Breakthrough Research on Liver Cell Development May Enhance Regenerative Therapies
Researchers at the University of Illinois have uncovered significant mechanisms that govern the maturation of liver cells and their transition into a polyploid state, where cells possess multiple sets of chromosomes. The study, published in Genes and Development, highlights the specialization of hepatocytes, which is crucial for advancements in regenerative medicine.
The liver is responsible for over 150 essential functions, including blood filtration, waste elimination, blood sugar regulation, and fat digestion. Hepatocytes, the primary cells in the liver, are fully formed at birth but remain inactive during the initial weeks of life. During this period, these cells gradually mature and acquire specialized capabilities.
For many years, scientists have sought to understand how liver cells mature after birth and how this knowledge can be utilized to improve liver regeneration, as it is the only internal organ capable of self-repair following injury. According to the lead researcher, advancements in isolating stem cells over the past two decades have shown promise for regenerative biology. While scientists can differentiate stem cells into various cell types, these cells often remain in an immature state, thus functioning inadequately when transplanted into damaged organs. The critical challenge now is determining how to facilitate the maturation of these rudimentary cells.
The research team investigated the role of the epithelial factor ESRP2, a regulatory protein that influences RNA splicing in the liver. ESRP2 is inactive during fetal development but becomes active after birth. The team sought to determine whether the activation of ESRP2 coincides with liver cell maturation or plays a direct role in this process.
Utilizing a combination of advanced genetic techniques, single-cell transcriptomics, and imaging approaches, the researchers created mouse models that allowed them to manipulate the function of ESRP2. They found that removing ESRP2 from hepatocytes resulted in the immaturity of adult livers, whereas activating ESRP2 prematurely in neonatal livers accelerated the maturation process and enhanced metabolic functions. The findings indicate that ESRP2 serves as a crucial factor in the maturation of hepatocytes.
The researchers also observed that post-transcriptional regulation fine-tunes the final stages of gene expression in the liver. They identified numerous changes in alternative splicing, which produce an array of protein variants necessary for liver maturation. Additionally, they discovered that ESRP2 interacts significantly with microRNA-122 (miR-122), a known regulator of hepatocyte polyploidy.
The liver experiences a substantial increase in polyploid hepatocytes following birth, a process driven by miR-122 that results in cytokinesis failure, the final step of cell division. This increase in ploidy is essential for the functional specialization of hepatocytes and provides the liver with a protective mechanism against cancer.
The research demonstrated that ESRP2 is necessary for the timely production of miR-122 and the subsequent polyploidization of liver cells after birth. The team plans to further investigate how ESRP2 influences RNA splicing and optimizes miR-122 production to regulate ploidy in hepatocytes.
As the liver lacks a dedicated reservoir of stem cells, it relies on existing healthy liver cells to generate new cells in adults. Typically, hepatocytes remain inactive, but in response to injury or cell loss, surviving hepatocytes revert to an immature state before they can divide. Understanding how to manipulate these adult cells to transition between immature and fully functional states could significantly enhance regenerative responses in the liver.
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