Comparative global immune-related gene profiling of somatic cells, human pluripotent stem cells and their derivatives: implication for human lymphocyte proliferation

Abstract

Human pluripotent stem cells (hPSCs), including embryonic stem cells (ESCs) and induced PSCs (iPSCs), represent potentially unlimited cell sources for clinical applications. Previous studies have suggested that hPSCs may benefit from immune privilege and limited immunogenicity, as reflected by the reduced expression of major histocompatibility complex class-related molecules. Here we investigated the global immune-related gene expression profiles of human ESCs, hiPSCs and somatic cells and identified candidate immune-related genes that may alter their immunogenicity. The expression levels of global immune-related genes were determined by comparing undifferentiated and differentiated stem cells and three types of human somatic cells: dermal papilla cells, ovarian granulosa cells and foreskin fibroblast cells. We identified the differentially expressed genes CD24, GATA3, PROM1, THBS2, LY96, IFIT3, CXCR4, IL1R1, FGFR3, IDO1 and KDR, which overlapped with selected immune-related gene lists. In further analyses, mammalian target of rapamycin complex (mTOR) signaling was investigated in the differentiated stem cells following treatment with rapamycin and lentiviral transduction with specific short-hairpin RNAs. We found that the inhibition of mTOR signal pathways significantly downregulated the immunogenicity of differentiated stem cells. We also tested the immune responses induced in differentiated stem cells by mixed lymphocyte reactions. We found that CD24- and GATA3-deficient differentiated stem cells including neural lineage cells had limited abilities to activate human lymphocytes. By analyzing the transcriptome signature of immune-related genes, we observed a tendency of the hPSCs to differentiate toward an immune cell phenotype. Taken together, these data identify candidate immune-related genes that might constitute valuable targets for clinical applications. Genetic manipulation of certain immune-related genes in stem cells could protect grafts and transplants from immune system rejection. The rejection of stem cells by the immune system remains a major problem in developing successful regenerative therapies. Hsin-Fu Chen at the National Taiwan University in Taipei and co-workers examined the differences in immune-related gene expression between several undifferentiated human pluripotent stem cell (hPSC) types, their derived stem cells and three parental ‘somatic‘ cell types found naturally in the body. They found that derivatives of hPSCs were distinct from somatic cells in terms of gene expression needed for immune function, and identified key genes involved in the ability of hPSCs to provoke an immune response (their immunogenicity). Chen's team also found that inhibiting a key immunity-related signalling pathway in differentiated hPSCs suppressed their immunogenicity.