Tag Archives: #livertransplant

Toward A Feasible Alternative to Liver Organ Transplant (Medicine)

New findings could lead to ways to keep transplanted adult liver cells functioning long term

New insights into how fetal and adult liver cells differ could be used to help make liver cell transplants successful long term. Transplanting functioning liver cells into a patient’s liver can help replace liver function that is impaired due to disease.

Today there are many more patients waiting for liver transplants than there are donor organs available. Because liver cell transplantation only requires a portion of cells isolated from a liver, it could allow multiple patients to be treated from one donated organ.

Although liver cell transplants offer a promising life-saving alternative to transplanting the whole organ, the effects aren’t long-lasting when adult liver cells are used. Clinical trials and animal studies have shown that when fetal liver cells are used for liver cell transplants, they multiply and maintain function for long periods of time. However, fetal liver cells cannot be readily obtained for clinical use.

“Our work aims to characterize the mechanisms by which fetal liver cells — or hepatocytes — repopulate an injured adult liver,” said Anders Ohman, a doctoral candidate in the laboratory of Jennifer Sanders, PhD, at Brown University. “We can then use this information to develop novel culture conditions and therapeutic strategies that can make liver cell transplantation feasible.”

Ohman will present the research at the American Society for Investigative Pathology annual meeting during the virtual Experimental Biology (EB) 2021 meeting, to be held April 27-30.

To better understand why fetal hepatocytes maintain their function, the researchers transplanted fetal rat hepatocytes into the spleen of mice that had part of their liver removed. Over 10 months, the fetal cells regenerated the liver and made up an increasing percentage of the organ. The researchers then used a technique called laser capture microdissection to collect normal adult liver tissue as well as tissue derived from the transplanted fetal cells.

“Our analysis of these samples identified a number of fetal characteristics that are durably retained months after transplantation into the adult liver microenvironment,” said Ohman. “We also found gene expression and cellular processes that are distinct to the fetal-cell-derived tissue.”

Next, the researchers aim to identify specific biological drivers of cell growth and proliferation that are responsible for the competitive advantage that the fetal cells have in repopulating the liver.

Anders Ohman will present the findings in poster R3514 (abstract). Contact the media team for more information or to obtain a free press pass to access the meeting.

Featured image: This figure shows the rat hepatocyte transplant and microdissection technique used in the study (top) with the transcriptomic and histone proteomic principal component analyses shown below. © Anders Ohman

Provided by ASIP

About Experimental Biology 2021

Experimental Biology is an annual meeting comprised of thousands of scientists from five host societies and multiple guest societies. With a mission to share the newest scientific concepts and research findings shaping clinical advances, the meeting offers an unparalleled opportunity for exchange among scientists from across the United States and the world who represent dozens of scientific areas, from laboratory to translational to clinical research. http://www.experimentalbiology.org

About the American Society for Investigative Pathology (ASIP)

ASIP is a society of biomedical scientists who investigate mechanisms of disease. Investigative pathology is an integrative discipline that links the presentation of disease in the whole organism to its fundamental cellular and molecular mechanisms. ASIP advocates for the practice of investigative pathology and fosters the professional career development and education of its members. http://www.asip.org

Researchers Develop A Technique to Produce Transplantable Livers In The Laboratory (Biology)

Researchers at the Human Genome and Stem Cell Research Center (HUG-CELL), hosted by the University of São Paulo’s Institute of Biosciences (IB-USP) in Brazil, have developed a technique to reconstruct and produce livers in the laboratory.

The proof-of-concept study was conducted with rat livers. In the next stage of their research, the scientists will adapt the technique for the production of human livers in order in future to increase the supply of these organs for transplantation.

The study was supported by FAPESP and is reported in an article published in Materials Science and Engineering: C.

