UC San Francisco researchers have utilized the CRISPR-Cas9 gene-editing system to make the first pluripotent stem cells that are practically “invisible” to the immune system, an accomplishment of natural building that, in lab studies, avoided dismissal of stem cell transplants. Since this “universal” stem cell can be produced more productively than stem cells customized for every patient – the individualized methodology that dominated before endeavours – they bring the guarantee of regenerative medication a bit nearer to the real world.
“Scientists often tout the therapeutic potential of pluripotent stem cells, which can mature into any adult tissue, but the immune system has been a major impediment to safe and effective stem cell therapies,” said Tobias Deuse, MD, the Julien I.E. Hoffman, MD, Endowed Chair in Cardiac Surgery at UCSF and lead author of the new study, published Feb. 18 in the journal Nature Biotechnology.
The immune system is unforgiving. It’s customized to destroy anything it sees as an outsider, which secures the body against infections and different intruders that could unleash ruin whenever given free rein. Likewise implies transplanted organs, tissues or cells are viewed as a conceivably risky remote attack, which perpetually incites a fiery safe reaction prompting transplant rejection. When this occurs, donor and recipient are said to be — in medical parlance — “histocompatibility mismatched.”
“We can administer drugs that suppress immune activity and make rejection less likely. Unfortunately, these immunosuppressants leave patients more susceptible to infection and cancer,” explained Professor of Surgery Sonja Schrepfer, MD, PhD, the study’s senior author and director of the UCSF Transplant and Stem Cell Immunobiology (TSI) Lab at the time of the study.
Scientists once thought that the problem of rejection was solved by induced pluripotent stem cells (iPSCs), which are created from fully-mature cells. These are reconstructed in manners that enable them to form into any of the myriad cells that include the body’s tissues and organs. If the cells received from iPSCs were transplanted into the same patient who gave the original cells, the reasoning went, the body would see the transplanted cells as “self,” and would not mount an immune attack. But in practice, clinical use of iPSCs has proven difficult.
“This is the first time anyone has engineered cells that can be universally transplanted and can survive in immunocompetent recipients without eliciting an immune response,” Deuse said.
The scientists originally utilized CRISPR to erase two genes that are basic for the proper functioning of a group of proteins known as major histocompatibility complex (MHC) class I and II. MHC proteins sit on the outside of practically all cells and show molecular signs that assistance the immune system recognizes an interloper from a native. Cells that are missing MHC genes don’t present these signs, so they don’t enlist as remote or foreign. In any case, cells that are missing MHC proteins progressed towards the target of immune cells known as natural killer (NK) cells.
Working with Professor Lewis Lanier, PhD — study co-author, chair of UCSF’s Department of Microbiology and Immunology, and an expert in the signals that activate and inhibit NK cell activity — Schrepfer’s team found that CD47, a cell surface protein that acts as a “do not eat me” signal against immune cells called macrophages, also has a strong inhibitory effect on NK cells.
Trusting that CD47 may hold the key to totally closing down rejection, the scientist loaded the CD47 gene into a virus, which conveyed additional duplicates of the gene into the mouse and human stem cells in which the MHC proteins had been knocked out.
CD47 surely ended up being the missing bit of the riddle. At the point when the scientist transplanted their triple-engineered mouse stem cells into mismatched mice with a normal immune system, they find no rejection. At that point transplanted comparatively built human stem cells into so-called humanized mice whose immune system have been replaced with segments of the human immune system to emulate human immunity – and indeed no rejection was found.
Also, the scientist’s determined different sorts of human heart cells from these triple-engineered stem cells, which they again transplanted into humanized mice. The stem cell-derived cardiac cells could accomplish long term survival and even started shaping rudimentary blood veins and heart muscle, raising the likelihood that triple-engineer stem cells may one day be utilized to fix repair hearts defects.
“Our technique solves the problem of rejection of stem cells and stem cell-derived tissues, and represents a major advance for the stem cell therapy field,” Deuse said. “Our technique can benefit a wider range of people with production costs that are far lower than any individualized approach. We only need to manufacture our cells one time and we’re left with a product that can be applied universally.”