During their development, Schwann cells (SCs) exist as Schwann cell precursors (SCPs), immature non-myelinating SCs, and mature myelinating SCs (Jessen and Mirsky, 2005). As a major type of glial cell in the peripheral nervous system (PNS), SCs function in myelin-sheath formation, nerve impulse transmission, and the secretion of a variety of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and neurotrophin-3 (NT-3), and extracellular matrix components that provide a beneficial microenvironment for neuronal survival and axonal growth (Ndubaku and de Bellard, 2008). Transplanted SCs can myelinate PNS as well as CNS Tyrosine Kinase Inhibitor Library and contribute to improving or restoring conduction and function in demyelinated axons (Golden et al., 2007; Levi et al., 1994); thus, human SCs (hSCs) represent one of the most promising targets for the development of effective treatments for PNS and CNS injuries.
Autologous primary hSCs are highly desirable for disease modeling, phenotypic drug discovery, and treating nerve injuries, but their utility is restricted by limitations such as insufficient numbers of cells due to their low division rate and fibroblast contamination over time in in vitro culture, as well as by technical issues related to isolation and purity (Rutkowski et al., 1995; Xu et al., 2008). For large-scale production, primary SC-like immortalized hSC lines have been established using the SV40 large T-antigen and human telomerase reverse transcriptase expression vectors, and their potential for use in drug development has been suggested (Lehmann et al., 2012). In addition, progress in stem cell research has contributed to expanding the feasible sources of hSCs to include not only neural crest stem cells (NCSCs) (Al-Zer et al., 2015; Ren et al., 2013; Sakaue and Sieber-Blum, 2015), but also a broad range of tissue-specific adult stem cells such as skin-derived precursors (Chen et al., 2012; Krause et al., 2014; McKenzie et al., 2006), adipose-derived stem cells (Razavi et al., 2015; Tomita et al., 2013), dental pulp stem cells (Martens et al., 2014), muscle-derived stem cells (Lavasani et al., 2014), and umbilical cord blood mesenchymal stem cells (Xiao and Wang, 2015). In another approach, hSCs can also be produced from transient neural precursors that are converted from human fibroblasts using cellular reprogramming via treatment with small-molecule inhibitors of multiple kinases, specifically AMPK, PKA, MSK1, SGK1, ROCK2, and PKGa (Thoma et al., 2014).
Currently, much attention has been paid to human pluripotent stem cells (hPSCs), including human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), due to their excellent abilities to differentiate into many cell types, including in particular a wide variety of neural crest derivatives. The hSCs can be indirectly induced by a stepwise in vitro continuous differentiation protocol of hPSCs via an induction of multipotent NCSCs (Lee et al., 2010; Liu et al., 2014; Ziegler et al., 2011). Lineage-specific differentiation of hPSCs into NCSCs can be achieved by pharmacological modulation of key signaling pathways in neural crest development, specifically by the inhibition of both transforming growth factor β (TGF-β) signaling and BMP-dependent Smad signaling in combination with the activation of Wnt signaling (Kreitzer et al., 2013; Menendez et al., 2011). To increase the differentiation efficiency, hPSC-differentiated NCSCs (hPSC-NCSCs) can be purified by fluorescence-activated cell sorting (FACS) for the neural crest marker nerve growth factor receptor (NGFR) and then expanded for seven passages (Liu et al., 2014). The functionality of hSCs derived from hPSC-NCSCs in vitro has been determined by their myelination capacity as evaluated using a dorsal root ganglion (DRG) neuron-SC co-culture system (Liu et al., 2012; Ziegler et al., 2011). However, such approaches still suffer from a low yield and purity of the differentiated SCs, a complicated and time-consuming differentiation process, and a lack of functionality.