Neuron-glia signaling and the protection of axon function by Schwann cells

The interaction between neurons and glial cells is a feature of all higher nervous systems. In the vertebrate peripheral nervous system, Schwann cells ensheath and myelinate axons thereby allowing rapid saltatory conduction and ensuring axonal integrity. Recently, some of the key molecules in neuron–Schwann cell signaling have been identified. Neuregulin-1 (NRG1) type III presented on the axonal surface determines the myelination fate of axons and controls myelin sheath thickness. Recent observations suggest that NRG1 regulates myelination via the control of Schwann cell cholesterol biosynthesis. This concept is supported by the finding that high cholesterol levels in Schwann cells are a rate-limiting factor for myelin protein production and transport of the major myelin protein P0 from the endoplasmic reticulum into the growing myelin sheath. NRG1 type III activates ErbB receptors on the Schwann cell, which leads to an increase in intracellular PIP3 levels via the PI3-kinase pathway. Surprisingly, enforced elevation of PIP3 levels by inactivation of the phosphatase PTEN in developing and mature Schwann cells does not entirely mimic NRG1 type III stimulated myelin growth, but predominantly causes focal hypermyelination starting at Schmidt–Lanterman incisures and nodes of Ranvier. This indicates that the glial transduction of pro-myelinating signals has to be under tight and life-long control to preserve integrity of the myelinated axon. Understanding the cross talk between neurons and Schwann cells will help to further define the role of glia in preserving axonal integrity and to develop therapeutic strategies for peripheral neuropathies such as CMT1A.     

Overexpression of ErbB2 and ErbB3 receptors in Schwann cells of patients with Charcot-Marie-tooth disease type 1A

Axon-derived neuregulins (NRGs) are a family of growth factors whose binding to ErbB tyrosine kinase receptors promotes the maturation, proliferation and survival of Schwann cells (SCs). Correct NRG/ErbB signaling is essential for the homeostasis of axonal-glial complexes and seems to play a role in peripheral nerve repair. The potential involvement of ErbB receptors in human peripheral neuropathies has not been clarified. Therefore, we assessed the immunoreactivity for EGFR (ErbB1), ErbB2, and ErbB3 in nerve biopsies from patients with different forms of Charcot-Marie-Tooth disease, type 1, (CMT1), as compared to others with inflammatory neuropathies and controls. The most notable changes consisted in the overexpression of ErbB2 and ErbB3 by SCs of nerves from CMT1A patients. These findings are consistent with an impairment of SC differentiation and expand the molecular phenotype of CMT1A. The upregulation of these receptors may play a role in the inhibition of myelination or in the promotion of recurrent demyelination and axonal damage.     

Glial cell line‐derived neurotrophic factor–secreting genetically modified human bone marrow‐derived mesenchymal stem cells promote recovery in a rat model of Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive degeneration of nigrostriatal dopaminergic (DA) neurons. The therapeutic potential of glial cell line‐derived neurotrophic factor (GDNF), the most potent neurotrophic factor for DA neurons, has been demonstrated in many experimental models of PD. However, chronic delivery of GDNF to DA neurons in the brain remains an unmet challenge. Here, we report the effects of GDNF‐releasing Notch‐induced human bone marrow‐derived mesenchymal stem cells (MSC) grafted into striatum of the 6‐hydroxydopamine (6‐OHDA) progressively lesioned rat model of PD. Human MSC, obtained from bone marrow aspirates of young, healthy adult volunteers, were transiently transfected with the intracellular domain of the Notch1 gene (NICD) to generate SB623 cells. SB623 cells expressing GDNF and/or humanized Renilla green fluorescent protein (hrGFP) following lentiviral transduction or nontransduced cells were stereotaxically placed into rat striatum 1 week after a unilateral partial 6‐OHDA striatal lesion. At 4 weeks, rats that had received GDNF‐transduced SB623 cells had significantly decreased amphetamine‐induced rotation compared with control rats, although this effect was not observed in rats that received GFP‐transduced or nontransduced SB623 cells. At 5 weeks, rejuvenated tyrosine hydroxylase‐immunoreactive (TH‐IR) fibers that appeared to be host DA axons were observed in and around grafts. This effect was more prominent in rats that received GDNF‐secreting cells and was not observed in controls. These observations suggest that human bone‐marrow derived MSC, genetically modified to secrete GDNF, hold potential as an allogeneic or autologous stem cell therapy for PD. © 2010 Wiley‐Liss, Inc.     

