Liver Organoids Offer Hope for Drug Development

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Imagine a world without the agonizing wait for liver transplants. What if damaged livers could be repaired with bioengineered mini-livers grown in a lab? Thanks to a breakthrough at Keio University, that future may be closer than you think.

The Dawn of Liver Organoids: A New Hope for Liver Disease

Researchers at keio University school of Medicine in Japan have achieved a monumental feat: creating long-lasting, functional human liver organoids from frozen hepatocytes research. This isn’t just another incremental step; it’s a potential paradigm shift in how we approach liver regeneration, disease modeling, and drug development. but what exactly are organoids, and why is this such a big deal?

what are Liver Organoids?

Think of organoids as miniature, simplified versions of organs grown in a lab. They’re three-dimensional cellular clusters that mimic the structure and function of a real organ. Liver organoids, in particular, are designed to replicate the complex functions of the human liver, including metabolism, detoxification, and protein synthesis [[1]].

Fast fact: The liver performs over 500 vital functions, making it one of the most complex organs in the human body.

The Liver’s Unique Challenges

Replicating the liver’s complexity has been a long-standing challenge. While scientists have successfully created organoids for other organs, the liver’s intricate functions and high energy demands have made it particularly arduous to recreate in the lab. Hepatocytes, the liver’s main working cells, often struggle to survive and maintain thier function in typical lab conditions. They tend to morph into cholangiocyte-like cells, which line the bile duct, and their hepatic functions rarely last more than a week or two.

As stem cell researcher Toshiro Sato explains, “When prioritizing growth and survival, hepatocytes lose their identity.” This limitation has significantly hampered progress in creating liver organoids that truly mirror human physiology.

The Keio University Breakthrough: A Million-Fold Proliferation

Lead by ryo Igarashi and Mayumi Oda, the Keio University team overcame these challenges by developing hepatocyte organoids from cryopreserved adult human hepatocytes. These cells were directly harvested from patients and stored for future use. The key to their success? A signaling protein called oncostatin M.

Oncostatin M: The Game-Changing Growth Signal

By treating the cryopreserved hepatocytes with oncostatin M, a protein involved in inflammation, the researchers unlocked unprecedented growth. The organoids proliferated a million-fold, sustaining this growth for over three months while retaining functionality for up to six months. This is a game-changer because it allows for the creation of a large, stable supply of functional liver tissue in the lab.

Expert Tip: Oncostatin M’s role in inflammation might seem counterintuitive, but it appears to play a crucial role in promoting hepatocyte survival and proliferation in the organoid model.

“We only know a few molecules that unlock a stem cell’s potential to grow into organoids and proliferate,” says Sato. “This one is brand-new and opens up opportunities for developing new types of organoids that researchers have struggled to create.”

Restoring Liver Function in Mice: A Preclinical Success

The true test of any new technology is its ability to perform in a real-world setting. To that end, the researchers transplanted the human hepatocyte organoids into mice with damaged livers and suppressed immune systems.The results were remarkable: the organoids began replacing the mice’s liver cells and restored liver function. This preclinical success is a critical step toward future therapeutic applications in humans.

The Future of Liver Regeneration: Scalability and Beyond

The Keio University breakthrough opens up exciting possibilities for liver regeneration. Liver transplants are in high demand, but severely limited by donor shortages and the rapid degradation of harvested organs. Cryopreserved hepatocytes have shown some promise, but they often lose viability. The success of this organoid method could revitalize their regenerative capacity,offering a new strategy for organ repair.

Scaling Up: From Mice to Humans

While the mouse studies are encouraging, the challenge now is to scale up the organoid growth to a level sufficient for human liver regeneration. as Sato points out, “Our study demonstrated that liver organoid transplants can be triumphant in mice. But to regenerate a human liver, organoid growth has to scale up to thousands of millions, because the human body is larger. If realized, this approach could be a game-changer for patients awaiting transplantation.”

To regenerate a human liver, organoid growth has to scale up to thousands of millions, as the human body is larger.

This scaling-up process will require meaningful advancements in bioreactor technology and cell culture techniques. Researchers will need to develop methods for growing organoids in a controlled, high-throughput manner while maintaining their functionality and preventing them from differentiating into unwanted cell types.

Incorporating Other Liver Cells: Building a More Realistic Model

The current organoids primarily consist of hepatocytes.Tho, the liver is a complex organ composed of various cell types, including cholangiocytes, Kupffer cells (immune cells), and stellate cells (involved in fibrosis). To create a more realistic and functional liver organoid, researchers will need to incorporate these other cell types into the model [[3]].

This will require a deeper understanding of the interactions between different liver cell types and the development of new culture methods that can support the growth and differentiation of these cells within the organoid.

Revolutionizing Drug Development and Disease Modeling

Beyond transplantation, liver organoids offer immediate benefits for liver disease modeling and pharmaceutical testing. Traditional human hepatocytes, costing up to $2,000 per vial, lose their function within days and vary significantly in quality. In contrast,hepatocyte organoids are more cost-effective,reliable,and long-lasting.

A More accurate Disease Model

The Keio University study demonstrated the potential of organoids for disease modeling by showing that they naturally produced fats, which disappeared after being treated with drugs targeting metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic steatohepatitis (NASH). This provides a more accurate disease model than traditional lipid-injection methods, which can be artificial and less representative of the actual disease process.

The team also succeeded in gene-editing the organoids to mimic ornithine transcarbamylase deficiency,a rare genetic disorder,highlighting their potential for studying inherited liver diseases. This opens up new avenues for understanding the mechanisms underlying these diseases and developing targeted therapies.

