20051212

Satellite glial cell as neural stem cell? ---- Mission is possible • Henry Li • Department of Human Physiology, Flinders Medical Centre, • Flinders University of South Australia, Adelaide, Dec.,SA, 12,Australia. 2005

SGCs are originated from neural crest

For adult neurogenesis to occur, the DRG must maintain the appropriate precursor cell niche in the perineuronal zone, which is likely to be dependent on the developmental mechanisms at play in forming the DRG

Organization of cranial motor nerves and sensory ganglia in the mouse •

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A schematic diagram shows the cranial motor nerves and sensory ganglia of the mouse. Cell bodies of the motor nerves are at different medio-lateral positions within the hindbrain, while those of the sensory ganglia are located flanking the hindbrain. III-oculomotor nerve; IVthe trochlear nerve; V- the trigeminal nerve; VIthe abducens nerve; VII-the facial nerve; VIII-the acoustic nerve; IX- the glossopharyngeal nerve; X-the vagus nerve; XI- the spinal accessory nerve; and XII- the hypoglossal nerve. The IV, VI and XII nerves are somatic motor nerves and have ventrally exiting axons. Axons from the branchiomtor (V, VII, IX, X, XI) and visceromotor (III, VII, IX, X) nerve axons exit the neural tube dorsally in distinct exit points located in the even-numbered rhombomeres or in the case of the oculomotor nerve in the midbrain. Sensory ganglia and motor nerves use the same exit points. Mb-midbrain; fp-floorplate;sc-spinal cord; ov-otic vesicle. (Adapted from Lumsden, 1989 (Lumsden and Keynes, 1989).) B. A sagittal view of a 10.5dpc mouse embryo stained with antineurofilament antibody shows the distinct appearance of each cranial ganglia. The oculomotor nerve is marked with an asterisk. Mar et al., 2005 A Genetic Screen for Mutations That Affect Cranial Nerve Development in the Mouse. J Neurosci 25:11787-11795

A pathway of pain BDNF as a crucial mediator of microglial–neuronal signalling during neuropathic pain •

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Coull and colleagues3 reveal that microglial–neuronal signalling mediated by BDNF disrupts inhibition of rat lamina I spinal-cord neurons and maintains neuropathic pain. a, Activation of GABAA receptors (GABAAR) normally leads to an influx of anions (principally chloride, Cl-), causing hyperpolarization (inhibition), because the potential at which the anion flux switches from inward to outward (Eanion) is negative with respect to the resting membrane potential of the neuron (Vrest). b, Following peripheral nerve injury, activated microglia (with ATPstimulated P2X4 receptors) release BDNF, which acts on the TrkB receptor to modify Eanion, probably by reducing levels of the potassiumchloride co-transporter KCC2. As Eanion is now positive with respect to Vrest, GABAA-receptor activation leads to an efflux of anions, depolarizing the lamina I neurons. Blockade of this microglial–neuronal signalling pathway alleviates chronic neuropathic pain in the rat model. From the following article: Neuroscience: A painful factor Carole Torsney and Amy B. MacDermott Nature 438, 923-925 (15 December 2005) doi:10.1038/438923a

Endothelial cells provide a niche for haematopoietic stem cells (HSCs). •

Osteoblasts in the endosteal niche expressing Jagged-1 (Jag1) and Ncadherin contact and maintain HSCs by activation of Notch, and might further regulate HSC activity through N-cadherin and -catenin signalling. Endothelial cells in the vascular niche also contact HSCs and provide unknown maintenance signals (question mark). HSCs might be transported between niches and could be subject to differential regulation in each niche (dashed lines). Endothelial cells expressing vascular cell-adhesion molecule 1 (VCAM-1) also associate closely with megakaryocytes and their progenitors through very late activation antigen 4 (VLA4) in response to chemotactic factors, stromal cell-derived factor-1 (SDF1) and fibroblast growth factor-4 (FGF4), and provide a niche for megakaryocyte maturation and platelet production. The immediate juxtaposition of HSCs to endothelial cells also facilitates their rapid mobilization and entry into circulation in response to stress and, in the case of megakaryocytes, release of platelets directly into the blood. HSCs and haematopoietic progenitor cells as well as megakaryocytes produce VEGF and other angiogenic factors, which might act in a feedback loop to support endothelial cells in the bone marrow and in the periphery at sites of normal and pathologic angiogenesis.

