Identification of hepatocyte-primed cholangiocytes in the homeostatic liver by in vivo lentiviral gene transfer to mice and non-human primates

Liver regeneration is supported by hepatocytes and, in certain conditions, biliary epithelial cells (BECs). BECs are facultative liver stem cells that form organoids in culture and engraft in damaged livers. However, BEC heterogeneity in the homeostatic liver remains to be fully elucidated. Here, we exploit systemic lentiviral vector (LV) administration to achieve efficient and lifelong gene transfer to BECs in mice. We find that LV-marked BECs retain organoid formation potential and predominantly respond to liver damage; however, they are less clonogenic and display a hepatocyte-primed transcriptome compared to untransduced BECs. We thus identify a BEC subset committed to hepatocyte lineage in the absence of liver damage, characterized by a transcriptional network orchestrated by hepatocyte nuclear factor 4α. We also report in vivo targeting of such BECs in non-human primates. This work highlights intrinsic BEC heterogeneity and that in vivo LV gene transfer to the liver may persist following BEC-mediated repair of hepatic damage.

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Publication Details

Journal
Cell Reports
Published
2025-02-24
DOI
https://doi.org/10.1016/j.celrep.2025.115341
Citations
3
Primary Topic
Liver physiology and pathology
Type
article
Field-Weighted Citation Impact
3.97

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article

Identification of hepatocyte-primed cholangiocytes in the homeostatic liver by in vivo lentiviral gene transfer to mice and non-human primates

Francesco Starinieri, Tiziana Plati, Valeria Berno, Mauro Biffi et al.
3 citations
Cell Reports
Liver physiology and pathology
3.97
article

Identification of hepatocyte-primed cholangiocytes in the homeostatic liver by in vivo lentiviral gene transfer to mice and non-human primates

Francesco Starinieri, Tiziana Plati, Valeria Berno, Mauro Biffi, Ivan Merelli, Francesca Sanvito, Fabio Russo, Rossana Norata, Alessio Cantore, Luigi Aloia, Michela Milani, Meritxell Huch, Luigi Naldini, Cesare Canepari, Stefano Beretta, Anna Fabiano
article en
3 citations

Abstract

Liver regeneration is supported by hepatocytes and, in certain conditions, biliary epithelial cells (BECs). BECs are facultative liver stem cells that form organoids in culture and engraft in damaged livers. However, BEC heterogeneity in the homeostatic liver remains to be fully elucidated. Here, we exploit systemic lentiviral vector (LV) administration to achieve efficient and lifelong gene transfer to BECs in mice. We find that LV-marked BECs retain organoid formation potential and predominantly respond to liver damage; however, they are less clonogenic and display a hepatocyte-primed transcriptome compared to untransduced BECs. We thus identify a BEC subset committed to hepatocyte lineage in the absence of liver damage, characterized by a transcriptional network orchestrated by hepatocyte nuclear factor 4α. We also report in vivo targeting of such BECs in non-human primates. This work highlights intrinsic BEC heterogeneity and that in vivo LV gene transfer to the liver may persist following BEC-mediated repair of hepatic damage.

Cell ReportsVol. 44(3)
Vita-Salute San Raffaele University (IT), University of Cambridge (GB), The Gurdon Institute (GB), The San Raffaele Telethon Institute for Gene Therapy (IT), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Institute of Biomedical Technologies (IT), Max Planck Institute of Molecular Cell Biology and Genetics (DE), Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT)
Fondazione Telethon, Horizon 2020 Framework Programme
Zero hunger
Openalex Percentile: Top 7%
Liver physiology and pathology
3.97
DOIOpen Access PDFOpenAlex
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