CRISPR makes stem cells invisible to the immune system.

Scientists from the University of California atSan Francisco used the CRISPR-Cas9 gene editing system to create the first pluripotent stem cells that are functionally “invisible” to the immune system. Such an event of biological engineering in the laboratory allowed us to prevent the rejection of stem cell transplants. Since these “universal” stem cells can be made more efficiently than stem cells, which are made specifically for each patient — as they have often done before — a new discovery brings regenerative medicine one step closer to reality.

CRISPR and stem cells

"Scientists often advertise therapeuticthe potential of pluripotent stem cells that can mature into any adult tissue, but the immune system was a major obstacle to safe and effective stem cell therapy, ”says Tobias Deuz, MD and lead author of a study published in Nature Medicine on February 18.

The immune system does not forgive. It is programmed to destroy everything that is perceived as alien, and thus protects the body from infectious agents and other intruders who can be harmful if given freedom of action. It also means that transplanted organs, tissues or cells are considered as potentially dangerous penetration from the outside, which invariably triggers a strong immune response, leading to transplant rejection. When this happens, the donor and the recipient are said to be “incompatible for histocompatibility.”

"We can inject drugs that inhibitimmune activity and reduce the likelihood of rejection. Unfortunately, immunity suppressors make patients more susceptible to infections and cancer, ”explains surgery professor Sonia Schröpfer, the senior author of the study.

In the field of stem cell transplantation, scientistsonce it was decided that the rejection problem can be solved using induced pluripotent stem cells (iPSCs), which are created from fully mature cells, such as skin or fat cells, reprogrammed to develop into any of the many cells that make up the tissues and organs body. If cells derived from iPSCs were transplanted to the same patient who donated the original cells, the scientists thought, the body would see the transplanted cells as “its own” and would not attack them with the help of the immune system.

However, in practice, the clinical use of iPScturned out to be difficult. For reasons not yet understood, the cells of many patients were immune to reprogramming. In addition, the production of iPSCs was expensive and time consuming for each patient who was treated with stem cell therapy.

“The ipcc technology has many problems, butbig obstacle is quality control and reproducibility. We don’t know what makes some cells un-reprogrammable, but most scientists agree that it’s not yet possible to find out, ”says Deoes. “Because of this, most approaches to individualized iPSS therapy have been abandoned.”

Deuze and Shrepfer wondered if it was possible to get aroundthese problems, creating a "universal" iPSCs that can be used by any patient in need. In their new article, they describe how, after changing the activity of only three genes, iPSCs were able to avoid rejection after transplantation to recipients with incompatibility for histocompatibility, with a fully functional immune system.

"This is the first time anyone getsengineering cells that can be universally transplanted and that can survive in immunocompetent recipients without eliciting an immune response, ”says DeWes.

Scientists first used CRISPR to removetwo genes that are necessary for the proper functioning of the family of proteins, known as the major histocompatibility complex (GCGS) of class I and II. GCGS proteins are located on the surface of almost all cells and display molecular signals that help the immune systems distinguish the foreign from the native. Cells in which there are no GCGS genes do not give out such signals, therefore they are not registered as alien. However, cells lacking GCGS proteins become targets of immune cells known as natural cell killer (NK) cells.

Working with Professor Lewis Lanier, the teamSchrepfer discovered that CD47, a cell surface protein that gives out a “do not eat me” signal to immune cells — macrophages — also has a strong inhibitory effect on NK cells.

Assuming that the CD47 can store the key to the fullTo stop rejection, the researchers loaded the CD47 gene into a virus that delivered additional copies of the gene to mouse and human stem cells, from which MHC proteins were removed.

CD47 actually turned out to be the missing partpuzzles. When researchers transplanted their three-part mouse stem cells to incompatible mice with a normal immune system, they did not see any rejection. Then they transplanted similarly constructed human stem cells to so-called humanized mice - in which the immune systems are replaced by components of the human immune system - and again did not see anything.

In addition, researchers have extracted various typeshuman heart cells from these triple engineered stem cells. Heart cells derived from stem cells have been able to live for a long time and even form rudimentary blood vessels and heart muscle. Perhaps one day they can be used to restore the failed hearts.

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