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Spatio-temporal dynamics of the mouse liver shapes hepatocytes heterogeneity and impacts in vivo gene transfer and gene editing [RNA-seq]

ABSTRACT: The liver is a central organ for physiology and metabolism, with hepatocytes being the main cell type responsible for most of its functions. Several previous studies investigated the cell types involved in tissue homeostasis and regeneration, however the mechanisms underlying post-natal liver growth and establishment of the mature hepatocyte phenotypes remain to be fully understood. Moreover, genetic modification of hepatocytes is emerging as a promising therapeutic approach, particularly for genetic diseases of the coagulation system and hepatic metabolism. Here, we investigate liver tissue dynamics in mice during post-natal growth and turnover in adulthood, by spatial transcriptomics, clonal analysis, and lineage tracing. We observe progressive establishment of metabolic zonation of hepatocytes and that only a fraction of hepatocytes proliferates in the newborn liver, generating most of the adult tissue. We assess the impact of these changes on both in vivo liver gene transfer and gene editing. We show that the age at treatment affects both the efficiency and lobule distribution of lentiviral vector-mediated gene transfer, and that preferential targeting of the more proliferating hepatocytes allows expansion of the genetically modified liver area. Overall, our findings provide new insights into the spatio-temporal dynamics of the liver during post-natal growth and hepatocyte heterogeneity, with broad implications for liver biology and therapeutic applications.

ORGANISM(S): Mus musculus

PROVIDER: GSE236423 | GEO | 2023/08/01

REPOSITORIES: GEO

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Project description:Genomic analysis of human hepatocellular carcinoma (HCC) is potentially confounded by the differentiation state of the hepatic cell-of-origin. Here we integrated genomic analysis of mouse HCC (with defined cell-of-origin) along with normal liver development. We found a major shift in expression of Wnt and RXR-Î± pathway genes (up and down, respectively) coincident with the transition from hepatoblasts to hepatocytes. A combined Wnt and RXR-Î± gene signature categorized HCCs into two subtypes (high Wnt, low RXR-Î± and low Wnt, high RXR-Î±), which matched cell-of-origin in mouse models and the differentiation state of human HCC. Suppression of RXR-Î± levels in hepatocytes increased Wnt signaling and enhanced tumorigenicity, whereas ligand activation of RXR-Î± achieved the opposite. These results corroborate that there are two main HCC subtypes that correspond to the degree of hepatocyte differentation and that RXR-Î±, in part via Wnt signaling, plays a key functional role in the hepatocyte-like subtype and potentially could serve as a selective therapeutic target. Total RNA from whole livers taken at different developmental timepoints (embryonic day 14, embryonic day 18, post-natal day 5 and post-natal day 56) along with hepatoblasts isolated from E14 livers and immature hepatocytes isolated from E18 livers was extracted and purified using the Qiagen RNeasy Mini Kit. RNA purity and integrity were assayed by the Bioanalyser 2100 (Agilent Technologies). For each sample, 2 Âµg of total RNA was reverse transcribed and amplified by using an RNA amplification kit from Ambion. Fifteen micrograms of amplified RNA were labeled by direct chemical coupling to the Cy5 NHS ester (Amersham Biosciences). Normal adult mouse liver (Agilent) was used as control and Cy3 labeled. Labeled RNAs were purified, fragmented, and used as probes to hybridize microarrays. Gene expression profiling was done with the 4x44k mouse Agilent platform. Expression profiling of the 23 human HCC samples was previously described

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Spatio-temporal dynamics of the mouse liver shapes hepatocytes heterogeneity and impacts in vivo gene transfer and gene editing [RNA-seq]

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