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Sertoli cells are essential nurse cells in the testis that regulate the process of spermatogenesis and establish the immune-privileged environment of the blood-testis-barrier (BTB). The induction of human Sertoli cells from fibroblasts could provide cellular sources for fertility and transplantation treatments. Here, we report the in vitro reprogramming of human fibroblasts to Sertoli cells and characterize these human induced Sertoli cells (hiSCs).Initially, five transcriptional factors (NR5A1, GATA4, WT1, SOX9 and DMRT1) and a gene reporter carrying the AMH promoter were utilized to obtain the hiSCs. We further reduce the number of reprogramming factors to two, i.e., NR5A1 and GATA4, and show that these hiSCs have transcriptome profiles that are similar to those of primary human Sertoli cells. Consistent with the known cellular properties of Sertoli cells, hiSCs attract endothelial cells and exhibit high number of lipid droplets in the cytoplasm. More importantly, hiSCs can sustain the viability of spermatogonia cells harvested from mouse seminiferous tubules. In addition, hiSCs suppress the production of IL-2 and proliferation of human T lymphocytes. When hiSCs were cotransplanted with human embryonic kidney cells, these xenotransplanted human cells survived longer in mice with normal immune systems. hiSCs also allow us to determine a gene associated with Sertoli-only syndrome (SCO), CX43, is indeed important in regulating the maturation of Sertoli cells.To determine whether hiSCs reprogrammed with the 5TFs (5F-hiSCs) are similar to human Sertoli cells, we compared the transcriptomes of the AMH:EGFP+ 5F-hiSCs, dH1 cells infected with p2k7 empty virus (dH1-2K7) as negative controls, and primary adult Sertoli cells (aSCs) from human biopsy samples. We focused our analysis on the differentially expressed genes (DEGs, > 2-fold change, p-value < 0.05) between 5F-hiSCs and dH1-2K7 and between aSCs and dH1-2K7. In total, 7533 genes were differentially expressed between 5F-hiSCs and dH1-2K7, including 4528 upregulated genes and 3005 down-regulated genes (Fig. 2a,b). Additionally, 5377 genes were differentially expressed between aSCs and dH1-2K7, including 3343 upregulated genes and 2034 down-regulated genes (Fig. 2a, b).The Venn analysis showed that 3626 genes were shared among the DEGs in both hiSCs and aSCs, accounting for approximately 67% of the DEGs in aSCs. Among this shared group of DEGs (CO-DEGs), 1973 genes were upregulated, while 1314 genes were down-regulated in both the hiSCs and aSCs (Fig. 2c), indicating that the trends in transcriptional expression between the hiSCs and aSCs were the same in these genes. The cluster analysis of dH1-2K7, hiSCs and aSCs also showed that the CO-DEGs had a similar expression pattern between the hiSCs and aSCs, and consistency was observed between duplicate samples (Fig. 2d). The Gene Ontology (GO) analysis of the CO-DEGs showed that among the 1973 upregulated genes, many genes were involved in the regulation of cell communication, regulation of immune response processes, re...
Sertoli cells are essential nurse cells in the testis that regulate the process of spermatogenesis and establish the immune-privileged environment of the blood-testis-barrier (BTB). The induction of human Sertoli cells from fibroblasts could provide cellular sources for fertility and transplantation treatments. Here, we report the in vitro reprogramming of human fibroblasts to Sertoli cells and characterize these human induced Sertoli cells (hiSCs).Initially, five transcriptional factors (NR5A1, GATA4, WT1, SOX9 and DMRT1) and a gene reporter carrying the AMH promoter were utilized to obtain the hiSCs. We further reduce the number of reprogramming factors to two, i.e., NR5A1 and GATA4, and show that these hiSCs have transcriptome profiles that are similar to those of primary human Sertoli cells. Consistent with the known cellular properties of Sertoli cells, hiSCs attract endothelial cells and exhibit high number of lipid droplets in the cytoplasm. More importantly, hiSCs can sustain the viability of spermatogonia cells harvested from mouse seminiferous tubules. In addition, hiSCs suppress the production of IL-2 and proliferation of human T lymphocytes. When hiSCs were cotransplanted with human embryonic kidney cells, these xenotransplanted human cells survived longer in mice with normal immune systems. hiSCs also allow us to determine a gene associated with Sertoli-only syndrome (SCO), CX43, is indeed important in regulating the maturation of Sertoli cells.To determine whether hiSCs reprogrammed with the 5TFs (5F-hiSCs) are similar to human Sertoli cells, we compared the transcriptomes of the AMH:EGFP+ 5F-hiSCs, dH1 cells infected with p2k7 empty virus (dH1-2K7) as negative controls, and primary adult Sertoli cells (aSCs) from human biopsy samples. We focused our analysis on the differentially expressed genes (DEGs, > 2-fold change, p-value < 0.05) between 5F-hiSCs and dH1-2K7 and between aSCs and dH1-2K7. In total, 7533 genes were differentially expressed between 5F-hiSCs and dH1-2K7, including 4528 upregulated genes and 3005 down-regulated genes (Fig. 2a,b). Additionally, 5377 genes were differentially expressed between aSCs and dH1-2K7, including 3343 upregulated genes and 2034 down-regulated genes (Fig. 2a, b).The Venn analysis showed that 3626 genes were shared among the DEGs in both hiSCs and aSCs, accounting for approximately 67% of the DEGs in aSCs. Among this shared group of DEGs (CO-DEGs), 1973 genes were upregulated, while 1314 genes were down-regulated in both the hiSCs and aSCs (Fig. 2c), indicating that the trends in transcriptional expression between the hiSCs and aSCs were the same in these genes. The cluster analysis of dH1-2K7, hiSCs and aSCs also showed that the CO-DEGs had a similar expression pattern between the hiSCs and aSCs, and consistency was observed between duplicate samples (Fig. 2d). The Gene Ontology (GO) analysis of the CO-DEGs showed that among the 1973 upregulated genes, many genes were involved in the regulation of cell communication, regulation of immune response processes, re...
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