Scientists Set Record for Growing Miniature Functional Liver Models

Scientists have achieved a major breakthrough by successfully growing the most advanced miniature functional liver models ever created. These lab-grown livers closely mimic the structure and function of human livers, marking a significant step forward in biomedical research. The achievement holds promise for more accurate drug testing, personalized medicine, and improved understanding of liver diseases. This record-setting advancement could reduce the need for animal testing and accelerate the development of new treatments for liver-related conditions.

Organoids are designed to imitate human organs, but the liver’s intricate functions and high energy requirements have made it particularly difficult to grow organoids that thrive and perform effectively, according to Sato. In lab environments where growth and survival are emphasized, liver cells known as hepatocytes tend to shift into cholangiocyte-like cells, which typically line the bile ducts. As a result, these hepatocytes only maintain their functional properties for about one to two weeks.

A research group at Keio University School of Medicine, led by Ryo Igarashi and Mayumi Oda, created hepatocyte organoids using cryopreserved liver cells sourced from actual patients. By treating these cells with oncostatin M - a signaling molecule linked to inflammation - the researchers saw a dramatic increase in cell growth, reaching levels millions of times higher than in earlier experiments where growth remained minimal. These organoids kept expanding over a period of three months and remained viable for six months while preserving their capacity to differentiate.

The team also introduced a new hormone-based method to encourage the organoids to mature. Once matured through this process, the organoids began displaying key liver functions, including the production of substances like glucose, bile acid, cholesterol, triglycerides, urea, and albumin. Albumin secretion reached quantities on par with that found in human liver cells. The organoids also developed intricate canal networks that allowed bile acids to flow through.

Identifying oncostatin M’s role in organoid development was a major discovery, Sato explains. Few molecules are known to trigger stem cells to develop and multiply into organoids, and this newly identified molecule could help overcome longstanding obstacles in creating complex organoids.

When the organoids were transplanted into mice with impaired immune systems and liver failure, the human cells gradually took over the role of the mice’s damaged liver cells and restored liver function.

This discovery could significantly impact the future of liver regeneration. Since donor livers are in short supply and deteriorate quickly after being harvested, transplantation opportunities are limited. Although efforts exist to freeze and preserve hepatocytes for future use, these approaches have shown limited efficacy.

Sato suggests that converting frozen hepatocytes into organoids could restore their ability to multiply, making them more suitable for regenerative treatments. He points out that while the current study demonstrated successful liver function restoration in mice, regenerating a human liver would require scaling up the process to produce billions of organoids. If achievable, this strategy could revolutionize transplant medicine for patients on waiting lists.

In the short term, this research could improve drug testing for liver-related illnesses by lowering the cost of toxicity evaluations. Currently, pharmaceutical companies rely on hepatocytes from human donors due to notable differences in liver biology across species. These donor cells, which lose functionality quickly, are expensive - costing anywhere from 670 to 2,000 USD per vial - and show significant variability in performance. In contrast, organoids offer a more uniform and cost-effective alternative for research.

The organoids also provide more accurate models for studying liver diseases. In the experiment, the organoids produced their own lipids, which were reduced after treatment with medication targeting MASLD (Metabolic dysfunction-associated steatotic liver disease). This model better reflects real disease conditions compared to methods that rely on artificial lipid injection. Moreover, the researchers used gene-editing to mimic ornithine transcarbamylase deficiency - a rare genetic condition affecting the urea cycle - further advancing tools for studying inherited liver disorders.

Sato concludes that future research must focus on exponentially increasing organoid production and incorporating other liver cell types into the models. These developments are essential for expanding the potential of organoids in medical science and therapy.

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Source: worldpharmanews‍