Activation and Spatial Redistribution of RNA Splicing Factors Trigger Hepatic Regeneration

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BACKGROUND & AIMS: Tissue injury with regenerative obstacle leads to liver failure and inevitable consequent hepatic diseases. Yet, precise spatial and molecular alterations to initiate liver regeneration remain unknown. METHODS: We employed spatiotemporal sequencing of regenerating liver combined with high-throughput single-cell RNA sequencing of established hepatocyte organoids (Hep-Orgs) mimicking the regenerative start, elucidate that splicing factors (SFs) were key factors responsible for liver regeneration. Additionally, we verify the function of splicing factors in knockout mice models in vivo. RESULTS: We observed that the upregulation of SFs in regenerative zone of liver and precycling or cycling hepatocytes subpopulation of Hep-Orgs. We demonstrated that the splicing inhibitors suppress liver regeneration by increasing ribosomal proteins. Moreover, we identified HNRNPU as the key SF for liver regeneration benefit to preventing chronic liver diseases like metabolic dysfunction-associated steatotic liver disease. CONCLUSIONS: The spatial remodeling of upregulated RNA SFs drives the first regenerative wave from the periportal zone. The reprogrammed subpopulations defined by highly expressed SFs represent original repopulating hepatocytes. Inhibiting RNA splicing leads to cellular upregulation of ribosomal proteins (RPs), less proliferative signals, and abnormal lipid accumulation. Knockout of SFs leads to failure of liver regeneration and zonal disorder. SF reduction marks severe metabolic dysfunction-associated steatotic liver disease in patients and knockout mouse models. Our results lay the molecular foundation for tissue repair initiation and further developing potential therapeutic targets for liver disease.