From the following article: Endothelial cells and VEGF in vascular development Leigh Coultas, Kallayanee Chawengsaksophak and Janet Rossant Nature 438, 937-945 (15 December 2005) doi:10.1038/nature04479

Adult neurogenesis and VEGF

From the following article: From angiogenesis to neuropathology David A. Greenberg and Kunlin Jin Nature 438, 954-959 (15 December 2005) doi:10.1038/nature04481

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a, Neurogenesis in the subventricular zone (SVZ). Neurons that arise in the rostral SVZ migrate by way of the rostral migratory stream (RMS) to the olfactory bulb (OB). b, Neurogenesis in the dentate gyrus (DG). Neurons arise in the dentate subgranular zone (SGZ) and migrate into the adjacent granule cell layer (GCL); AH, Ammon's horn of hippocampus. c, Concept of the 'vascular niche' and VEGF-induced neurogenesis. Neurogenesis is often observed close to vasculature, and certain growth factors, such as VEGF, stimulate both angiogenesis and neurogenesis. Possible explanations include parallel, independent effects of VEGF on endothelial and neuronal stem cells, or VEGF-induced production by endothelial cells of other growth factors, like BDNF, that act on neuronal stem cells to stimulate neurogenesis.

Gliogenesis in PNS •

Multipotent NCCs migrate from the neural tube and then aggregate to form PNS ganglia where they differentiate to neurons and glia. As PNS neurons and glia differentiate in the same environment, it has been puzzling to understand how NCCs choose to adopt either neuronal or glial fate. Early cell fate determination of NCSCs to SCs and the subsequent differentiation occur under the influence of multiple signals from the environment, which are integrated and together with intracellular factors are interpreted by the cells to elicit a cell type-specific response The differentiation of NCCs to neurons is instructively promoted by local environmental signals, but the glial differentiation is dominant influenced by lateral inhibition of the neurons (Wakamatsu et al., 2000; Kubu et al., 2002; Morrison et al., 2000; Morrison, 2001b, 2001a ).

Overview of SGCs • SGCs are a distinct type of glial cells that is not fully similar to either astrocytes or oligodendrocyes • SGCs and sensory neuron envelop as a functional unit • Barrier function • Gap junction

Plasticity of SGCs • In normal, uninjured mice SGCs behave as a homogenous, slowly replicating population based on 5-bromo-2′-deoxyuridine (BrdU) labeling suggested that the probability of the existence of a population of ganglionic stem cells (Elson et al., 2004b). A body of studies have shown that plasticity of SGCs involving in nerve injury and neuropathic pain, glial cells in sensory ganglia will display considerable change following damage because they can undergo mitosis(Elson et al., 2004a) and are highly plastic (reviewed by Hanani, 2005).

Molecular markers of SGCs • • • •

GFAP (glial fibrillary acidic protein) S100 GS (glutamine synthetase) : Trigeminal ganglia Erm: The first molecular marker that enables Schwann cells to be distinguished from the SGCs. Both types of neural crest-derived glial cells can be molecularly distinguished by expression and function of erm transcription factor (Hagedorn et al., 2000; Paratore et al., 2002).. Only the satellite cells were found to express the Ets-domain erm transcription factor that regulates precursor cell proliferation (Paratore et al., 2002).

SGCs & NG2 •

Cultured SGCs from DRG of embryonic and neonatal rats express NG2, can transform into astrocytes, Schwann cells and oligodendrocytes (Svennigsen et al, 2004). • NG2 is expressed by SGCs in adult dorsal root ganglia (DRG) after injury, NG2+ cells are progenitors?(Rezajooi et al., 2004). • ________________________________________________ •

Postnatal NG2 proteoglycan-expressing progenitor cells in CNS are intrinsically multipotent and generate functional neurons (Belachew et al., 2003; Aguirre and Gallo, 2004; Aguirre et al., 2004).

SGCs & Nestin •

After injury, reactive SGCs are also nestin immunoreactive (our data and Kuo et al., 2005), indeed, uninjured SGCs in adult DRG also express nestin (our data).They are potential candidates for neuronal precursor cells. • If satellite cells are able to differentiate into neurons (they did in vitro ), their role would be analogous to the role played by Müller glia following injury to the retina (Fischer and Reh,2001), • Radial glial cells in adult CNS which express nestin and GFAP are bona fade neural stem cell (Goldman, 2003; Anthony et al., 2004; Mori et al., 2005).