Cadm3 (Necl‐1) interferes with the activation of the PI3 kinase/Akt signaling cascade and inhibits Schwann cell myelination in vitro

Axo‐glial interactions are critical for myelination and the domain organization of myelinated fibers. Cell adhesion molecules belonging to the Cadm family, and in particular Cadm3 (axonal) and its heterophilic binding partner Cadm4 (Schwann cell), mediate these interactions along the internode. Using targeted shRNA‐mediated knockdown, we show that the removal of axonal Cadm3 promotes Schwann cell myelination in the in vitro DRG neuron/Schwann cell myelinating system. Conversely, over‐expressing Cadm3 on the surface of DRG neuron axons results in an almost complete inability by Schwann cells to form myelin segments. Axons of superior cervical ganglion (SCG) neurons, which do not normally support the formation of myelin segments by Schwann cells, express higher levels of Cadm3 compared to DRG neurons. Knocking down Cadm3 in SCG neurons promotes myelination. Finally, the extracellular domain of Cadm3 interferes in a dose‐dependent manner with the activation of ErbB3 and of the pro‐myelinating PI3K/Akt pathway, but does not interfere with the activation of the Mek/Erk1/2 pathway. While not in direct contradiction, these in vitro results shed lights on the apparent lack of phenotype that was reported from in vivo studies of Cadm3^−/− mice. Our results suggest that Cadm3 may act as a negative regulator of PNS myelination, potentially through the selective regulation of the signaling cascades activated in Schwann cells by axonal contact, and in particular by type III Nrg‐1. Further analyses of peripheral nerves in the Cadm^−/− mice will be needed to determine the exact role of axonal Cadm3 in PNS myelination. GLIA 2016;64:2247–2262     

Schwann cell‐derived exosomes enhance axonal regeneration in the peripheral nervous system

Axonal regeneration in the peripheral nervous system is greatly supported by Schwann cells (SCs). After nerve injury, SCs dedifferentiate to a progenitor‐like state and efficiently guide axons to their original target tissues. Contact and soluble factors participate in the crosstalk between SCs and axons during axonal regeneration. Here we show that dedifferentiated SCs secrete nano‐vesicles known as exosomes which are specifically internalized by axons. Surprisingly, SC‐derived exosomes markedly increase axonal regeneration in vitro and enhance regeneration after sciatic nerve injury in vivo. Exosomes shift the growth cone morphology to a pro‐regenerating phenotype and decrease the activity of the GTPase RhoA, involved in growth cone collapse and axon retraction. Altogether, our work identifies a novel mechanism by which SCs communicate with neighboring axons during regenerative processes. We propose that SC exosomes represent an important mechanism by which these cells locally support axonal maintenance and regeneration after nerve damage. GLIA 2013;61:1795–1806     

MMP‐9 controls Schwann cell proliferation and phenotypic remodeling via IGF‐1 and ErbB receptor‐mediated activation of MEK/ERK pathway

Phenotypic remodeling of Schwann cells is required to ensure successful regeneration of damaged peripheral axons. After nerve damage, Schwann cells produce an over 100‐fold increase in metalloproteinase‐9 (MMP‐9), and therapy with an MMP inhibitor increases the number of resident (but not infiltrating) cells in injured nerve. Here, we demonstrate that MMP‐9 regulates proliferation and trophic signaling of Schwann cells. Using in vivo BrdU incorporation studies of axotomized sciatic nerves of MMP‐9?/? mice, we found increased Schwann cell mitosis in regenerating (proximal) stump relative to wild‐type mice. Treatment of cultured primary Schwann cells with recombinant MMP‐9 suppressed their growth, mitogenic activity, and produced a dose‐dependent, biphasic, and selective activation of ERK1/2, but not JNK and p38 MAPK. MMP‐9 induced ERK1/2 signaling in both undifferentiated and differentiated (using dbcAMP) Schwann cells. Using inhibitors to MEK and trophic tyrosine kinase receptors, we established that MMP‐9 regulates Ras/Raf/MEK—ERK pathways through IGF‐1, ErbB, and PDGF receptors. We also report on the early changes of MMP‐9 mRNA expression (within 24 h) after axotomy. These studies establish that MMP‐9 controls critical trophic signal transduction pathways and phenotypic remodeling of Schwann cells. © 2009 Wiley‐Liss, Inc.     