“The plan is to produce human livers in the laboratory to scale. This will avoid having to wait a long time for a compatible donor and reduce the risk of rejection of the transplanted organ,” Luiz Carlos de Caires-Júnior, first author of the article, told Agência FAPESP. He is a postdoctoral fellow of HUG-CELL, one of the Research, Innovation and Dissemination Centers (RIDCs) funded by FAPESP.

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 various solutions containing detergents or enzymes to remove all the cells from the tissue, leaving only the extracellular matrix with the organ’s original structure and shape. The extracellular matrix is then seeded with cells taken from the patient. The technique avoids immune system reactions and the risk of rejection in the long term.

“It’s comparable to transplanting a ‘reconditioned’ liver. It won’t be rejected because it uses the patient’s own cells, and there’s no need to administer immunosuppressants,” said Mayana Zatz, HUG-CELL’s principal investigator and last author of the article.

The technique can also be used to reconstitute organs considered borderline and non-transplantable, increasing the supply of organs for patients on the waiting list, Caires-Júnior explained.

“Many organs available for transplantation can’t actually be used because the donor has died in a traffic accident. The technique can be used to repair them, depending on their status,” he said.

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

To surmount this obstacle, the HUG-CELL researchers enhanced the technique by introducing an extra stage between decellularization and recellularization.

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

“Enrichment of the extracellular matrix with these molecules lets it become much more similar to that of a healthy liver,” Caires-Júnior said.

Rat liver extracellular matrices were treated with the solution, and hepatocytes, endothelial cells, and mesenchymal cells were introduced into the material. The mesenchymal cells were derived from human induced pluripotent stem cells (iPSCs), produced by reprogramming adult skin cells (or cells from other easily accessible tissues) into an embryonic-like pluripotent state.

“The study shows it’s possible to induce human stem cell differentiation in cell lineages that are part of a liver and use these cells to reconstruct the organ so that it’s functional. It’s proof of concept, the first demonstration that the technique works,” Zatz said.

The liver cells were injected with a syringe pump into rat liver extracellular matrices to produce an organ with human characteristics. It grew for five weeks in an incubator that simulated the conditions in the human body. Analysis showed that extracellular matrix enrichment with SPARC and TGFB1 significantly improved recellularization.

“The treatment made the liver cells grow and function more vigorously,” Caires-Júnior said. “We plan to build a bioreactor to decellularize human livers and study the possibility of producing them to scale in the laboratory.”

The technique can be adapted to produce other organs, such as lungs, hearts, and skin, he added.

Organ factories

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

Through a project conducted in partnership with pharmaceutical company EMS and supported by FAPESP under the auspices of its Research Partnership for Technological Innovation Program (PITE), the HUG-CELL researchers aim to modify pig organs such as kidneys, hearts and skin for transplantation into humans (read more at: agencia.fapesp.br/29771/). 

Pig livers would be rejected if they were transplanted into humans, so the researchers are pursuing other strategies, such as 3D printing (read more at: agencia.fapesp.br/32217/), as well as decellularization and recellularization. 

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

The Materials Science and Engineering: C article “Pre-coating decellularized liver with HepG2-conditioned medium improves hepatic recellularization” (doi: 10.1016/j.msec.2020.111862) by Luiz Carlos Caires-Júnior, Ernesto Goulart, Kayque Alves Telles-Silva, Bruno Henrique Silva Araujo, Camila Manso Musso, Gerson Kobayashi, Danyllo Oliveira, Amanda Assoni, Valdemir Melechco Carvalho, Antônio Fernando Ribeiro-Jr, Renata Ishiba, Karina Andrighetti Oliveira Braga, Natalia Nepomuceno, Elia Caldini, Thadeu Rangel, Silvano Raia, Peter I. Lelkes and Mayana Zatz is at: www.sciencedirect.com/science/article/abs/pii/S0928493120337814.

Featured image: Extracellular matrix of a decellularized liver. An extracellular matrix obtained by controlled decellularization is used to reconstruct the liver with human-like characteristics (photo: HUG-CELL/USP)

Provided by FAPESP