a subset of clonogenic hepatocytes (15-20%) in the newborn liver generates >90% of the adult tissue and co-localizes with hematopoietic islands within a spatial niche. Preferential gene editing of these clonogenic hepatocytes resulted in an increased proportion of the gene-engineered liver area, supporting their role in liver growth. Age-dependent hepatocellular heterogeneity affected the efficiency of lentiviral gene delivery in vivo and its distribution throughout the hepatic lobule. The gradual…
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