人参皂甙Rb1对体外培养雪旺细胞作用的实验研究

目的 研究人参皂甙Rb1对体外培养雪旺细胞增殖分化的影响,探讨其促进神经再生的作用和机制.方法 取8个月月龄的新西兰兔的坐骨神经雪旺细胞体外培养第2代,加入不同浓度的人参皂甙Rb1,继续培养10d,相差显微镜观察计数,绘制各自的增殖曲线.在36h和72h对各组细胞进行流式细胞分析.结果活细胞计数显示：含20μg/ml人参皂甙Rb1组的倍增时间为5.3d,明显优于对照组（P＜0.01）.用含20μg/ml人参皂甙Rb1培养36h、72h后雪旺细胞增殖的流式细胞分析,处于S期的雪旺细胞较对照组明显增高（P＜0.01）.结论 人参皂甙Rb1具有促进体外培养雪旺细胞快速增殖分化的作用,有助于损伤神经的再生.     

Transplantation of human bone marrow stromal cell‐derived Schwann cells reduces cystic cavity and promotes functional recovery after contusion injury of adult rat spinal cord

The aim of this study was to evaluate whether transplantation of human bone marrow stromal cell‐derived Schwann cells (hBMSC‐SC) promotes functional recovery after contusive spinal cord injury of adult rats. Human bone marrow stromal cells (hBMSC) were cultured from bone marrow of adult human patients and induced into Schwann cells (hBMSC‐SC) in vitro. Schwann cell phenotype was confirmed by immunocytochemistry. Growth factors secreted from hBMSC‐SC were detected using cytokine antibody array. Immunosppressed rats were laminectomized and their spinal cords were contused using NYU impactor (10 g, 25 mm). Nine days after injury, a mixture of Matrigel and hBMSC‐SC (hBMSC‐SC group) was injected into the lesioned site. Five weeks after transplantation, cresyl‐violet staining revealed that the area of cystic cavity was smaller in the hBMSC‐SC group than that in the control group. Immunohistochemstry revealed that the number of anti‐growth‐associated protein‐43‐positive nerve fibers was significantly larger in the hBMSC‐SC group than that in the control group. At the same time, the number of tyrosine hydroxylase‐ or serotonin‐positive fibers was significantly larger at the lesion epicenter and caudal level in the hBMSC‐SC group than that in the control group. In electron microscopy, formation of peripheral‐type myelin was recognized near the lesion epicenter in the hBMSC‐SC group. Hind limb function recovered significantly in the hBMSC‐SC group compared with the control group. In conclusion, the functions of hBMSC‐SC are comparable to original Schwann cells in rat spinal cord injury models, and are thus potentially useful treatments for patients with spinal cord injury.     

人参皂甙Rb1对体外培养雪旺细胞作用的实验研究

目的研究人参皂甙Rb1对体外培养雪旺细胞增殖分化的影响,探讨其促进神经再生的作用和机制。方法取8个月月龄的新西兰兔的坐骨神经雪旺细胞体外培养第2代,加入不同浓度的人参皂甙Rb1,继续培养10d,显微镜观察计数,绘制各自的增殖曲线。在36h和72h对各组细胞进行流式细胞分析。结果活细胞计数显示:含20μg/ml人参皂甙Rb1组的倍增时间为5.3d,明显优于对照组(P<0.01)。用含20μg/ml人参皂甙Rb1培养36h、72h后雪旺细胞增殖的流式细胞分析,处于S期的雪旺细胞较对照组明显增高(P<0.01)。结论人参皂甙Rb1具有促进体外培养雪旺细胞快速增殖分化的作用,有助于损伤神经的再生。     

