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Medical Research Archives. Volume 5, Issue 2. February 2017 IFRS1 for the Study of Myelination

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Medical Research Archives. Volume 5, Issue 2. February 2017 IFRS1 for the Study of Myelination Medical Research Archives. Volume 5, Issue 2. February 2017 IFRS1 for the study of myelination Immortalized Schwann cells IFRS1 as a new strategic tool for the study of myelination and demyelination Authors Abstract Naoko Niimi* Spontaneously immortalized Schwann cell lines were Shizuka Takaku* established from long-term cultures of adult Fischer rat Hideji Yako* peripheral nerves. One of them, termed as immortalized Kazunori Sango# Fischer rat Schwann cells 1 (IFRS1), has been shown to Affiliations retain distinct Schwann cell phenotypes, such as Diabetic Neuropathy Project, spindle-shaped morphology with expression of glial cell Department of Sensory and markers (S100, glial fibrillary acidic protein and p75 Motor Systems, Tokyo low affinity neurotrophin receptor) and transcription Metropolitan Institute of factors (Krox20, Oct6 and SOX10), synthesis and Medical Science, secretion of neurotrophic factors and cytokines, and Setagaya-ku, Tokyo fundamental ability to myelinate neurites in cocultures 156-8506, Japan with adult rat dorsal root ganglion neurons and nerve #Correspondence: growth factor-primed PC12 cells. Consequently, IFRS1 Kazunori Sango, M.D., Ph.D. cells and their cocultures with neuronal cells can be Project Leader, Diabetic beneficial tools for exploring the precise mechanisms of Neuropathy Project, Tokyo myelination as a result of neuron-Schwann cell Metropolitan Institute of interactions and the pathogenesis of demyelinating Medical Science, 2-1-6 neuropathies. Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan Keywords: immortalized Schwann cells; coculture; E-mail: myelination; demyelination [email protected] TEL: 81368342359 FAX: 81353163150 Note* These authors contributed equally to this work. Copyright 2017 KEI Journals. All Rights Reserved Page | 1 Medical Research Archives. Volume 5, Issue 2. February 2017 IFRS1 for the study of myelination 1. Introduction (Midroni & Bilbao, 1995; Scherer, 1997; Dalakas, 2015). Schwann cells, the glial cells in the Culture of Schwann cells and their peripheral nervous system (PNS), play coculture with neuronal cells have been key roles in development, differentiation, utilized to investigate the mechanisms for physiologic homeostasis, and axonal myelination and demyelination in the regeneration and remyelination after PNS (Rosenbluth & Moon, 2003; injury. They provide trophic support for Felitsyn et al., 2007; Syed et al., 2010). the growth and maintenance of neurons In most of the previous studies, however, and ensheath their axons in either a Schwann cells and neurons were obtained myelinating or an unmyelinating form from embryonic or neonatal animals. (Kidd et al., 2015). Upon peripheral Because it is recognized that some nerve injury, Schwann cells lose axonal biological properties of these cells change contact and change their phenotype in with maturation and aging (Horie et al., favor of axonal regeneration and 1990; Mirsky et al., 2001), culture functional repair. The ‘activated’ systems of adult animal neurons and/or Schwann cells migrate toward the site Schwann cells appear to mimic peripheral distal to the injury where they participate nerve degeneration and regeneration in the process of Wallerian degeneration better than those of embryonic or by eliminating axonal and myelin debris neonatal animal cells. Although the in concert with macrophages. They primary culture of adult rodent Schwann proliferate to form the bands of Büngner cells has been established (Suzuki et al., as guideposts for regenerating neurites, 1999; Kaewkhaw et al., 2012), it needs a secrete various neurotrophic and time-consuming process to obtain good chemotactic factors to help direct neurites yields of Schwann cells and sufficiently toward the target tissues and protect eliminate fibroblasts and other cells from injured neurons from cell death, and the connective tissue-enriched mature finally remyelinate neurites (Susuki, peripheral nerves. Schwann cell lines 2014; Ferguson & Smith, 2015). established from adult animal tissues and Schwann cell abnormalities are closely tumor cells possess high proliferative associated with the development and activity, and are easy to handle for progression of peripheral neuropathies molecular and biochemical analyses. However, the characteristics of these cell Copyright 2017 KEI Journals. All Rights Reserved Page | 2 Medical Research Archives. Volume 5, Issue 2. February 2017 IFRS1 for the study of myelination lines differ to some extent from those of culture, spontaneously emerging the original Schwann cells, and few of Schwann cell colonies were isolated and them have been proved to be capable of further expanded. One of these cell lines myelinating neurites in coculture with were designated as IFRS1 and further neuronal cells (De Vries & Boullerne, characterized. 