Liver Maturation Insights Boost Regenerative Medicine

New insights into liver maturation and specialization could advance regenerative medicine

By Jeni Bushman,

Biochemistry professor Nash Kalsotra Credit: University of Illinois at Urbana-Champaign

Researchers from the University of Illinois have identified a key process coordinating liver maturation and polyploidization, a state in which cells carry more than two sets of chromosomes. Their findings, published in Genes & Development, provide insight into hepatocyte specialization that will aid efforts in regenerative medicine.

The Many Functions of the Liver

The human liver performs over 150 specialized functions, including filtering blood, removing waste, regulating blood sugar, and digesting fats. Hepatocytes—the main cell type of the liver—are fully formed by birth but remain dormant for the first few weeks of life. During this time, they gradually mature and develop specialized attributes.

Understanding Hepatocyte Maturation

For decades, biologists have pondered how hepatocytes mature after birth and achieve their dedicated functions. Further, how can scientists leverage this knowledge to improve liver regeneration, as the liver is unique among internal organs in its ability to regenerate or repair itself after injury?

"Over the past 15 to 20 years, biologists have made significant progress in isolating stem cells," said Nash Kalsotra, a professor of biochemistry at the University of Illinois and the lead author of the paper. "We can differentiate these stem cells into various cell types, creating much promise in regenerative biology. However, the challenge remains: how do we take these rudimentary cells and help them mature?"

Research Focus: ESRP2

Kalsotra's lab aims to address this issue by examining the epithelial factor ESRP2, which is known to control RNA splicing in the liver. Absent in the fetus, ESRP2 is activated after birth.

"We know that ESRP2 is turned on at the time when liver cells start to mature," Sushant Bangru (Ph.D., biochemistry), the first author of the study, explains. "But we sought to determine if this activation is merely coincidental or if ESRP2 plays a critical role in liver maturity."

The lab utilized a combination of genetics, single-cell transcriptomics, and imaging approaches, generating mouse models that allow for the manipulation of ESRP2 protein function.

Key Findings

The research revealed:

• Removal of ESRP2 from hepatocytes resulted in the immaturity of adult livers.
• Accelerated maturation and metabolic functions occurred when ESRP2 was activated earlier than normal in mouse pups.

This indicates that ESRP2 is a crucial factor influencing liver function and prompting hepatocytes' transition to maturity.

Post-Transcriptional Regulation

Kalsotra noted that "post-transcriptional regulation fine-tunes the final phases of gene expression." This process plays a pivotal role in producing the right assortment of protein variants necessary for a maturing liver.

Exploring ESRP2's Regulatory Network

The research team also worked to identify both direct and indirect targets of ESRP2, unveiling its entire regulatory network. A significant finding was the binding of ESRP2 to non-coding microRNA-122 (miR-122), which regulates hepatocyte polyploidy.

"The liver acquires a high percentage of polyploid hepatocytes after birth, and miR-122-driven cytokinesis failure is critical during this process," Kalsotra explained. "The postnatal surge in ploidy is essential for the functional specialization of hepatocytes and provides protection against cancer."

Table 1: Key Insights from ESRP2 Research

The Implications for Regenerative Medicine

Understanding how the liver prefers to cope with injuries is crucial. "The liver does not have a dedicated reservoir of stem cells," Kalsotra remarks. "Only healthy liver cells can produce new cells in adults. Normally, hepatocytes are quiescent, but in response to injury or cell death, the surviving hepatocytes first lose their maturity before dividing."

Currently, researchers are exploring how to induce adult cells to revert to an immature state and subsequently back to full maturity. This shift is pivotal in enhancing the regenerative response to match the organism's needs.

Conclusion

Advancements in understanding postnatal liver maturation through ESRP2 provide a pathway toward improved regenerative therapies. By fine-tuning the regenerative processes within the liver, we can hope to mitigate the challenges faced during liver damage and disease.

Further Reading

For more insights into this study, refer to the publication: Sushant Bangru et al, ESRP2–microRNA-122 axis promotes the postnatal onset of liver polyploidization and maturation, Genes & Development (2025).

[1] Lifespan.io