Gene editing techniques have been used successfully to help create stem cells “invisible” to the immune system, researchers have reported.
Researchers report that altering the activity of just three genes, through techniques including the CRISPR-Cas9 gene-editing system, helped to stop stem cell transplants from being rejected in mice.
The study, published in the latest edition of Nature Biotechnology, was co-authored by Dr Tobias Deuse and Dr Xiaomeng Hu of University of California San Francisco (UCSF), USA.
Senior study author Professor Sonja Schrepfer, director of the UCSF Transplant and Stem Cell Immunobiology (TSI) Lab at the time of the study, said while immunosuppressants can be given to patients who receive cell transplants, including bone marrow, they can leave them more susceptible to cancer and infection.
Scientists once believed that the problem of immune rejection could be solved by induced pluripotent stem cells (iPSCs). These cells are created from fully-mature cells donated by the patients, and are then reprogrammed to allow them to develop into the cells that comprise the body's tissues and organs. Since the transplanted cells are derived from the patient’s own body, the chance of rejection by the immune system is small.
However, clinical use of iPSCs has proven difficult, with patients' cells proving unreceptive to reprogramming. It is also expensive and time-consuming to produce iPSCs for every patient who would benefit from stem cell therapy, the researchers say.
In this study, Professor Schrepfer’s team, attempted to sidestep those issues by creating ‘universal’ iPSCs that could be used in any patient.
They used CRISPR to delete two genes that are essential for the proper functioning of major histocompatibility complex (MHC) class I and II. They loaded the CD47 gene into a virus, which delivered extra copies of the gene into mouse iPSCs in which the MHC proteins had been knocked out.
They worked with Professor Lewis Lanier, chair of UCSF's Department of Microbiology and Immunology, and showed that cell surface protein CD47 has a strong inhibitory effect on Natural Killer (NK) cells.
When the researchers transplanted their triple-engineered mouse iPSCs into mismatched mice with normal immune systems, no rejection was observed. Mature heart cells derived from these iPSCs also showed long-term engraftment in these allogenic mice.
Importantly, the results were the same when they transplanted similarly engineered human iPSCs into ‘humanised mice’ – mice carrying human immune cells.
“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,” said Dr Deuse.
“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.”
Source: Deuse, T., Hu. X., Gravina, A., Wang, D., Tediashvili, G., De, C., Thayer, W.O., Wahl, A., Garcia, J.V., Reichenspurner, H., Davis, M.M., Lanier, L.L., Schrepfer, S. (2019) “Hypoimmunogenic derivatives of induced pluripotent stem cells evade immune rejection in fully immunocompetent allogeneic recipients”, Nature Biotechnology, available from doi: 10.1038/s41587-019-0016-3
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