American scientists first used the T-lymphocytes to combat senescent cells, the appearance of which accompanies the aging of tissues. For this, they used the technology of CAR-T: modified immune cells so they recognize abundant on the surface of senescent cells protein. The method was effective not only in vitrobut also in vivo, and improved the condition of mice with fibrosis of the lungs and liver, as well as in steatohepatitis. In addition, in minimum doses, it caused no side effects. A study published in the journal Nature.
Senescent cells that accumulate in tissues during aging, largely resemble tumor. They just do not perform their main functions in the tissue, but instead launch the restructuring of the intercellular substance, and similarly blocked the mechanisms of cellular suicide — apoptosis.
Therefore, as of Sinaiticus drugs that are designed to clear the fabric from old cells — test some anticancer drugs, as they act selectively on cells with blocked apoptosis. In separate experiments sinaitici has already demonstrated its ability to prolong the lives of mice and improving (though still insignificant) the condition of people with various age-related diseases, for example inflammation of a joint, fibrosis of lungs and diabetes.
Amor Corina (Corina Amor) together with colleagues from Memorial cancer center Sloan-Kettering in new York suggested to use to protiviti senescent cells another weapon, originally invented to fight cancer — technology CAR-T (more on this technology read our article “Chimera against cancer”). It is genetically modified T lymphocytes that Express a chimeric receptor gene, that is programmed to recognize a specific molecule on the cell surface and destroy its bearer.
To identify the protein, which is most convenient to distinguish senescent cells from any other, the authors have otsenival RNA in cultures of cells aged in different ways — under the effect of antitumor therapy by expression of the oncogene or just long cultivation. They identified a list of genes that were intensively working after turning in senescent cells and compared it with the list of genes that must work in normal vital organs (according to the Atlas of Human Proteins).
As a result, the as a distinctive feature has been selected gene PLAURthat encodes the uPAR protein — surface receptor on the cells. At a signal from him the cells start the destruction of the intercellular substance, and tumors, it transmits a signal about the beginning of the movement. After binding with its ligand, the receptor uPAR is partially digested and turns into blood. It has repeatedly found in the composition of the SASP — inflammatory protein cocktail that distinguish senescent cells, and it serves as a marker of certain diseases such as renal failure and diabetes. All this, according to the authors, indicates that uPAR is a good target for CAR-T cells.
Researchers have verified that uPAR is indeed expressed on the surface of senescent cells not only in cultures but also in tissues of patients with age-related diseases such as atherosclerosis and fibrosis of the liver.
Then the authors created cells CAR-T receptor for uPAR and tested on cultures of mouse cells that they attack only those cells that carry the uPAR on the surface. After that the system tested in vivo. For this the researchers took immune deficient mice and injected them into the blood senescent cells expressing luciferase. They are usually excreted, but retained in the liver. After a while in the liver of mice introduced CAR-T-cells, and after that senescent cells was significantly less.