A Technique To Produce Transplantable Livers In The Laboratory

Breakthrough in Liver Regeneration
Researchers at the Human Genome and Stem Cell Research Center (HUG-CELL), housed at the University of São Paulo's Institute of Biosciences (IB-USP) in Brazil, have made significant strides in regenerating and producing livers in a laboratory setting. This groundbreaking technique, initially tested on rat livers, aims to eventually increase the availability of human livers for transplantation. The study, funded by FAPESP, was published in Materials Science and Engineering: C.

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Study Details and Methodology
Luiz Carlos de Caires-Júnior, the study's first author, explained that the objective is to produce human livers in the lab to reduce wait times for compatible donors and minimize the risk of organ rejection. The methodology used involves decellularization and recellularization, advanced tissue bioengineering techniques developed to create organs for transplantation.

1. Decellularization: This process involves treating a donated liver with solutions containing detergents or enzymes to remove all cells, leaving behind only the extracellular matrix—the organ's structural framework.
2. Recellularization: The extracellular matrix is then seeded with the recipient’s cells, which significantly reduces the risk of immune rejection since the organ is essentially rebuilt with the patient’s own cells.

Mayana Zatz, HUG-CELL's principal investigator, emphasized that this technique can also rejuvenate borderline non-transplantable organs, thereby increasing the pool of available organs.

Challenges and Solutions
One of the challenges identified in the decellularization process is the loss of crucial extracellular matrix components, such as molecules that facilitate cell multiplication and blood vessel formation. To address this, researchers introduced an intermediary stage between decellularization and recellularization. After decellularizing rat livers, they enriched the extracellular matrix with a solution containing proteins like SPARC and TGFB1, which are essential for liver health and functionality. These proteins are produced by liver cells in a lab-grown conditioned medium and are vital for instructing liver cells to proliferate and form blood vessels.

By enriching the extracellular matrix with these proteins, the researchers found that liver cells adhered better and functioned more effectively. Hepatocytes, endothelial cells, and mesenchymal cells derived from human induced pluripotent stem cells (iPSCs) were introduced into the treated extracellular matrix. The enriched matrix closely resembled that of a healthy liver, allowing the liver cells to grow and function more vigorously.

Results and Future Plans
The liver cells were injected into the extracellular matrices of rat livers using a syringe pump, and the reconstructed organs were grown in an incubator mimicking human body conditions for five weeks. Analysis showed significant improvements in recellularization due to the matrix enrichment. The researchers now plan to construct a bioreactor to decellularize human livers and scale up production in the laboratory.

The ultimate goal is to adapt this technique to produce other organs, such as lungs, hearts, and skin. The project aligns with broader research goals at HUG-CELL to generate transplantable organs through various techniques, including decellularization and recellularization and 3D printing.

Organ Factories and Future Prospects
In collaboration with pharmaceutical company EMS and supported by FAPESP’s Research Partnership for Technological Innovation Program (PITE), HUG-CELL researchers are also working on modifying pig organs for human transplantation. While pig livers are currently unsuitable for direct transplantation into humans, alternative strategies like 3D printing and tissue engineering offer promising avenues.

Mayana Zatz envisions a future where "transplant organ factories" become a reality, providing a reliable source of organs for transplantation and significantly improving patient outcomes.

Conclusion
The innovative work by HUG-CELL represents a major step forward in bioengineering and transplantation medicine. By developing techniques to reconstruct and produce organs in the laboratory, researchers are paving the way for more accessible and less risky organ transplants. As these techniques advance and are scaled up, the dream of readily available lab-grown human organs could soon become a reality, transforming the landscape of transplantation and saving countless lives.

For more details, you can read the full study here.

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