SOX9 Is a Key Factor for the Postnatal Maturation of the Intrahepatic Bile Duct Network.

Aim: The sex-determining region Y-box 9 (SOX9) plays a critical role in the development of intrahepatic bile ducts (IHBDs) during the embryonic stage. However, its role in postnatal IHBD maturation remains unclear. This study aimed to investigate the function of SOX9 in the postnatal development of the bile duct network, with particular emphasis on its role in structural organization.

Methods: Three-dimensional imaging analysis was conducted using a mouse model in which SOX9 deficiency is predominant after birth to assess the structural organization of IHBDs. Additionally, transcriptional profiling was performed in Sox9 conditional knockout (cKO) mice to elucidate mechanisms underlying abnormal IHBD morphogenesis.

Results: In Sox9 cKO mice, bile ductules were significantly reduced in the middle region at 1, 5, and 10 weeks, whereas a ductular reaction was observed in the peripheral region at 5 and 10 weeks, likely in response to cholestatic liver injury, compared to control mice. SOX9 was essential for IHBD maturation and structural organization, in particular, in establishing connections between bile ductules and also between bile ductules and bile canaliculi. Furthermore, transcriptome analysis of Sox9 cKO mice revealed activation of compensatory pathways involved in bile acid transport and metabolism, whereas intercellular adhesion pathways were downregulated.

Conclusions: These findings underscore the pivotal role of SOX9 in postnatal bile duct network development, demonstrating its critical involvement in maintaining structural organization. The results suggest that SOX9 plays a more substantial role in bile duct maturation than previously recognized, providing new insights into its regulatory mechanisms in liver development.