SGCs & GFAP • SGCs are GFAP+ after injury in vivo, or migratory out from explants culture in vitro. • The predominant neural stem cell isolated from postnatal and adult forebrain are GFAP-expressing cells (Dougherty et al., 2005 ; Imura et al., 2003; Imura et al., 2005)

Neural crest cells as stem cell • Differentiated glial cells and melanocytes in vitro can reverse to their common bipotent ancestor upstream in NC lineage hierarchy (Dupin et al., 2000; Le Douarin and Dupin, 2003; Reali et al., 2005), Production of pigment cells from Schwann cells was found in vivo in adult mice subjected to nerve injury severe enough to trigger exit of Schwann cells from the lesion (Rizvi et al., 2002), an alternative phenotype can be adopted by differentiated Neural crest cells (NCC) if they are forced to escape from their normal environmental context. Together with recent discoveries regarding the plasticity of somatic stem cells (Weissman et al., 2001; Raff, 2003; Christensen et al., 2004; Corti et al., 2004; Leri et al., 2005; Sun et al., 2005) , NCCs with various degrees of commitment might be recruited to function as stem cells.

Stem cell niche in DRG •

Growth factors released from SGCs are major contributors to sympathetic sprouting (Zhou et al., 1999) and SGC can form perineuronal ring structures with sprouting sensory neurons after spinal nerve injury (Li and Zhou, 2001), these injury-induced profound structural changes along the sensory pathways resulted in the disruption the normal milieu of the supposed tight niche(Ohlstein and Spradling, 2005), it may consist of by SGC (reserved stem cell or undifferentiated, quiescent precursors) and its enveloped neurons (niche cell or anchor cell) through gap-junction in DRG, the mobilization of stem cell/precursor may be ongoing process to initiate addition of new-born neuron to replace the dying/death neuron for a long run. SGCs also express P75NTR(Zhou et al., 1999; Li et al., 2003) and nestin (present data), two markers routinely used for identifying neuralcrest stem cell(Rao and Anderson, 1997; Mujtaba et al., 1998) .

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In our another previous studies, we found that transforming growth factor α (TGF-α), one member of Epidermal growth factor (EGF) family molecules (Xian and Zhou, 1999b), were constitutively expressed b y satellite cells in normal adult DRG, after sciatic nerve lesion, TGF-alpha was up-regulated by SGC ,but the expression of its EGF receptor was down-regulated in SGC in vivo (Xian and Zhou, 1999a), the functional redundancy within the EGF family through a compensatory expression mechanism should be considered (Xian et al., 2001), the reactive proliferation of SGC possibly contributed by, maybe by EGF, and also fibroblast growth factor-2 (FGF2) and its receptors(Grothe et al., 1997), the potent mitogens commonly used in expansion of adult neural stem cell(Kuhn et al., 1997; Cedrola et al., 2003; Deleyrolle et al., 2005) and adult neural crest stem cell(Kruger et al., 2002).

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The present in vitro analysis shows that migratory cells express Neu and ErbB4 may be resulted from the loss of the supposed niche signal in our culture. Therefore, combining in vitro multipotential and neurogenic differentiation of these cells and self-renewal capacity, it is reasonable that SGCs-neuron function unit is a potential candidate of neural stem cell niche in adult DRG. Since axon injury, reactive Satellite cell are still associated with neurons by the formation of bridges connecting previously separate perineuronal sheaths and the formation of new gap junctions, resulting in more extensive cell coupling (Pannese et al., 2003), It seems that the global structure of niche is not seriously interrupted, may be it is a nonpermissive niches in the adult DRG, unlike its counterpart for cell genesis in the adult CNS(Goldman, 2003)

• To further define this niches in adult neurogenesis in vivo, selective destruction the niche cell, e.g.,the enveloped neurons,by neurotoxin or using genetic model, will provide more clear-cut evidence. At present selective glial toxins are not available, but genetic methods have been developed to selectively ablate glial cells in the peripheral nervous system (Bush et al, 1998; Cornet et al, 2001) and reactive astrocytes in the CNS (Garcia et al., 2004), which might be adapted for lesioning SGCs.

• Any suggestions will be appreciated!

•Thanks