Abstract
Pluripotent stem cell transplantation is a promising regenerative strategy for treating intractable diseases. However, securing human leukocyte antigen (HLA)-matched donor stem cells is extremely difficult. The traditional approach for generating such cells is to establish homozygous pluripotent stem cell lines. Unfortunately, because of HLA diversity, this strategy is too time-consuming to be of practical use. HLA engineering of donor stem cells has been proposed recently as a means to evade graft-versus-host rejection in stem cell allotransplantation. This approach would be advantageous in both time and cost to the traditional method, but its feasibility must be investigated. In this study, we used CRISPR/Cas9 to knockout HLA-B from inducible pluripotent stem cells (iPSCs) with heterogenous HLA-B and showed that the HLA-B knockout iPSCs resulted in less immunogenicity in HLA-B antisera than that in the control. Our results support the feasibility of HLA-engineered iPSCs in stem cell allotransplantation.
Highlights
Stem cell therapy is a promising regenerative medicine approach for treating patients with intractable diseases
The guide RNAs (gRNAs) human leukocyte antigen (HLA)-B.g2 was cloned into the expression vector pBT-U6-Cas9–2AGFP (Fig. 1c)
According to the IPDIMGT/HLA database, the gRNA HLA-B.g2 showed a perfect match to the HLA-B*40 allele, whereas it had three mismatches to the HLA-B*54 allele
Summary
Stem cell therapy is a promising regenerative medicine approach for treating patients with intractable diseases. For stem cell therapy to be successful, at least two criteria must be met before transplantation: the donor and recipient must be HLA-matched, and a sufficient number of donor stem cells must be secured[1,2,3]. Mesenchymal stem cells (MSCs) have been the most widely used source of stem cells[4], but it is difficult to acquire sufficient numbers of these cells for transplantation[5,6,7]. Inducible pluripotent stem cells (iPSCs) have emerged as an alternative source of MSCs; these cells are both highly expandable and reproducible[8,9,10], enabling the preparation of sufficient numbers of donor stem cells in advance of transplantation. HLA-matched donor stem cells are still difficult to secure. We developed immunocompatible, ready-to-use donor stem cells and tested their suitability for transplantation availability by HLA-targeted complement-dependent cytotoxicity assays
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