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Researchers are developing a technique for producing an implantable liver in the laboratory

The extracellular matrix obtained by controlled cellular epithelization is used to reconstruct the liver with human-like properties

Researchers at the Research Center for Human Genome and Stem Cells (HUG-Cell), hosted by the Institute of Biological Sciences of the University of São Paulo (IB-USP) in Brazil, have developed a technique for reconstructing and producing the liver in the laboratory.

A proof-of-concept study was performed on rat livers. In the next phase of their research, scientists will work to adapt the technology to produce human liver in order to increase the supply of these organs for transplantation in the future.

The study was supported by FAPESP and reported in an article published in Materials Science and Engineering: c.
“The plan is to produce a human liver in the laboratory on a large scale. This will avoid having to wait a long time for a compatible donor and reduce the risk of rejection of the transplanted organ,” said Luiz Carlos de Caires Jr., the article’s first author, to Agência FAPESP. PhD in HUG-CELL, a Research, Innovation and Publishing Center (RIDCs) funded by FAPESP.

The methodology is based on cell removal and re-cellular, tissue bioengineering techniques that have been developed in recent years for the production of organs for transplantation. An organ from a deceased donor, in this case the liver, is treated with various solutions that contain detergents or enzymes to remove all cells from the tissue, leaving only the extracellular matrix that has the structure and shape of the original organ. Then the extracellular matrix is ​​implanted with cells taken from the patient. This technique avoids immune system reactions and the risk of long-term rejection.

“It can be compared to a“ regenerated liver. ”“ It will not be rejected because it uses the patient’s own cells, and there is no need to use immunosuppressants, ”said Mayana Zatz, lead investigator at HUG-Cell and the last author of the article.

The technology can also be used to reconstruct organs that are borderline and non-implantable, Cairis Jr explained, increasing the supply of waiting-list organs.

“Many of the organs available for transplantation cannot actually be used because the donor died in a traffic accident. This technique can be used to repair them, depending on their condition.”

However, the cell removal process removes key components of the extracellular matrix, such as molecules that tell cells to proliferate and form blood vessels, for example. This impairs cell adhesion to the extracellular matrix and affects cellular remodeling.

To overcome this obstacle, HUG-CELL researchers have enhanced the technology by introducing an additional stage between cell removal and re-cellularization.

After isolating rat livers and removing cellular cells, they injected a solution rich in molecules such as SPARC and TGFB1 into the extracellular matrix, which are proteins produced by laboratory-grown liver cells in conditioned medium. These proteins are essential for liver health because they tell liver cells to proliferate and form blood vessels.

“The enrichment of the extracellular matrix with these molecules makes them more similar to those in a healthy liver,” said Caires Jr.

The extracellular arrays of rat liver were treated with solution, and hepatocytes, endothelial cells and mesenchymal cells were introduced into the material. Mesenchymal cells were derived from human induced pluripotent stem cells (iPSCs), which are produced by reprogramming adult skin cells (or cells from other easily accessible tissues) into a pluripotent, fetal-like state.

The study shows that it is possible to stimulate the differentiation of human stem cells into the lineages of cells that are part of the liver and use these cells to rebuild the organ so that it functions. “It’s a proof of concept, the first proof of the success of this technology,” said Zatz.

Hepatocytes were injected with a syringe pump into the extracellular matrices of rat liver to produce an organ with human properties. I slept for five weeks in an incubator that simulated conditions in the human body. The analysis showed that extracellular fertilization with SPARC and TGFB1 significantly improved cell remodeling.

“The treatment made the liver cells grow and function more strongly,” Caires Jr. said. “We are planning to build a bioreactor to remove cells from human liver and study the possibility of mass producing them in the laboratory.”

He added that this technology could be adapted to produce other organs, such as lungs, hearts and skin.

Member factories

The project is part of one of the research lines pursued by HUG-CELL to produce or reconstruct transplant organs using various technologies.

Through a project conducted in partnership with the pharmaceutical company EMS and with support from FAPESP (São Paulo Research Foundation) under the auspices of the Research Partnership for the Technology Innovation Program (PITE), HUG-CELL researchers aim to modify pig organs such as kidneys, hearts and skin for transplantation in humans (read more at : Agency.fapesp.br/29771/).

Pig livers will be rejected if transplanted into humans, so researchers are pursuing other strategies, such as 3D printing (read more on: Agency.fapesp.br/32217/), in addition to cell stripping and remodeling.

“These are complementary approaches. We expect to see transplant factories in the future,” said Satz.

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About the Sao Paulo Research Foundation (FAPESP)

The São Paulo Research Foundation (FAPESP) is a public institution whose mission is to support scientific research in all areas of knowledge by granting scholarships, fellowships, and grants to researchers associated with higher education and research institutions in the state of São Paulo, Brazil. FAPESP understands that the best research can only be done by working with the world’s best researchers. Therefore, it has established partnerships with funding agencies and higher education, private companies and research organizations in other countries known for the quality of its research and encourages the scholars funded by its grants to develop their international collaborations. You can learn more about FAPESP at http: // www.fapesp.R /in a And visit the FAPESP news agency at http: // www.Agency.fapesp.R /in a To keep up with the latest scientific achievements that help FAPESP to achieve through numerous programs, awards and research centers. You can also subscribe to the FAPESP news agency at http: // Agency.fapesp.R /Subscription.

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