体外诱导获得雪旺细胞的可靠性研究

目的 研究骨髓基质细胞(BMSCs)在体外条件下向周围神经雪旰细胞(SCs)分化的可靠性. 方法 分离提取SD大鼠股骨和胫骨部位BMSCs.利用其贴壁生长的特性.培养纯化,传代扩增.用复合诱导因子(β.巯基乙醇+全反式维甲酸+血小板凝集抑制剂+m小板源性生长因子+碱性成纤维细胞生长因子)在体外诱导BMSCs分化.免疫细胞化学方法 检测P75、S-100及胶质原纤维酸性蛋白(GFAP)的表达,荧光实时定量PCR检测P75、S100及CD104的表达. 结果诱导后的BMSCs形态类似SCs,免疫荧光染色鉴定其具有SCs性质,表达SCs的表面标志物(GFAP、S100和P75).荧光实时定量PCR结果显示诱导后BMSCs S-100、CD104的表达量达到了SCs的表达量水平,但P75的表达量与SCs的表达量水平还有较大差距. 结论 体外诱导BMSCs可部分获得SCs的特征,传代后恢复至未诱导状态,这种预诱导加复合因子诱导的方法 尚待完善.     

脊髓来源神经干细胞分离培养及向雪旺氏细胞的诱导分化

目的 探讨新生大鼠脊髓来源神经干细胞(NSCs)的分离培养及在体外一定条件下向周围神经雪旺氏细胞分化的可行性. 方法 分离新生大鼠的脊髓组织,在含有B27(终浓度1%)、碱性成纤维细胞生长因子(bFGF)和表皮生长因子(EGF)(终浓度均为20 μg/L)培养基中分离培养出NSCs.用复合诱导因子(10%FBS+5 μmol/L血小板凝集抑制剂+10 ng/mL bFGF+5 ng/mE血小板源性生长因子)在体外诱导NSCs分化为雪旺氏细胞.免疫荧光细胞化学方法[一抗为p75、S-100、神经胶质纤维酸性蛋白(GFAP)]鉴定体外诱导分化结果.结果 培养的新生大鼠脊髓组织细胞nestin染色表达阳性;分离培养的大鼠脊髓来源NSCs经诱导分化后形态类似雪旺氏细胞,免疫荧光细胞化学方法显示诱导后细胞表达雪旺氏细胞的表面标志,GFAP、S-100和P75表达阳性.结论 新生大鼠脊髓来源NSCs可以在体外诱导分化为雪旺氏细胞.     

Myelinating cocultures of rodent stem cell line‐derived neurons and immortalized Schwann cells

Myelination is one of the most remarkable biological events in the neuron–glia interactions for the development of the mammalian nervous system. To elucidate molecular mechanisms of cell‐to‐cell interactions in myelin synthesis in vitro, establishment of the myelinating system in cocultures of continuous neuronal and glial cell lines are desirable. In the present study, we performed co‐culture experiments using rat neural stem cell‐derived neurons or mouse embryonic stem (ES) cell‐derived motoneurons with immortalized rat IFRS1 Schwann cells to establish myelinating cultures between these cell lines. Differentiated neurons derived from an adult rat neural stem cell line 1464R or motoneurons derived from a mouse ES cell line NCH4.3, were mixed with IFRS1 Schwann cells, plated, and maintained in serum‐free F12 medium with B27 supplement, ascorbic acid, and glial cell line‐derived neurotrophic factor. Myelin formation was demonstrated by electron microscopy at 4 weeks in cocultures of 1464R‐derived neurons or NCH4.3‐derived motoneurons with IFRS1 Schwann cells. These in vitro coculture systems utilizing the rodent stable stem and Schwann cell lines can be useful in studies of peripheral nerve development and regeneration.     

Fine structure and development of dorsal root ganglion neurons and Schwann cells in the newborn opossum Monodelphis domestica

The aim of these experiments was to determine the state of maturity of dorsal root ganglia and axons in opossums (Monodelphis domestica) at birth and to assess quantitatively changes that occur in early life. Counts made of dorsal root ganglion cells at cervical levels showed that the numbers were similar in newborn and adult animals, approximately 1,600 per ganglion. In cervical dorsal root ganglia of newborn animals, division of neuronal precursors cells had ceased. The number of axons in cervical dorsal roots was similar in newborn and adult animals (about 4,500). For each ganglion cell body, approximately three axons were counted in the dorsal root. At birth, dorsal roots contained several bundles about 30 μm in diameter consisting of small axons (0.05–2 μm in diameter). A few non-neural cells were identified as Schwann cell perikarya, each enclosing a number of neurites. Later, marked changes occurred in Schwann cells and in their relationship to axons in the roots. Thus, at 12 days, an increase occurred in the number of Schwann cells and fibroblasts, and the bundles had enlarged to about 80 μm with little increase in axon diameter (0.1–2 μm). By 18 days, the bundles were larger, and myelination had already started. At 23 days, the dorsal root contained more than 500 myelinated axons that could reach 5 μm in diameter. The adult dorsal root enclosed about 900 myelinated axons. Throughout this time, the relationship between the Schwann cells and axons changed. Together, these results indicate that the number of axons and cell bodies of sensory dorsal root ganglia in opossum do not show major changes after birth. In addition, these results set the stage for quantitative studies of regeneration of dorsal column fibers in injured neonatal opossum nervous system. J. Comp. Neurol. 396:338–350, 1998. © 1998 Wiley-Liss, Inc.     

