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  • HSF which negatively regulates OCT expression upon heat

    2018-11-02

    HSF1, which negatively regulates OCT4 expression upon heat shock, has been shown to be important for the development of extraembryonic lineages (Xiao et al., 1999). We thus examined alteration of mRNA expression levels of 1) 21 genes involved in the trophectoderm development (the genes with GOBPs of trophectoderm cell fate commitment and differentiation and trophectodermal cellular morphogenesis) and 2) 57 genes involved in the endoderm development (the genes with GOBPs of endoderm formation and development) by treatments of heat shock and siHSF1 under the heat shock condition (Table S11). Out of the 21 genes, three and six were altered in their expression by heat shock and siHSF1, respectively. Among the 57 genes, three and ten were altered in their expression by heat shock and siHSF1, respectively. These results revealed that more genes were changed in their expression by siHSF1 treatment, suggesting potential roles of HSF1 in the trophectoderm and endoderm, consistent to the previous finding in Xiao et al. (1999). However, differential expression patterns of these genes belonged to four different clusters in Fig. 3C — C1 (2 genes), C2 (7 genes), C3 (3 genes), and C5 (3 genes), which suggests the complex regulation of these genes by heat shock and/or HSF1 in association with trophectoderm and endoderm developments. Therefore, detailed studies should be carried out to understand a molecular basis for the link of HSF1 to trophectoderm and endoderm developments. In this study, we showed that heat shock affects differentiation of hESCs. Heat shock also affects cell proliferation in various types of cells. For example, hyperthermic therapy in human epithelial ovarian cancer reduced tumor size by inducing apoptosis of tumor GS-9973 (Kim et al., 2010). Moreover, heat shock reduced the proliferation rate of cultured GS-9973 porcine muscle satellite cells, leading to the reduction of muscle growth (Kamanga-Sollo et al., 2011). The capability of heat shock in modulating cell proliferation and differentiation suggests that heat shock can serve as a useful means to control proliferation and differentiation of ESCs and various stem cells. However, the utility of heat shock should be highly dependent on the knowledge of the mechanisms underlying the effects of heat shock on cell proliferation and differentiation. Previously, mechanisms underlying the effects of heat shock on cell proliferation and differentiation have been suggested based on HSP-dependent indirect regulation by modulating protein folding and transport. In this study, we showed the direct regulation of heat shock on self-renewal networks involving the negative regulation of the expression of core stem cell regulators by HSF1. Therefore, the HSF1-dependent direct regulation, together with HSP-dependent indirect regulation, provides a fundamental basis for controlling cell differentiation and proliferation of hESCs in a broad spectrum of applications of stem cells. The following are the supplementary data related to this article.
    Introduction Adult human mesenchymal stem cells (MSCs) are multipotent cells that have been isolated from various tissues and differentiated in vitro into multiple mesodermal lineages such as osteoblasts, adipocytes, and chondrocytes (Caplan, 1991). These cells offer certain practical advantages over embryonic stem cells for therapeutic use, as adult human MSCs can be self-donated (Hare et al., 2012), have exhibited lower risk of teratomas (Knoepfler, 2009), and are not subject to the same ethical issues (Zomorodian and Baghaban Eslaminejad, 2012). Bone marrow stromal cells (BMSCs), a subset of which has been shown to be stem cells (also known as bone marrow-derived mesenchymal stem cells) are currently in clinical trials for graft versus host disease (GVHD), and are widely studied for both tissue repair and immune therapies. However, BMSC-based therapies in humans have produced inconsistent results that have been attributed to donor-to-donor variability (Siddappa et al., 2007), differing isolation/culturing protocols (Seeger et al., 2007), and functional heterogeneity within primary cell cultures or clonal populations of bone marrow-derived MSCs (Muraglia et al., 2000).