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    • purchase latrunculin br List of abbreviations and convention

    2018-11-06


    List of abbreviations and conventions for paper AP+ SSEA4+-Stage Specific Embryonic Antigen 4
    Disclosure of potential conflicts of interest
    Acknowledgments The authors thank Miss Heidi Mjoseng for help with tissue culture during the course of this project. This project was supported by core funding to the MRC Human Reproductive Sciences Unit (RM) and EUFP7 funding to the BEST SC project (223410) co-ordinated by PDS.
    Introduction Oligodendrocyte progenitor purchase latrunculin (OPCs) are important in mediating remyelination in response to demyelinating lesions (Fancy et al., 2011; Cummings et al., 2005; Einstein et al., 2009; Franklin and Ffrench-Constant, 2008). As such, OPCs represent an attractive cell population for use in cell replacement therapies to promote remyelination for treatment of human demyelinating diseases (Ben-Hur and Goldman, 2008; Faulkner and Keirstead, 2005; Martino et al., 2011; Potter et al., 2011; Watson and Yeung, 2011) . High-purity OPCs generated from hESC and have been shown to initiate remyelination associated with improved motor skills in animal models of demyelination (Hatch et al., 2009b; Nistor et al., 2005; Sharp et al., 2010). While promising, there is an extensive literature demonstrating that cultured mouse OPCs are susceptible to apoptosis in response to exposure to the pleiotropic cytokine IFN-γ (Baerwald and Popko, 1998; Balabanov et al., 2007; Buntinx et al., 2004a, 2004b; Horiuchi et al., 2006; Pouly et al., 2000; Vartanian et al., 1995). This is relevant as many human demyelinating diseases e.g. multiple sclerosis (MS) and spinal cord injury (SCI) are associated with inflammation consisting of activated lymphocytes secreting proinflammatory cytokines including IFN-γ (Ankeny and Popovich, 2009; Rodriguez Guerrero et al., 2012; Sospedra and Martin, 2005; Weiner, 2004). One potential reason for remyelination failure in many human demyelinating diseases may be IFN-γ-induced death of OPCs (Itoh et al., 2011; Pouly et al., 2000). Transplantation of hESC-derived OPCs within an inflammatory microenvironment suggests these cells would also be susceptible to IFN-γ-induced apoptosis. The molecular mechanisms associated with regulating apoptosis as well as survival of hESC-OPCs have not been well-characterized and represent an important gap in our knowledge on the biology of these cells. Therefore, determining if OPCs generated from hESCs are susceptible to IFN-γ-induced death also represents an important and unanswered question.
    Materials and methods
    Results
    Discussion Cultured mouse OPCs are highly sensitive to IFN-γ-mediated apoptosis (Baerwald and Popko, 1998; Balabanov et al., 2006, 2007; Buntinx et al., 2004b; Horiuchi et al., 2006; Lin et al., 2006, 2008; Vartanian et al., 1995; Wang et al., 2010). Supporting this are recent studies from our laboratory that have shown that one mechanism by which IFN-γ contributes to mouse OPC apoptosis is through induction of the chemokine CXCL10 that subsequently binds to the receptor CXCR3 (Tirotta et al., 2011). This study also indicated that IFN-γ/CXCL10-mediated apoptosis was associated with cleavage of caspase 3 (Tirotta et al., 2011). Signaling through the chemokine receptor CXCR2 blocks mouse OPC apoptosis by muting caspase 3 cleavage and increasing expression of Bcl-2 which helps protect against apoptosis (Tirotta et al., 2011). The present study was undertaken to ascertain if human OPCs were susceptible to apoptosis in response to IFN-γ/CXCL10 treatment and also determine if CXCR2 signaling elicited protection in a manner similar to mouse OPCs. Our findings reported in this study support and extend earlier findings and indicate that one mechanism by which IFN-γ evokes apoptosis of hOPCs is through a CXCL10-dependent mechanism. hOPC-mediated apoptosis following treatment with either IFN-γ or CXCL10 was associated with the presence of cytosolic cytochrome c and cleaved caspase 3. Importantly, signaling through CXCR2 protects hOPCs from both IFN-γ and CXCL10-mediated apoptosis and is associated with impaired release of cytochrome c and blocking the cleavage of caspase 3. Therefore, these data show that hES-derived OPCs are susceptible to apoptotic death in response to exposure of proinflammatory molecules and that CXCR2 signaling exerts a protective effect.