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    • Dedifferentiation has been considered as

    2018-11-09

    Dedifferentiation has been considered as one of the mechanisms rerouting cell fate by reverting differentiated cells to an earlier, more primitive phenotype. Interestingly, previous studies from both our group and others have demonstrated that dedifferentiation is a prerequisite for bone marrow stromal cells (BMSCs) to change their cell fate and re-differentiate into a different linage (Liu et al., 2010; Poloni et al., 2012). In addition, our recent studies demonstrated that MSCs derived from rat bone marrow (rBMSCs) could be reprogrammed in vitro via differentiation and dedifferentiation with enhanced therapeutic efficacy in tissue repair (Liu et al., 2011; Rui et al., 2015). Interestingly, our microarray profiling and gene ontology analysis reveals that the genes involved in cell motility and migration are differentially expressed between De-neu-rBMSCs and unmanipulated rBMSCs (Liu et al., 2011). Thus, we undertook the present study to evaluate the effect of dedifferentiation-mediated reprogramming on the migratory capability of BMSCs and their efficacy in glioma targeting and killing.
    Results
    Discussion While our previous study demonstrated that De-neu-BMSCs exhibited stronger anti-apoptosis ability and higher neuronal differentiation potential, our present work has revealed that De-neu-BMSCs are endowed with enhanced migratory and tumor-homing ability as well. This feature is critical for the therapeutic value of BMSC in cancer targeting, considering that BMSCs must migrate to tumor sites to exert their function. In our transwell assay, De-neu-BMSCs are more attracted by PDGF-BB and EGF (Figure 4B), which are highly secreted by various types of cancer cells. It should be noted that the origin of U87 has been questioned recently (Dolgin, 2016) and, while we used U87 as glioma model and focused on glioma in this study, it is very likely that the enhanced tumor tropic effect exhibited by De-neu-BMSCs is not limited to glioma. Indeed, we have found that besides glioma, De-neu-BMSCs exhibit enhanced migratory ability toward different types of cancer cells (Figure 1E). On the other hand, inflammation plays a critical role in every stage of tumor progression, and pro-inflammatory cytokines in the tumor microenvironment are crucial in modulating the tumor-homing effects of MSCs (Grivennikov et al., 2010). Of note, De-neu-BMSCs show an enhanced chemotaxis effect toward TGF-β1 and interferon γ as well (Figures S3C and S3D), indicating that pro-inflammatory cytokines existing in the inflammatory milieu of the tumor microenvironment may contribute to the increased recruitment of De-neu-BMSCs in situ. Consistent with the in vitro data, we have demonstrated that De-neu-BMSCs present augmented glioma-tropic effects in the orthotopic xenograft mouse model (Figure 5). While unmanipulated rBMSCs-GFP show limited homing ability, De-neu-rBMSCs-GFP can specifically migrate to the other side of the igf1r inhibitor and integrate into the tumor mass. Furthermore, De-neu-hBMSCs elicit stronger glioma-killing effects together with CD/5-FC compared with unmanipulated hBMSCs (Figure 6). These results clearly indicate that the dedifferentiation strategy augments the tumor-homing ability of BMSCs, which is pivotal for the application of BMSC-based adjuvant therapy for cancer. Chemokines play a vital role in a biologic plethora of migration and are considered as guided cues for directional trafficking of stem cells (Wang and Knaut, 2014). Although CCL5 is a well-known pro-inflammatory chemokine that recruits white blood cells into inflammatory sites, and thereby has been believed to function in a paracrine manner (Marques et al., 2013), the present results have clearly revealed a pivotal role of the autocrine CCL5/CCR1/ERK axis in regulating cell migration in BMSCs, the alteration of which contributes to the differences observed between De-neu-BMSCs and BMSCs (Figure 2). More importantly, we have provided evidence that histone modification is involved in the regulation of chemokine activation in BMSCs. The increase of core active histone markers indicates that the chromatin structure on chemokine promoters becomes loose and open, making De-neu-BMSCs more predisposed for activation. It should be noted that H4ac, a marker of active gene transcription, occupies more on the promoter regions of chemokines than other histone markers, indicating that these chemokines are more susceptible to acetylation-mediated regulation. This result is consistent with the other reports showing that acetylation modification patterns are more responsive to culture condition in MSCs (Fani et al., 2016; Zhu et al., 2015). Moreover, in our previous study, we observed that the expression of multiple histone acetyltransferases was markedly increased in dedifferentiated-reprogrammed BMSCs (Rui et al., 2015). Consistently, in this study, we demonstrated that the expression of H4Ac was also significantly increased in the migrating De-neu-BMSCs toward glioma in vivo (Figure 5D). Based on these findings, we speculate that increased histone acetylation of key chemokine might contribute to the gene activation and enhanced migratory capability in De-neu-BMSCs. Indeed, the occupancy of H4ac on chemokine promoters is significantly increased upon growth factor stimuli (Figures 4D and 4E), and the enhanced migratory ability exhibited in De-neu-BMSCs is completely reversed by an HAT inhibitor, curcumin (Figure 4F). Furthermore, the VPA-induced tumor-homing effect could be completely alleviated by the CCR1 inhibitor (Figure 6A). Taken together, our results provide the documentation that the chemokine axis in MSCs is subject to histone modification-mediated epigenetic regulation, and that such a regulation can significantly influence the migratory capacity for homing of MSC. This demonstration raises questions regarding how the active histone markers are targeted to select chemokine genes and whether related pathways control MSC access to the stroma of infected, autoimmunity-afflicted, or cancer-bearing tissues. Conversely, aberrant chemokine silencing by suppressive histone modification may influence the mobility and responsiveness of the MSC to injury and subsequent repair process.