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Translated from:Bio Valley(Rights Protection)

The liver is the "central processor" of human metabolism, responsible for key missions such as converting nutrients into energy, storing fat, detoxification, and detoxification. However, over one-third of the global population is facing the threat of metabolic dysfunction associated fatty liver disease (MASLD), which can gradually erode liver function and even lead to liver failure. How to solve the dilemma of liver cells being difficult to maintain in the laboratory has become a major challenge in the field of regenerative medicine.

Recently, a research team from Keio University in JapanNatureA groundbreaking achievement was announced in the magazine (published online on April 16, 2025):They successfully utilized frozen adult liver cells from patients to cultivate fully functional liver cell organoids, achieving million fold expansion within 3-4 weeks while preserving core functions such as metabolism, detoxification, and protein synthesis.Professor Toshiro Sato, the corresponding author of the paper, exclaimed excitedly, "This is the closest we have come to an 'artificial mini liver'

Breaking the bottleneck

Traditional liver cell organoid culture faces two major challenges: either limited proliferation ability, or sacrificing function for survival - liver cells are prone to "defect" into bile duct like cells in the laboratory, and their function can only be maintained for 1-2 weeks. The research team drew inspiration from liver cancer genomics and discoveredThe combination of Oncostatin M (OSM) and STAT3 signaling pathway activation is the key to breakthrough.

OSM is like a precise 'molecular key' that can both turn on the switch for liver cell proliferation and firmly lock their 'liver identity'. ”The first author of the paper, Ryo Igarashi, explained. Experiments have shown that organoids treated with OSM continue to proliferate for 3 months, survive for 6 months and still differentiate, and successfully inhibit bile duct metaplasia caused by the YAP signaling pathway (a phenomenon of "lost cell identity").

Even more astonishing is that,A single human liver cell can generate organoids with an amplification efficiency of up to 10% -30%, comparable to other tissue stem cells!

Mini liver submits full score answer sheet

The research team further developed a hormone induced differentiation scheme to allow organoids to "graduate" into mature liver cells. The differentiated organoids not only form a bile capillary network, but also exhibit six core functions:

Metabolic King:Efficient synthesis of glucose, urea, cholesterol, triglycerides, with production capacity even surpassing that of primary liver cells;

Detoxification expert:The activity of cytochrome P450 enzyme is comparable to that of human liver cells, accurately simulating drug metabolism and toxic reactions;

Protein factory:The secretion of albumin reaches the human body level (50-150 μ g/day/million cells), and the production of coagulation factors surges;

Lipid Stewardship：Independently generating lipid droplets, PPAR agonists can reverse fat accumulation, providing an ideal model for MASLD drug screening;

Regenerated black technology:After transplantation into mice with liver injury, the organoids fully "take over" liver function and repair metabolic zoning structures;

Gene editing platform:Successfully knocked outG6PC、OTCAccurately simulate genetic diseases such as glycogen storage disorder and urea cycle disorders by waiting for genes.

OSM-STAT3 promotes stable expansion of human liver cell organoids

Freezing liver cells or turning them into 'seeds of life'

The current liver transplantation is facing a severe supply-demand contradiction - the survival window of the donor liver is short, and the proliferation ability of frozen liver cells after recovery is poor. ButThis study provides a new approach to solving the problem: transforming frozen liver cells into organoids can awaken their "regenerative potential" and become high-quality materials for transplantation.Professor Sato's outlook: "If we achieve amplification at the level of tens of millions of times, organ transplantation may completely change the treatment pattern of liver failure

The pharmaceutical industry has long relied on primary liver cells for toxicity testing, but these cells can be sold for up to 100000-30000 yen (approximately 5000-15000 yuan) per bottle, and their activity only lasts for a few days. In contrast, organoids are low-cost, batch stable, and more capable of simulating real disease states (such as autonomous lipid generation rather than artificial injection). The research team has successfully tested the toxicity of acetaminophen using organoids, with sensitivity surpassing traditional models.

This study is not only a paper, but also a paradigm revolution in liver research. Industry experts evaluate that with the combination of organoid amplification technology and gene editing, personalized liver disease treatment, precise drug screening, and even the vision of "artificial liver" are accelerating into reality.

reference material:

Ryo Igarashi et al, Generation of human adult hepatocyte organoids with metabolic functions, Nature (2025). DOI: 10.1038/s41586-025-08861-y.

(From: Biovalley)

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