Researchers develop technique to produce transplantable livers in the lab

Organ transplantation, although it can save lives or restore a normal life to some patients suffering from disabling chronic diseases, has major drawbacks, including an unstable success rate depending on the organ and above all, the need to follow an anti-rejection treatment for life (which is not without side effects), not to mention the wait for a healthy and compatible donor, which can sometimes be fatally long. To overcome this problem, the hope of medicine rests on the development of ultra-compatible organs.

To overcome this problem, the hope of medicine is the development of ultra-compatible semi-artificial organs. With this in mind, researchers from the Human Genome and Stem Cell Research Center (HUG-CELL), Institute of Biosciences at the University of São Paulo (IB-USP) in Brazil, have developed a technique for reconstructing and producing livers in the laboratory. The results were published in the journal Materials Science and Engineering: C.

The study, serving as a proof of concept, was carried out with rat livers. In the next stage of their study, the researchers will adapt the technique to the production of human livers in order to increase the supply of organs for transplants in the future. “ The goal is to produce human livers in the laboratory. This will avoid having to wait a long time for a matched donor and reduce the risk of rejection of the transplanted organ. », Told the FAPESP Luiz Carlos de Caires-Júnior, lead author of the study.

Decellularize to recellularize: the “reconditioning” of organs

The methodology is based on decellularization and recellularization, tissue bioengineering techniques developed in recent years to produce organs for transplantation. An organ from a deceased donor, in this case the liver, is treated with different solutions containing detergents or enzymes to remove all cells from the tissue, leaving only the extracellular matrix with the original structure and shape of the tissue. organ. The extracellular matrix is ​​then seeded with cells taken from the patient. This technique helps prevent immune system reactions and the risk of long-term rejection.

It is comparable to transplanting a “reconditioned” liver. It will not be rejected because it uses the patient’s own cells, and there is no need to administer immunosuppressants Explains Mayana Zatz, senior researcher at HUG-CELL and co-author of the study.

liver decellularizes reconstruction human liver
A decellularized rat liver. An extracellular matrix obtained by controlled decellularization is used to reconstruct the liver with human characteristics. © HUG-CELL / USP

The technique can also be used to replenish organs initially considered non-transplantable, thereby increasing the supply of organs for patients on the waiting list, explains Caires-Júnior. ” Many organs available for transplantation cannot in fact be used because the donor died in a traffic accident. The technique can be used to repair them, depending on their condition », He clarified.

Overcome the obstacles of decellularization

The researchers explain that the decellularization process, however, removes major components of the extracellular matrix, such as molecules that tell cells to multiply and form blood vessels. This weakens the adhesion of cells to the extracellular matrix and compromises recellularization.

To overcome this obstacle, the researchers improved the technique by introducing an additional step between decellularization and recellularization. After having isolated and decellularized rat livers, they injected into the extracellular matrix a solution rich in molecules such as SPARC and TGFB1 (among others), proteins produced by hepatic cells cultured in the laboratory in a conditioned medium. These proteins are essential for a healthy liver because they tell liver cells to proliferate and form blood vessels.

Enriching the extracellular matrix with these molecules allows it to become much more similar to that of a healthy liver. », Says Caires-Júnior. Rat liver extracellular matrices were treated with the solution, and hepatocytes, endothelial cells and mesenchymal cells were introduced into the material. Mesenchymal cells were derived from human induced pluripotent stem cells (iPSCs), produced by reprogramming adult skin cells (or cells from other readily accessible tissues) into an embryonic-like pluripotent state.

The study shows that it is possible to induce the differentiation of human stem cells into liver cell lines and to use these cells to rebuild the organ so that it is functional. This is a proof of concept, the first demonstration that the technique works Says Zatz.

The liver cells were injected into extracellular matrices of rat liver to produce an organ with human characteristics. This developed for five weeks in an incubator that simulated the conditions of the human body. Analysis showed that enrichment of the extracellular matrix with SPARC and TGFB1 significantly improved recellularization. ” The treatment allowed the liver cells to grow and function more vigorously “Said Caires-Júnior. ” We plan to build a bioreactor to decellularize human livers and study the possibility of producing them at scale in the laboratory. “. Caires-Júnior adds that the technique can be adapted to produce other organs, such as lungs, hearts and skin.

Adapting animal organs to humans

This new study is part of a large-scale HUG-CELL project aimed at producing or reconstructing transplant organs by different techniques. Thanks to a project carried out in partnership with the pharmaceutical company EMS, researchers at HUG-CELL aim to modify pig organs such as the kidneys, hearts and skin, in order to transplant them into humans.

Given some major biological differences, pig livers are currently rejected when transplanted into humans, which is why researchers are pursuing other strategies, such as 3D printing as well as decellularization and recellularization. . ” These are complementary approaches. We hope to see organ transplant factories in the future Says Zatz.

Materials Science and Engineering: C

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