Liver transplantation is currently the standard treatment in cases of severe liver failure. However, this approach faces two major challenges: first, there are not enough donated livers to meet everyone’s needs; second, patients must take strong medications for the rest of their lives to prevent their bodies from rejecting the new organ. An alternative approach that could overcome both challenges is hepatocyte transplantation.
“Hepatocyte” is the medical term for a liver cell. When transplanted, hepatocytes regenerate liver tissue for a short period because they have low engraftment efficiency and are subject to immune rejection. Not only could patients needing a liver transplant benefit from hepatocyte transplantations, but also people whose livers are being damaged by external factors such as viral infections, heavy alcohol use, or other toxic substances. These injuries can cause liver cells to die, which over time may lead to scarring (fibrosis), advanced liver disease (cirrhosis), and even liver cancer.
However, it is still unclear how transplanted mature liver cells can switch into a growth-ready state to repair damaged parts of the liver. “Understanding donor hepatocyte proliferation biology is key to overcoming these hurdles,” wrote a group of scientists from Tongji University in Shanghai, People’s Republic of China, in a recent study.
Ting Fang and colleagues investigated how mature transplanted liver cells can temporarily “reset” themselves into a more flexible state. In this state, the cells multiply quickly and help regenerate damaged liver tissue, while still preserving the essential metabolic functions that keep the liver working properly. The team also identified specific signals in the liver environment that prompted these cells to enter this growth-ready state. Understanding the signals that trigger this process could help pave the way for more effective regenerative therapies for liver disease. According to the authors, their findings provide “direct functional evidence for a novel regenerative therapy based on terminally differentiated cells,” meaning that even fully mature liver cells can be harnessed for tissue repair.
Tracking How Transplanted Hepatocytes Regenerate the Liver
Fang and the team studied the molecular processes that allow hepatocytes to reactivate from their normally resting (quiescent) state. Using genetic techniques in the lab, the scientists marked donor liver cells with fluorescent proteins that glow under a microscope. They then transplanted these glowing cells into mice with liver injury (using a mouse model of liver injury named Fah−/− to allow the comparison with human liver diseases), allowing them to track how the cells behaved after transplantation.
They collected samples at different time points after transplantation to analyze which genes were turned on or off at each stage. About one week after transplantation, the marked cells showed a gene expression pattern that differed from the one they had before transplantation. By week 12, however, their gene activity had shifted back to closely resemble that of the original cells. One of the principal marks of these temporarily reprogrammed cells was the overexpression of the Aft gene. “[T]ransplanted mature hepatocytes undergo extensive transcriptional remodeling during early engraftment, generating a transient subpopulation […] with stage-specific molecular signatures,” wrote the authors in the study. Because they found that these cells consistently express the AFP protein, they designated them as “Afp⁺ reprogrammed hepatocytes” (or “Afp⁺ rHeps” for short).
More than Just Proliferating
When the researchers compared naturally reprogrammed hepatocytes with normal hepatocytes from a genetic atlas covering different developmental stages, they found key differences: the Afp⁺ rHeps cells were not simply going to earlier stages in development to increase proliferation into new liver cells, but they also had activated genes for metabolic pathways that only mature hepatocytes have. The authors concluded that the results collectively indicate a coordinated metabolism-proliferation regulation.
The researchers later mapped the protein interaction network (interactome) of intracellular AFP protein to better understand the metabolism of transplanted hepatocytes. They used a technique called co-immunoprecipitation followed by mass spectrometry to compare the proteins that interact with AFP in hepatocytes from control livers with those overexpressing the AFP protein. The results showed that high expression of AFT was linked with the transcription factor Peroxisome Proliferator–Activated Receptor gamma (PPARγ), an important protein involved in metabolic functions in liver cells.
But as these results were obtained in mice, the researchers asked if the same mechanism was conserved in humans. They looked into a publicly available genetic dataset from patients with acute liver failure caused by acetaminophen overdose or certain types of hepatitis, finding that regenerating liver cells showed strong activation of the same key genes. “[T]he conserved activation of this core transcriptional module supports its fundamental role in acute repair,” they wrote. “This conservation underscores the translational relevance of the PPARγ/AFP‑driven regenerative program.”
Immune Signals that Trigger Liver Cell Proliferation
Because Afp⁺ rHeps cells showed a unique gene expression pattern, the scientists hypothesized that this gene modulation may result from signals in the microenvironments to which they were exposed. They analysed the immune responses happening in the injured liver and found that the Afp⁺ rHeps cells mainly responded to the inflammatory signal TNF-α, but not to IL-6, two inflammatory signaling proteins coming from different immune cells.
To determine the source of TNF-α in the injured livers, they examined the surrounding liver environment during regeneration. They discovered that neutrophils (a type of immune cell) were the main producers of TNF-α. Together, these findings show that TNF produced by neutrophils activates a gene program in transplanted liver cells, including AFP, and helps trigger their entry into a proliferative, regenerative state.
A New Strategy for Selecting Therapeutic Liver Cells
Overall, these findings offer new mechanistic insights into liver regeneration and, more importantly, introduce a new approach to selecting therapeutic hepatocytes for transplantation into a diseased liver. Instead of relying solely on traditional markers, as is done today, this strategy potentially allows the selection of liver cells based on a combination of metabolic fitness and their ability to proliferate.
The authors concluded that “these findings advance a functionally-validated model for how mature hepatocytes drive liver regeneration, providing a framework and identifying key targets for future therapeutic development.” Future studies will confirm the translation into clinical studies.
Reference: T. Fang et. al., Conversion of Transplanted Mature Hepatocytes into Afp+ Reprogrammed Cells for Liver Regeneration After Injury, Advanced Science (2026), DOI: 10.1002/advs.202517126
Featured Image by Gerd Altmann via Pixabay
