Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • SDCs and GPCs have been

    2018-10-20

    SDCs and GPCs have been reported to regulate cell adhesion, migration and differentiation and demonstrate specific expression and localisation during CNS development (Choi et al., 2011, Ford-Perriss et al., 2003). The depletion of SDC1, GPC1 and GPC4 in vitro in mouse NSC or neural precursor cells alters cell maintenance and proliferation (Abaskharoun et al., 2010, Fico et al., 2012, Wang et al., 2012) and the depletion of EXT1, NDST1, HS2ST1 or HS6ST1 in the mouse CNS results in calculate the concentration malformations and abnormalities (Grobe et al., 2005, Inatani et al., 2003, Pratt et al., 2006). Currently the role of HSPGs in human NSC (hNSC) lineage specification is limited and reliant upon rodent models: despite the acknowledged differences in development, structure and regulation between human and rodent nervous systems (reviewed in Oikari et al., 2014). To elucidate key HSPGs in hNSC regulation we expanded hESC-derived NSCs (hNSC H9 cells) and examined the expression of NSC self-renewal and neural cell lineage markers along with HS biosynthesis enzymes and SDC and GPC core proteins in basal and lineage specific differentiation (neuronal and glial) cultures. Our results identify HSPGs as potential regulators of hNSC lineage potential and support their use as additional markers of neural cell specification.
    Materials and methods
    Results
    Discussion Self-renewing and multipotent hNSCs provide an in vitro model to study human neurogenesis and have potential in the regenerative treatment of CNS injuries. Understanding the mechanisms regulating expansion, ‘stemness’ and lineage commitment of hNSCs is critical to our improved understanding of the cells for these applications. With the extracellular microenvironment contributing to the regulation of stem cell fate, cell-surface HSPGs associated with hNSCs and localised within the neural niche may provide novel markers for the characterisation and isolation of hNSCs and their progeny and with which to control hNSC lineage specification. The central findings of this study are summarised in Fig. 7, with several HSPGs proposed as novel markers of hNSCs and lineage specificity.
    Conclusions
    Financial support This study was supported by a QUT Postgraduate Award and Fee stipend (LEO), and the support of the Estate of the late Clem Jones, AO (LMH, LRG).
    Introduction Neurodegenerative diseases and neuropathy are difficult to study due to lack of relevant human models (Phillips et al., 2009). Cell culture systems and primary rodent cultures have proven to be indispensable to clarify disease mechanisms and provide insights into gene functions. However, the current models have not provided much in terms of therapy for inherited neuropathies (known collectively as Charcot–Marie-Tooth disease) (Ekins et al., 2015), and the only effective treatments for diabetic neuropathy are glucose control and pain management (Callaghan et al., 2012). Chemotherapy-induced peripheral neuropathy (CIPN) is a common neurotoxicity affecting 20–40% of patients receiving chemotherapy (Smith et al., 2013). To truly understand and find relevant druggable targets that are causative, a cellular model that represents neuropathy is essential. With recent advances in stem cell technology, the ability to differentiate human induced pluripotent stem cells (iPSCs) to neurons provides us with a new and potentially relevant human neuronal model. In addition, iPSC-differentiated neurons can be created from diseased individuals or individuals with severe sensitivity to neurotoxic chemotherapy to provide a model that will allow for the identification of in vitro phenotypic characteristics relevant to the disease or sensitivity to neurotoxic drug. These neurons may yield targets essential to overcoming and preventing symptoms associated with heritable neuropathy or CIPN. Stem cell technology has revolutionized the field of “in vitro disease modeling” (Sandoe and Eggan, 2013), as evidenced by the first set of drugs emerging into clinical trials from the use of iPSC derived neurons from patients with neurological diseases (Mullard, 2015).