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    • The generation of neural cells from

    2018-10-22

    The generation of neural EPZ-6438 from patients with MS is an important first step towards a new avenue of MS research. Disease modeling using iPS-generated cells has already improved understanding of a number of rare conditions including spinal muscular atrophy (Ebert et al., 2009), Timothy Syndrome (Yazawa et al., 2011) and familial dysautonomia (Lee et al., 2009). These conditions all have relatively simple and known pathogenic genetic mutations. This is in contrast to MS, which involves a complex interaction between genetic susceptibility and environmental exposure (Oksenberg and Baranzini, 2010). Indeed, epidemiological data suggest that genetic factors contribute significantly to disease susceptibility in MS as well as disease course and may explain much of the observed clinical and pathological heterogeneity (Oksenberg and Baranzini, 2010). The MHC region is by far the most significant region contributing to this disease, although an increasing number of non-MHC loci have been identified in the last few years (Fugger et al., 2009). These loci include genes involved in immune and neuronal function (Saha and Jaenisch, 2009). The real challenge is to prove a functional role for these genetic determinants, taking into account the complexity of gene regulation (Lucchinetti et al., 2000). The generation of clinically relevant models of MS that mimic the pathological heterogeneity of the disease has proved difficult, and thus cells containing the genetic fingerprint for MS may provide a useful model to study this disease and give insights into its pathophysiology and response to treatments (Lucchinetti et al., 2000; Saha and Jaenisch, 2009). Indeed, the possibility of performing a comprehensive transcriptional profile on neural differentiated iPS cells containing a genetic predisposition to MS, as well as assessing the influence of epigenetic factors, could potentially reveal a phenotype important to pathogenesis and amenable to treatment. For example the functional effects of MS associated genes such as the IL7R, which is differentially expressed in primary progressive MS compared with relapsing or secondary progressive patients (Booth et al., 2005), could be examined in differentiated iPS cells from patients with different forms of MS. The generation of MS patient-derived iPS cells also offers the possibility to study other potentially important aspects of MS pathogenesis, such as those contributing to the neurodegenerative process. These could include the examination of the role of mitochondrial failures (Su et al., 2009) and/or the potential of widespread DNA deletions in neurons, as well as the effect of the amiloride sensitive cation channel 1 (also known as ASIC 2) gene on axonal damage and loss (Bernardinelli et al., 2007; Friese et al., 2007). Neurons differentiated from stem cells and iPS cell-derived neurons have previously been characterized electrophysiologically (Kim et al., 2011). Electrical signaling is critical to neuronal function and thus regulation of ion channels in neurons and transmitter receptors are important determinants of appropriate function. Accordingly, the neural cells differentiated from MS fibroblasts were tested electrophysiologically and displayed characteristics of functional neurons. Their resting membrane potentials were robust and the amplitude of action potential large. These data are consistent with the characteristics of mature neurons. However, synaptic activity did not occur in these cells and this could be the result of the paucity of astrocytes which are necessary for synaptic development (Christopherson et al., 2005; Hu et al., 2007; Johnson et al., 2007). Alternatively, there could be differences in potassium, cation or chloride channels. Given that the value of the resting membrane potential is determined by the type, relative density and distribution of ion channels, it will be of interest in further studies to assess whether these variables are altered in response to demyelination (Waxman, 2006a; Krishnan et al., 2009). In contrast, H9-derived neurons fired action potentials spontaneously, with each action potential triggered by a spontaneous depolarization of around 10mV, clearly visible in the lead up to the spontaneous action potential and in the presence of TTX (Fig. 7).