Therefore, we explored whether LMP1 regulated transactivation of the cyclin D1

Discussion Important findings in this study are as follows, i NSPC iPSCs derived from MRC iPS 25 cells were susceptible to HCMV infection and allow the expression of viral gene products of both early and late functions and production ABT-888 PARP 阻害剤 of infectious virions. In contrast, MRC iPS 25 cells before induction of differentiation was either resistant to HCMV or did not support the expression of HCMV immediate early genes, ii the HCMV infected NSPCs undergo apop tosis, and iii the mechanism of the apoptosis included cytochrome c release from mitochondria to cytosol and activation of UPR related signaling pathways. Neuropathogenesis of HCMV infection has been stud ied mainly with neural cells isolated from human brain. These studies demonstrated that HCMV can infect hu man neural precursor cells isolated from fetal brains and interfere with their differentiation.<br><br> Luo et al. showed that HCMV infection in primary NPCs re duced the expression of Nestin, suggesting that HCMV affects the differentiation potential of NPCs. Afatinib 439081-18-2 Similar re sults were also obtained from experiments with mouse NSCs infected with MCMV. Those previous findings obtained from experiments with primary cul tures of brain derived neural cells were thus mostly reproduced in our experiments using NSPC iPSCs. In addition, similar to the results of Odeberg et al. that used NPCs derived from human brain, we also demon strated that HCMV infection induced apoptosis in NSPC iPSCs obtained from iPSCs. It is thus supposed that neural cells differentiated from iPSCs are a useful model to investigate neural pathogenesis of HCMV.<br><br> In the human brain, NSCs are predominantly found in the subventricular region where CMV infections preferen tially occur. Analysis on the effects of HCMV AG-1478 153436-53-4 in fection on NSPCs can be therefore particularly relevant. In the regulation of cellular apoptotic responses, mito chondrial dysfunction and ER stress are involved in the activation of the initiator caspase caspase 9 that functions as a trigger of cascade protease reactions lead ing to cell death. The finding of cytochrome c release from mitochondria to cytoplasm in HCMV infected NSPC iPSCs indicates that mitochondrial dysfunction is involved in the activation of caspase 9 in these cells.<br><br> In addition, the demonstration of phosphorylated forms of proteins involved in UPR, including PERK, JNK, IRE1, eIF2, as well as that of unconventional splicing of XBP1 mRNA and up regulation of CHOP, indicate that ER stress also plays a role in HCMV induced apoptosis of NSPC iPSCs. These results are in accordance with the work reported by Isler et al. who demonstrated that HCMV induced UPR in human foreskin fibroblasts. HCMV is known to encode anti apoptotic proteins such as viral inhibitor of caspase 8 induced apoptosis encoded by UL36, and pUL38 which protects against ER stress induced cell death by modulating the UPR pathway. Our RT PCR analysis demonstrated that such viral anti apoptotic genes were expressed at transcription level in NSPC iPSCs following HCMV in fection. Although these viral anti apoptotic proteins did not block apoptosis of NSPC iPSCs, they might have contributed for efficient viral replication by delaying apoptosis.