Clonogenic Hepatocytes Play a Key Role in Postnatal Liver Growth and Open New Possibilities for Pediatric Gene Therapy

Recent research highlights that a specific subset of liver cells, known as clonogenic hepatocytes, are essential drivers of liver growth after birth. In a study published in the Journal of Hepatology, scientists from the San Raffaele Telethon Institute for Gene Therapy (SR-Tiget) revealed that only about 15–20% of hepatocytes in newborn mice are responsible for producing over 90% of the adult liver mass. These clonogenic cells are located near hematopoietic islands and develop zonated identities as the liver matures, which has important implications for in vivo gene therapy approaches.

Using advanced techniques such as single-cell spatial transcriptomics, clonal tracing, and mathematical modeling, researchers identified not only the clonogenic hepatocytes but also the molecular signals and tissue environments that regulate their proliferation. Spatial transcriptomics provided detailed insights into the exact positioning and gene expression of these cells during postnatal liver development.

The study further demonstrated that gene editing via homology-directed repair (HDR) is highly enriched within clonogenic hepatocytes, leading to a larger proportion of the liver being genetically modified as the organ grows. Conversely, lentiviral vectors, commonly used for gene delivery, distribute more evenly but are less efficient in mature liver zones, particularly after weaning, due to increased proteasome activity that hinders transduction. Interestingly, pre-treatment with proteasome inhibitors improved gene transfer efficiency in adult hepatocytes.

Another notable discovery is the presence of a specialized regenerative niche in neonatal livers, where clonogenic hepatocytes are closely associated with hematopoietic progenitors. This spatial arrangement suggests shared signaling pathways that could be exploited for regenerative medicine.

These findings are vital for developing durable gene therapies for pediatric liver diseases. Understanding how liver growth and cellular identity influence gene delivery enables the rational design of more effective interventions. Dr. Alessio Cantore emphasizes that targeting specific hepatocyte populations early in life holds promise for long-lasting therapeutic effects. The team aims to further explore the underlying mechanisms and translate these insights into clinical applications.

This multidisciplinary research involved collaborations across molecular biology, biophysics, and bioinformatics, opening new avenues for treating genetic liver disorders in children and improving the efficacy of in vivo gene editing techniques.

Source: Medical Xpress