Diminished expression of major histocompatibility complex facilitates the use of human induced pluripotent stem cells in monkey

• Published in: Stem cell research & therapy Vol. 11; no. 1; pp. 1 - 334
• Main Authors: Wang, Xiaokai, Lu, Meng, Tian, Xiaoyu, Ren, Yansong, Li, Yijun, Xiang, Meng, Chen, Sifeng
• Format: Journal Article
• Language: English
• Published: London BioMed Central Ltd 03.08.2020; BioMed Central; BMC
• Subjects: Analysis; Antibodies; Cell proliferation; CIITA protein; Cloning; CRISPR; Deoxyribonucleic acid; DNA; Health aspects; Immune response; Immunogenicity; Induced pluripotent stem cells; Infiltration; Innate immunity; Laboratory animals; Leukocytes (mononuclear); Lungs; Lymphocytes; Lymphocytes B; Lymphocytes T; Macrophages; Major histocompatibility complex; Natural killer cells; Non-human primate; Patient safety; Peripheral blood mononuclear cells; Phosphatase; Pluripotency; Primates; Stem cell immunogenicity; Stem cell transplantation; Stem cells; Transplantation; Transplants & implants; Viruses; Wound healing; Canada; China
• ISSN: 1757-6512; 1757-6512
• DOI: 10.1186/s13287-020-01847-9

Background Stem cells, including induced pluripotent stem cells (iPSCs), have tremendous potential in health care, though with several significant limitations. Each of the limitations, including immunogenicity, may block most of the therapeutic potentials. Beta2 microglobulin (B2M) and MHC II transactivator (CIITA) are critical for MHC I and II, respectively. MHCs are responsible for immunogenic recognition. Methods B2M and CIITA were knocked out from human iPSCs, either separately or simultaneously. The effects of single or dual knockout of B2M and CIITA on iPSC properties were evaluated in a xenogeneic model of human-to-monkey transplantation. Results B2M or CIITA knockout in human induced pluripotent stem cells (iPSCs) diminishes the expression of MHC I or II alleles, respectively, without changing iPSC pluripotency. Dual knockout was better than either single knockout in preserving the ability of human iPSCs to reduce infiltration of T and B lymphocytes, survive, and promote wound healing in monkey wound lesions. The knockouts did not affect the xenogeneic iPSC-induced infiltration of macrophages and natural killer cells. They, however, decreased the iPSC-promoted proliferation of allogeneic peripheral blood mononuclear cells and T lymphocytes in vitro, although not so for B lymphocytes isolated from healthy human donors. Although the dual knockout cells survived long enough for suiting therapeutic needs, the cells eventually died, possibly due to innate immune response against them, thereby eliminating long-term risks. Conclusions Having these iPSCs with diminished immunogenicity-recognizable to allogeneic recipient may provide unlimited reproducible, universal, standardized "ready-to-use" iPSCs and relevant derivatives for clinical applications. Keywords: Induced pluripotent stem cells, Major histocompatibility complex, Stem cell immunogenicity, Non-human primate, Wound healing