Schwann cells (SCs) originate from the neural crest (SASAKI et al. 2011), develop from Schwann cell precursor cells (WOODHOO et al. 2007) and play an important role in peripheral nerve regeneration (KING-ROBSON 2011). SCs can be divided into distinct groups: myelinating and non-myelinating SCs (JESSEN et al. 2005). For the sake of clarity these SCs will be called peripheral Schwann cells (pSCs) throughout this thesis. Recently, a new group of SCs called central Schwann cells (cSCs), belonging to the group of aldynoglia has been described (GUDINO-CABRERA et al.
1999 and 2000, IMBSCHWEILER et al. 2012). These cells are also called Schwann cell-like glia, aldynoglial Schwann cells or CNS Schwann cells (ORLANDO et al.
2008, ZAWADZKA et al. 2010, IMBSCHWEILER et al. 2012). cSCs share characteristics with oligodendrocytes and astrocytes and resemble pSCs (GUDINO-CABRERA et al. 2000, NIETO-SAMPEDRO 2002, IMBSCHWEILER et al. 2012).
Most of the remyelinating cSCs have been shown to originate from Olig2/PDGFR-α expressing glial cells, presumably OPCs (Figure 3; BLAKEMORE 2005, ZAWADZKA et al. 2010). cSC development from Olig2/PDGFR-α expressing oligodendrocyte progenitor cells is favored by bone morphogenic proteins and an astrocyte-poor environment while in an astrocyte-rich environment development of oligodendrocytes from the same progenitor cells is preferred (Figure 4; ZAWADZKA et al. 2010). One characteristic of aldynoglia is the expression of p75NTR (ORLANDO et al. 2008, IMBSCHWEILER et al. 2012). Aldynoglia can be found in several areas of the adult brain (NIETO-SAMPEDRO 2003). Under pathological conditions like axonal damage or demyelination a differentiation of tissue-resident precursor cells into p75NTR expressing cSCs is described (BLAKEMORE 2005, IMBSCHWEILER et al. 2012).
Figure 3: Development of central Schwann cells (according to ZAWADZKA et al. 2010).
Remyelination of the CNS is carried out mainly by oligodendrocytes and to a lesser extent by Schwann cells (SCs). Most of the central SCs (cSCs) develop from oligodendrocyte progenitor cells which also contribute to the development of oligodendrocytes. cSC differentiation is encouraged by bone morphogenic proteins (BMPs) and an astrocyte-poor environment. Peripheral SCs can migrate into the CNS along the spinal nerves/routes and participate in CNS remyelination but this population has shown to be not the source of the central SC. In contrast to oligodendrocytes and SCs, reactive astrocytes originate from different, fibroblast growth factor 3 positive, progenitor cells.
CC-1=clone detects Adenomatous Polyposis Coli antigen in astrocytes and oligodendrocytes, FGFR3=fibroblast growth factor 3, NG-2=nerve glial antigen 2, PDGFRα=platelet derived growth factor alpha, Olig2=oligodendrocyte transcription factor 2, P0=protein zero, OCT6=octamer-binding transcription factor 6, SCIP/OCT6=POU-domain transcription factors SCIP/OCT6.
Peripheral SCs represent the major myelin producing cell type of the peripheral nervous system. In case of CNS lesions, SCs are known to participate in the process of remyelination. One specific feature of all developmental stages of SCs is the
NTR
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et al. 2005, BOCK et al. 2007). In addition, all types of SCs including their progenitor cells showed expression of O4, representing a typical oligodendroglial surface marker (IMBSCHWEILER 2009). An overview about the antigen expression of myelinating and non-myelinating pSCs as well as cSCs is given in table 1.
Table 1: Marker expression of myelinating and non-myelinating Schwann cells as well as central Schwann cells.
* also termed aldynoglial Schwann cells, Schwann cell-like brain glia or CNS Schwann cells.
** lower numbers of central Schwann cells expressed GFAP compared to peripheral Schwann cells (Imbschweiler et al. 2009).
GFAP=glial fibrillary acidic protein; HNK-1=human natural killer-1; MBP=myelin basic protein;
n.d.=not determined; O4=seminolipid sulfatide antigen; P0=protein zero; p75NTR=neurotrophin receptor p75.
