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  • Thus transplanted iNSCs inhibit NF B activation in the

    2018-11-08

    Thus, transplanted iNSCs inhibit NF-κB activation in the amyloid post-CHI. In brief, these results indicate that iNSC grafts may act through NF-κB signaling to regulate amyloid the immune response. Here are the details: 1) the levels of IL-1β and TNF-α secreted by immune cells are down-regulated as a result of decreases in the numbers of neutrophils, microglia/macrophages, T cells and astrocytes, as well as NF-κB inhibition (Philip et al., 2014; Ajibade et al., 2012); 2) the reductions in the concentrations of IL-8, which is produced by microglia/macrophages and astrocytes in the presence of IL-1β and TNF-α, result in decreased neutrophil recruitment after iNSC grafting (Ajibade et al., 2012; Skelly, 2013); and 3) the decreases in the numbers of immune cells and the levels of pro-inflammatory cytokines also result in decreased levels of NF-κB p65 and phospho-p65 in the setting of iNSC administration, compared to PBS treatment (Ajibade et al., 2012; Skelly, 2013). Our study has provided additional evidence regarding the beneficial effects of iNSC-based therapy on CHI (Neher et al., 2014; Johnson et al., 2013). Although we have confirmed that iNSCs, similar to NSCs, have immunoregulatory properties, the mechanisms by which iNSCs communicate with other immune cells are largely unknown. Therefore, subsequent works will continue to explore the interactions between iNSCs and other immune cells. We also showed that transplanted iNSCs exert anti-inflammatory effects in the early phase of CHI, such as down-regulating the levels of TNF-α. Note here that TNF-α can aggravate inflammation-mediated CNS damage and promote long term recovery after CHI (Baratz et al., 2015). Thus, systematic and comprehensive analyses of the immunomodulatory actions of iNSCs will be the subject of future studies. Furthermore, transplantation of iNSCs generated from somatic cells through in vitro reprogramming using non-integrative methods, such as small-molecule approaches, without fear of viral-mediated genetic or epigenetic instability, and in vivo direct reprogramming approaches may open new avenues for the treatment of CHI-induced neurological deficits (Zhang et al., 2016; Tang et al., 2016; Guo et al., 2014).
    Author contributions
    Conflict of interest
    Introduction The motor symptoms of Parkinson\'s disease (PD; e.g. tremor, bradykinesia, postural instability) are caused by loss of dopamine (DA) signaling in the caudate putamen (CPu) brought about by degeneration of DA neurons in the substantia nigra pars compacta (SNc). We know this because killing or interfering with SNc DA neurons in rodent and non-human primate models of PD produce similar motor dysfunctions (Gubellini and Kachidian, 2015) and administering drugs that elevate DA signaling or transplanting DA neurons into SNc or CPu normalizes movement in these models (Duty and Jenner, 2011; Bjorklund and Lindvall, 2017; Redmond et al., 2010). Indeed these same drugs are currently frontline treatments for PD where they effectively alleviate motor symptoms early in treatment but become less effective and produce debilitating side-effects, probably due to the unphysiological and untargeted DA signaling they induce (Barker et al., 2015). This has led many to believe the key to longer-lasting benefits with fewer side-effects is replacing SNc DA neurons, either by cell transplantation or by stimulating endogenous DA neurogenesis (Barker et al., 2015). Both of these cell-replacement approaches would benefit from an adult midbrain microenvironment that is conducive for DA neurogenesis. Unfortunately this does not appear to be the case. In adult rodents, SNc cells rendered bromodeoxyuridine-positive (BrdU+; a marker of dividing cells) remain either undifferentiated or differentiate into glia, not neurons (Aponso et al., 2008; Chen et al., 2005; Cooper and Isacson, 2004; Lie et al., 2002; Shan et al., 2006; Klaissle et al., 2012; Worlitzer et al., 2013, but see Zhao et al., 2003).On the other hand there is evidence that some progenitor cells in the rodent midbrain have neurogenic capacity. Retinoic acid-induced differentiation of cells isolated from adult rat SNc and cultured in the presence of fibroblast growth factors (FGF2 or FGF8) generate β-tubulin III+ cells (neurons) in vitro (Lie et al., 2002). Moreover, these same cells become NeuN+ (neurons) following transplantation into the hippocampus, an established neurogenic niché, but not when transplanted back into SNc of adult rats (Lie et al., 2002). Lie et al. (Lie et al., 2002) speculated that these cells are nestin-expressing neural progenitor cells (NPCs) and Shan et al. (Shan et al., 2006) reported evidence that nestin+cells can indeed generate new neurons, including DA neurons, within the microenvironment of the adult mouse midbrain.