Personalized Medicine: Tailoring Treatments to Individual Patients

One of the most exciting potential applications of liver organoids is in personalized medicine. By creating organoids from a patient’s own cells, doctors could test different drugs and therapies to determine which one is most effective for that individual. This could revolutionize the treatment of liver diseases, allowing for more targeted and effective therapies with fewer side effects.

Imagine a future where a patient with liver cancer has organoids grown from

Liver Organoids: A New era for Liver Regeneration and Disease Treatment?

Could lab-grown mini-livers revolutionize how we treat liver disease? A recent breakthrough at Keio University is generating important buzz. Here at Time.news, we spoke with Dr. Anya Sharma, a leading expert in regenerative medicine, to unpack this exciting advancement and its potential impact.

Time.news: Dr. Sharma, welcome. Let’s start with the basics. What exactly are liver organoids, and why are they such a big deal in the context of liver regeneration?

Dr. Sharma: Thanks for having me. Liver organoids are essentially miniature, 3D models of the liver grown in vitro, in a lab setting. They’re designed to mimic the structure and, crucially, the function of a real human liver [[1]]. The “big deal” lies in thier potential to address the critical shortage of donor livers for transplantation and provide better models for studying liver disease and testing new drugs. The liver performs over 500 essential functions, so replicating that complexity is a monumental task.

Time.news: This Keio University study seems notably promising. What makes their approach different from previous attempts to create liver organoids?

Dr. Sharma: The keio team, led by Ryo Igarashi and mayumi Oda, achieved two key breakthroughs. First, they were able to generate organoids from cryopreserved hepatocytes – liver cells that had been frozen and stored. This is important because it offers a readily available source of cells. Second, they discovered that treating these cells with oncostatin M, a signaling protein, triggered unprecedented proliferation. The organoids grew a million-fold and remained functional for up to six months. That’s a massive leap forward. Previous attempts frequently enough struggled with cell survival and the loss of liver-specific functions. Hepatocytes tend to transform into different cell types in culture.

Time.news: Oncostatin M sounds like a crucial component. Is its use a new finding, specifically for liver organoid development?

Dr. Sharma: While oncostatin M is known to be involved in inflammation, its specific role in promoting hepatocyte survival and proliferation within an organoid model is a significant finding. As Toshiro Sato noted in the study, identifying molecules that unlock a stem cell’s potential is rare, and this revelation opens new avenues for organoid research. It’s certainly an exciting new piece of the puzzle.

Time.news: The article mentions successful transplantation of these liver organoids into mice. How significant is this preclinical success for future therapeutic applications in humans?

Dr. Sharma: The mouse studies are a crucial proof-of-concept. They demonstrated that the transplanted liver organoids could integrate into the damaged livers of mice with suppressed immune systems, replace the damaged liver cells, and restore liver function. This shows that the organoids are not just functional in a dish,but can perform their intended role in vivo. However, it’s important to remember that mice are not humans. Scaling up organoid growth for human liver regeneration will require significant advancements in bioreactor technology and cell culture techniques. We need to produce “thousands of millions” more organoids to regenerate a human liver.

Time.news: Beyond liver regeneration, what other immediate benefits do liver organoids offer, particularly in drug development and disease modeling?

Dr. Sharma: This is where liver organoids can make a real impact now. Conventional human hepatocytes are expensive and don’t last long. Liver organoids offer a more cost-effective, reliable, and long-lasting alternative. The Keio study showed that organoids could accurately model metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as nonalcoholic steatohepatitis (NASH), and even mimic rare genetic disorders like ornithine transcarbamylase deficiency. This significantly improves drug testing accuracy and provides a more precise and ethical alternative to animal models. For example, organoids naturally produced fats, which then disappeared when treated with drugs targeting MASLD.

Time.news: The article briefly touches on personalized medicine. How could liver organoids contribute to tailoring treatments for individual patients?

Dr. Sharma: This is the long-term vision: creating organoids from a patient’s own cells to test different drugs and therapies. By assessing the organoid’s response, doctors could determine the most effective treatment for that particular individual, minimizing side effects and maximizing therapeutic benefit. Imagine growing liver organoids for a patient with liver cancer to test different chemotherapies on the organoid before applying them to the patient. It’s a move towards truly personalized and precision medicine.

Time.news: Are there any challenges or limitations to consider before liver organoids become a widespread clinical reality?

dr. Sharma: Absolutely. Scaling up production is a major hurdle, as mentioned before. Also, current organoids primarily consist of hepatocytes. The liver is a complex organ with multiple cell types, including cholangiocytes, Kupffer cells, and stellate cells. Incorporating this cellular diversity to build more realistic and functional model [[3]]. requires further research. ensuring long-term functionality and preventing unwanted differentiation within the organoids are ongoing challenges.

Time.news: What’s your outlook on the future of liver organoid technology? What should our readers be watching for in the coming years?

Dr. Sharma: I’m optimistic. The Keio University breakthrough is a significant milestone, but it’s just the beginning. We need to see further advancements in bioreactor technology, cell culture techniques, and our understanding of cell-cell interactions within the liver. Look for progress in scaling up organoid production, incorporating diverse cell types, and demonstrating long-term efficacy and safety in preclinical models. if these challenges can be overcome, liver organoids have the potential to transform the treatment of liver diseases and revolutionize drug development.

Time.news: Dr. Sharma, thank you for sharing your expertise with us today.

Dr. Sharma: My pleasure.