Current status and future perspectives of HLA-edited induced pluripotent stem cells
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(2020) 40:23
REVIEW
Inflammation and Regeneration
Open Access
Current status and future perspectives of HLA-edited induced pluripotent stem cells Keiko Koga1,2, Bo Wang1,3 and Shin Kaneko1,3*
Abstract In 2007, Human-induced pluripotent stem cells (iPSCs) were generated by transducing four genes (Oct3/4, Sox2, Klf4, c-Myc). Because iPSCs can differentiate into any types of cells in the body and have fewer ethical issues compared to embryonic stem (ES) cells, application of iPSCs for regenerative medicine has been actively examined. In fact, iPSCs have already been used for clinical applications, but at present, only autologous iPSC-derived grafts or HLA homozygous iPSC-derived grafts are being transplanted into patients following HLA matching. HLA is an important molecule that enables the immune system differentiates between self and non-self-components; thus, HLA mismatch is a major hurdle in the transplantation of iPSCs. To deliver inexpensive off-the-shelf iPSC-derived regenerative medicine products to more patients, it is necessary to generate universal iPSCs that can be transplanted regardless of the HLA haplotypes. The current strategy to generate universal iPSCs has two broad aims: deleting HLA expression and avoiding attacks from NK cells, which are caused by HLA deletion. Deletion of B2M and CIITA genes using the CRISPR/Cas9 system has been reported to suppress the expression of HLA class I and class II, respectively. Transduction of NK inhibitory ligands, such as HLA-E and CD47, has been used to avoid NK cell attacks. Most recently, the HLA-C retaining method has been used to generate semi-universal iPSCs. Twelve haplotypes of HLA-C retaining iPSCs can cover 95% of the global population. In future, studying which types of universal iPSCs are most effective for engraftment in various physiological conditions is necessary.
Background Pluripotent ES cells are used in regenerative medicine as source cells [1]. However, they were deemed unethical as their preparation involves the destruction of embryos. The introduction of human iPSCs prepared from fibroblasts and blood cells in a relatively non-invasive manner in 2007 [2] has led to an increase in their feasibility for clinical application. In 2014, the world’s first surgery was performed to transplant a sheet of retinal pigment epithelial cells derived from the iPSCs of a patient with age-related macular degeneration. The 2-year follow-up revealed that the transplanted sheet had remained intact, * Correspondence: [email protected] 1 Takeda-CiRA Joint Program (T-CiRA), 2-26-1, Muraoka-Higashi, Fujisawa, Kanagawa 251-8555, Japan 3 Shin Kaneko Laboratory, Department of Cell Growth and Differentiation, Center for iPS cell research (CiRA), Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan Full list of author information is available at the end of the article
and the patient’s visual acuity did not worsen [3]. However, due to the high costs and large amounts of time required to generate patient-specific iPSCs, it is nece
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