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    • Previous studies have demonstrated that

    2018-11-08

    Previous studies have demonstrated that the effects of stem cell transplantation in animal experiments vary with different times of cell grafting (Chen et al., 2001; Hofstetter et al., 2002). One possible explanation for this may be that the tissue microenvironment at the site of stem cell transplantation changes along with time after injury and this would cause different behaviors of transplanted cells. Therefore, unraveling the molecular signals underlying NSCs and niche interactions would provide valuable insight into potential usage of NSCs for neural treatment. Considering the pivotal roles of astrocytes in neurogenesis (Jiao and Chen, 2008; Song et al., 2002) and our previous report that molecules secreted from activated astrocytes during different stages of inflammation affected bone marrow-derived mesenchymal stem GSK461364 in different manners (Wang et al., 2009), it remains to be elucidated if molecules derived from astrocytes with distinct inflammatory states would likewise regulate the cell fate determination of NSCs. It is well documented that activation of astrocytes and its related functions in vivo is a complex process which may involve different stimulating factors. In the present study, astrocytes were stimulated by lipopolysaccharide (LPS), a potent inflammatory activator of astrocytes, to mimic partially the astrocytic reactions following an inflammatory injury in vivo. NSCs were then incubated with conditioned medium from LPS-stimulated astrocytes to determine the effects of inflammation-activated astrocytes on the proliferation and differentiation of NSCs and possible molecular signals involved in the process in vitro. The findings would help explain on how the functional changes of astrocytes in different phases of CNS diseases or injuries would affect the stem cells. The study would also provide a cellular and molecular basis for designing and selecting a proper time window for an effective NSC transplantation in clinic.
    Results
    Discussion This study investigated the effects of inflammation-activated astrocytes at different stages on the proliferation and differentiation of NSCs as well as the possible molecular mechanisms involved in the processes. We showed that inflammatory ACMs promoted the proliferation and differentiation of NSCs, notably the 36h ACM which exerted a greater effect on NSCs than other ACMs. Moreover, we identified astrocyte-derived IL-6 as a molecule important for ACM-induced proliferation and differentiation via the phosphorylation of Stat3 signaling pathway. In addition, the bHLH transcription factors such as Mash1, Neurog1 and Hes5 also participate in the ACM-induced NSCs differentiation. Accumulating evidence has demonstrated that astrocytes play important roles in modulating the proliferation and differentiation of NSCs (Ma et al., 2005; Song et al., 2002) However, little is known on how activated astrocytes under inflammatory CNS circumstances regulate the behavior of NSCs. The present results have shown that compared with N-ACM, 36h and 72h ACM significantly promoted proliferation and differentiation of NSCs (Figs. 1 and 2), suggesting that inflammation-activated astrocytes exerted greater effects in cell fate determination of NSCs than unstimulated astrocytes. It has been reported that in response to stimulation, astrocytes significantly upregulate the production of a plethora of molecules, including pro- and anti-inflammatory cytokines, growth factors and trophic factors (Ridet et al., 1997; Lieberman et al., 1989; Lafon-Cazal et al., 2003; Vesce et al., 2007). Most of the secreted factors, such as IL-6, TNF-α, retinoic acid, nerve growth factor and ciliary neurotrophic factor (CNTF), have been demonstrated to participate in the proliferation and differentiation of NSCs (Ma et al., 2005; Cattaneo and McKay, 1990; Bonni et al., 1997; Ricci-Vitiani et al., 2006; Környei et al., 2007; Johansson et al., 2008). It would appear therefore that the increased factors from activated astrocytes in combination might form a special stem cell microenvironment that may facilitate the proliferation and differentiation of NSCs. Horner and others have reported that astrocytes activated by ischemia or mechanical-lesion significantly accelerate the proliferation and differentiation of neural stem/progenitor cells (Faijerson et al., 2006; Horner and Palmer, 2003). Taken together, it is suggested that optimally activated astrocytes under inflammatory CNS conditions may promote the proliferation and differentiation of NSCs.