The process of myelination depends on various interactions between axons and the respective myelinating glial cells (JESSEN et al. 2005). pSCs myelinate axons with a diameter larger than 1µm while pSCs in contact with smaller axons form non-myelinating associations (JESSEN et al. 2005). SCs ensheathing non-myelinated axons are also called Remak cells by some authors (SUMMERS et al. 1995a, THOMAS et al. 1997). pSCs show a pronounced plasticity with most of the developmental steps being reversible, e.g. axonal alterations induce a phenotype switch of mature myelinating or non-myelinating SCs to a phenotype similar to Marker
immature SCs (JESSEN et al. 2005). Therefore, an increased expression of myelin-genes like P0 or MBP is correlated with a down-regulation of GFAP, NCAM and p75NTR expression (MORGAN et al. 1991). pSC development and differentiation is a complex process which is mediated by numerous transcription factors, growth hormones and cytokines (Figure 4). In general, the sex determining region Y-box 10 (SOX10) is essential for the development and differentiation of all glial cells from the neural crest while bone morphogenic proteins (BMPs) block their development/differentiation (SHAH et al. 1994, BRITSCH et al. 2001, JESSEN et al.
2005). Neuregulin 1 (NRG1) has been shown to support Schwann cell precursor (SCP) survival and NRG1 as well as FGF-2 and Notch induce the differentiation of SCP to immature SCs (DONG et al. 1999, BRENNAN et al. 2000, GARRATT et al.
2000, MORRISON et al. 2000, WOLPOWITZ et al. 2000, LEIMEROTH et al. 2002, JESSEN et al. 2005). In contrast, transcription factor activator protein 2 (AP2) and endothelins delay SCP differentiation (BRENNAN et al. 2000, JESSEN et al. 2005).
The survival of immature SCs is supported by autocrine factors like NRG1, Ets and laminin, whereas TGFβ and p75NTR induce SC death (GRINSPAN et al. 1996, TRACHTENBERG et al. 1996, MEIER et al. 1999, SYROID et al. 2000, PARKINSON et al. 2001, JESSEN et al. 2005, YU et al. 2005). Furthermore, the induction of myelination is promoted by NRG1, insulin-like growth factors (IGFs), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), laminin, octamerbinding transcription factor 6 (OCT6) and progesterone (BUNGE 1993, KOENIG et al. 1995, STEWART et al. 1995, CHAN et al. 2001, HÖKE et al.
2003, JAEGLE et al. 2003, MICHAILOV et al. 2004, JESSEN et al. 2005). On the other hand, myelination is inhibited by c-Jun, paired box gene 3 (PAX3), SOX2, Notch, Neurotrophin 3 (NT3) and ATP (KIOUSSI et al. 1995, FIELDS et al. 2000, CHAN et al. 2001, PARKINSON et al. 2004, JESSEN et al. 2005, LE et al. 2005).
Selecting SCPs for transplantation bears important advantages: Firstly, SCPs migrate through the normal CNS although they were not directly injected into the lesion and secondly, SCPs form an extensive amount of myelin (BACHELIN et al.
2005, WOODHOO et al. 2007). Disadvantages for selecting mature SCs for
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SCs do not significantly migrate from the implantation site, iii) SCs fail to integrate with recipient oligodendrocytes and astrocytes and iv) the presence of an astrocyte-rich environment significantly reduces myelin-formation of SCs (WOODHOO et al.
2007).
Figure 4: Development and differentiation of peripheral Schwann cells (modified according to JESSEN et al. 2005).
The development and differentiation of peripheral Schwann cells (pSCs) from neural crest cells to myelinating and non-myelinating pSCs is regulated at several steps by numerous growth- and transcription factors. Green color indicates an induction of development/differentiation while red color stands for an inhibition/blockage. AP2α=transcription factor AP-2-alpha; ATP=adenosine triphosphate; BDNF=brain derived neurotrophic factor; BMP=bone morphogenic protein; Ets=transcription factor E-twenty six; FGF-2=fibroblast growth factor 2;
GDNF=glial cell line-derived neurotrophic factor; IGF=insulin-like growth factor;
NRG1=neuregulin 1; NT3=Neurotrophin 3; SOX-2=sex determining region Y-box 1; SOX-10=sex determining region Y-box 10; p75NTR=p75 neurotrophin receptor; TGFβ=tumor growth factor β.