Abstract
Although human induced pluripotent stem cells (iPSCs) can serve as a universal cell source for regenerative medicine, the use of iPSCs in clinical applications is limited by prohibitive costs and prolonged generation time. Moreover, allogeneic iPSC transplantation requires preclusion of mismatches between the donor and recipient human leukocyte antigen (HLA). We, therefore, generated universally compatible immune nonresponsive human iPSCs by gene editing. Transcription activator-like effector nucleases (TALENs) were designed for selective elimination of HLA DR expression. The engineered nucleases completely disrupted the expression of HLA DR on human dermal fibroblast cells (HDF) that did not express HLA DR even after stimulation with IFN-γ. Teratomas formed by HLA DR knockout iPSCs did not express HLA DR, and dendritic cells differentiated from HLA DR knockout iPSCs reduced CD4+ T cell activation. These engineered iPSCs might provide a novel translational approach to treat multiple recipients from a limited number of cell donors.
Highlights
Since induced pluripotent stem cells (iPSCs) are autologous or customizable pluripotent stem cells derived from somatic cells, they overcame two major hurdles of ES cells, namely, ethical controversies and immune rejection following transplantation in patients
[8] This study demonstrated that human leukocyte antigen (HLA) DR knockout iPSCs could differentiate to dendritic cells (DCs) with efficiency comparable to that of wild-type iPSCs
To generate universally compatible and immune nonresponsive human iPSCs, we knocked out HLA DR in human fibroblasts using Transcription activator-like effector nucleases (TALENs), which have fewer off-target events than Cas9 and are more maneuverable than ZFNs [12]
Summary
Since iPSCs are autologous or customizable pluripotent stem cells derived from somatic cells, they overcame two major hurdles of ES cells, namely, ethical controversies and immune rejection following transplantation in patients. This approach has several limitations with respect to genetic mutations in patients in addition to the expense of treatment in addition to prolonged durations required for the generation and manipulation of autologous iPSCs. The timely availability of the desired cells, when required by multiple patients, is often not feasible. It was estimated that up to 30 HLA homozygous iPS cell lines, which show a three-locus (HLA-A, -B, and -DR) match in 82.2% of the Japanese population, would be available
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