Stem Cells: Scientists in China have revealed that genetically modified human erypotent stem cells evade immune system recognition, laying the groundwork for a common 'off-the-go' cell transplant.

September 23, 2020 /--- Human Pluripotent Stem Cells (hPSCs) have a promising future in regenerative medicine because they can produce all other types of cells in the body and they have the ability to proliferate indefinitely.
, however, their potential is hampered by the body's tendency to reject any "foreign" cells or tissues, which means that the cells come from donors rather than patients.
this rejection is due to the body's immune system labeling cells "foreign invaders" and launching a series of strategies to defend against what it considers attacks, which has led scientists to scramble to find ways to circumvent such protections.
study, researchers from Tongji University School of Medicine and Zhejiang University in China detailed a possible solution to the problem.
they reported how they genetically edited a group of key proteins found on the surface of HPSC cells, essentially making them invisible to the body's immune system.
results were published online September 15, 2020 in the journal Stem Cells under the title "Generation of hypomunogenic human pluripotent stem cells via expression of the mail-bound and secreted beta-2m-HLA-G fusions."
and Lin Ma of Tongji University School of Medicine.
genetically modified human erypotent stem cells, pictured from AlphaMed Press.
Zhang said, "What we did was build a low immunogenic HPSC using non-classical human leucinocyte antigen (HLA) molecules that are the main targets that trigger isoglobial rejection.
Our strategy not only improves the body's main immune rejection weapons ---T cells (especially CD8 plus T cells), natural killer (NK) cells, and antigen delivery cells, but also reduces immunogenicity in cell-killing and allogeneic transplant environments caused by cell contact.
" study stems from their understanding of the HLA-G family, one of the most prominent HLA I molecules in the placenta, which works to protect fetal tissue from the mother's immune system.
, "This is a remarkable example of mammalian immunomodulation," said Dr. Zhang.
In this, we used CRISPR/Cas9 gene editing techniques to knock out the beta-2 microglobulin (beta 2m) gene, or to perform HLA-G1 double allele knock-in (biallelic knock-in) within the endo-beta 2m site for genetic modification of hpSC.
removal of HLA protein surface expression protects HPSC from CD8-plus T cells and NK cell-mediated cytotoxicity.
expression of HLA proteins also leads to the absence of self-identification and abnormal NK cell activation.
Jan Nolta, editor-in-chief of stem cells, said, "Developing this approach to protect cells produced by erypotent stem cells from the immune system is a game changer in this area."
if the innovative technology advances to clinical trials, it means that recipients who transplant these cells will not need immunosuppression.
we are delighted to be publishing this new and potentially transformative study.
Ma added, "To our knowledge, this is the first study to report that the genetically modified beta-2m-HLA-G5 protein is soluble, secretable, and effective in protecting the cells of the provider from immune responses."
not only provides a new strategy for producing low immunogenic human cells for allogeneic transplantation, but also reveals the role of HLA-G in immune tolerance and organ transplantation during pregnancy.
" Dr. Zhang and Dr. Ma say the next step will be to address any safety issues with these genetically modified HPSC cells, including whether they have a higher risk of tumor growth, given their ability to evade immune surveillance.
Ma said, "The introduction of a controlled suicide gene may provide an effective way to eliminate risk."
if all goes well, genetically modified HPSC could serve as an infinite source of cells to produce generic 'off-the-job' cell transplants in the future.
" (bioon.com) Reference: 1. Lei Shi et al. Generation of hypoimmunogenic human pluripotent stem cells via expression of the system-bound and secreted beta 2m-HLA-G fusion proteins. Stem Cells, 2020, doi:10.1002/stem.3269.2.Stem cells engineered to evade immune system hold promise for 'off-the-shelf' grafts.