2010). In our recent study (Sango et al., 2.2. Expression of glial cell markers and 2011a), spontaneously immortalized neurotrophic factors Schwann cell lines were established from long-term cultures of adult Fischer 344 IFRS1 cells displayed spindle-shaped rat dorsal root ganglia (DRG) and morphology under phase-contrast peripheral nerves. One of these cell lines, microscopy with intense designated immortalized Fischer rat immunoreactivity for glial cell markers, Schwann cells 1 (IFRS1), has been shown such as S100 protein, glial fibrillary to retain characteristic features of acidic protein (GFAP) and p75 low Schwann cells as illustrated in the affinity neurotrophic factor receptor following sections, thereby being a useful (p75NTR) (Fig.1). RT-PCR analysis tool for exploring the mechanisms of revealed the mRNA expression of peripheral nerve degeneration and neurotrophic factors (nerve growth factor regeneration. (NGF), glial cell line-derived neurotrophic factor (GDNF) and ciliary 2. Characterization of IFRS1 cells neurotrophic factor (CNTF)), cell adhesion molecules (L1, neural cell 2.1 Establishment of IFRS1 cells adhesion molecule (NCAM) and Primary and long-term cultures of N-cadherin), transcription factors Schwann cells from DRG and peripheral (Krox20, Oct6 and SOX10), myelin nerves from adult Fischer 344 rats were proteins (myelin protein zero (MPZ), maintained in serum-free medium with peripheral myelin protein 22 (PMP22) N2 supplement, 40 ng/mL neuregulin and myelin-associated glycoprotein (NRG)-1 and 5 M forskolin, and were (MAG)) and NRG-1 receptors (ErbB2 passaged once every 4-6 weeks, during and ErbB3) in IFRS1 cells (Sango et al., which neurons and fibroblasts ceased to 2011a). These molecules are also grow in the cultures. After 4-5 months in expressed in primary cultured Schwann Copyright 2017 KEI Journals. All Rights Reserved Page | 3 Medical Research Archives. Volume 5, Issue 2. February 2017 IFRS1 for the study of myelination cells and immortalized mouse Schwann Schwann cell phenotypes such as cells 32 (IMS32) (Watabe et al., 1995, spindle-shaped morphology (A) as well 2003). as immunoreactivity for S100 (B), [Figure 1] IFRS1 cells showed distinct p75NTR (C) and GFAP (D). 2.3. Synthesis and secretion of promoting activities of CM at 20% in neurotrophic molecules medium were comparable to those of NGF at 50 ng/mL, whereas cotreatment Conditioned medium (CM) obtained with anti-NGF neutralizing antibody from IFRS1 cells promoted the survival attenuated the activity of NGF, but not and neurite outgrowth of adult rat DRG CM. In addition, NGF had no significant neurons in a concentration-dependent effects on the viability of DRG neurons manner (10%<20%<100%) (Fig.2), (Sango et al., 2011a). These findings suggesting that IFRS1 cells secrete indicate that neurotrophic and neurotrophic molecules required for neuroprotective molecules other than neuron survival and axonal regeneration NGF released from IFRS1 cells play a after injury. The neurite-outgrowth major role in the sustained viability of Copyright 2017 KEI Journals. All Rights Reserved Page | 4 Medical Research Archives. Volume 5, Issue 2. February 2017 IFRS1 for the study of myelination neurons. In our previous studies, reducing extracellular environment. The members of the interleukin-6 cytokine growing evidence suggests that both family, such as CNTF, leukemia reduced and oxidized forms of GAL-1 inhibitory factor, oncostatin M and are involved in the process of Wallerian cardiotrophin-1 promoted both survival degeneration and subsequent axonal and neurite outgrowth of DRG neurons regeneration with functional recovery (Sango et al., 2008, 2014). It seems likely (Camby et al., 2006), and GAL-1 in the that IFRS1 cells produce and secrete oxidized form lacks lectin activity but these molecules, however, we have not could promote axonal regeneration and obtained the direct evidence to prove this. Schwann cell migration as a cytokine-like Protein expression of galectin-1 molecule (Takaku et al., 2016). (GAL-1), a member of a family of – galactoside-binding animal lectins, was [Figure 2] Conditioned medium (CM) detected in IFRS1 cells and their culture obtained from IFRS1 cells promoted supernatant (Sango et al., 2012b; Takaku survival and neurite outgrowth of et al., 2013). Despite lacking a signal cultured adult rat DRG neurons. For the leading peptide, GAL-1 is subject to neurite outgrowth assay, DRG neurons externalization by a non–classical were maintained in serum-free medium secretory pathway (Sango et al., 2004). (control; A) or CM (B) for 2 days and Following externalization, some of the were immunostained with anti-III galectin molecules associate with surface tubulin antibody. For the survival
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