CGRP1 receptor activation induces piecemeal release of protease‐1 from mouse bone marrow‐derived mucosal mast cells

Background The parasitized or inflamed gastrointestinal mucosa shows an increase in the number of mucosal mast cells (MMC) and the density of extrinsic primary afferent nerve fibers containing the neuropeptide, calcitonin gene‐related peptide (CGRP). Currently, the mode of action of CGRP on MMC is unknown. Methods The effects of CGRP on mouse bone marrow‐derived mucosal mast cells (BMMC) were investigated by measurements of intracellular Ca²⁺ [Ca²⁺]_i and release of mMCP‐1. Key Results Bone marrow‐derived mucosal mast cells responded to the application of CGRP with a single transient rise in [Ca²⁺]_i. The proportion of responding cells increased concentration‐dependently to a maximum of 19 ± 4% at 10^?5 mol L^?1 (mean ±SEM; C48/80 100%; EC₅₀ 10^?8 mol L^?1). Preincubation with the CGRP receptor antagonist BIBN4096BS (10^?5 mol L^?1) completely inhibited BMMC activation by CGRP [range 10^?5 to 10^?11 mol L^?1; analysis of variance (anova) P < 0.001], while preincubation with LaCl₃ to block Ca²⁺ entry did not affect the response (P = 0.18). The presence of the CGRP1 receptor on BMMC was confirmed by simultaneous immunofluorescent detection of RAMP1 or CRLR, the two components of the CGRP1 receptor, and mMCP‐1. Application of CGRP for 1 h evoked a concentration‐dependent release of mMCP‐1 (at EC₅₀ 10% of content) but not of β‐hexosaminidase and alterations in granular density indicative of piecemeal release. Conclusions & Inferences We demonstrate that BMMC express functional CGRP1 receptors and that their activation causes mobilization of Ca²⁺ from intracellular stores and piecemeal release of mMCP‐1. These findings support the hypothesis that the CGRP signaling from afferent nerves to MMC in the gastrointestinal wall is receptor‐mediated.     

壳聚糖支架与大鼠施万细胞体外组织相容性研究壳聚糖支架与大鼠许旺细胞的体外组织相容性☆

背景：与聚乳酸、胶原等材料相比，壳聚糖作为一种新的生物材料研究时间较短，在神经修复方面的工作开展的较少。 目的：介绍一种简单的壳聚糖支架制备方法并分析其与许旺细胞的生物组织相容性。 设计、时间及地点：体外对比观察实验，于2008-11/2009-07在包头医学院生物医学中心实验室完成。 材料：Wistar 乳鼠10只用于分离培养许旺细胞。医用级壳聚糖粉(脱乙酰度为99%)由浙江澳兴生物科技有限公司提供。 方法：以6%壳聚糖乙酸水溶胶制备壳聚糖支架，取乳鼠坐骨神经采用酶消化后组织块贴壁培养的方法培养许旺细胞。实验分为正常对照组和实验组，实验组将壳聚糖支架平铺于孔底，超净工作台内干燥，然后将许旺细胞接种到培养板内培养，24 h后培养液中加入4,6-二氨基-2-苯基吲哚孵育过夜，去除未与细胞结合的4,6-二氨基-2-苯基吲哚继续培养1周。正常对照组不加任何干预，同样在37 ℃和体积分数为5%CO2的条件下培养1周。 主要观察指标：培养第1，3，5，7天分别选择细胞总数不低于100和200个的视野进行照像，应用图像分析软件(Image pro plus 6.0)分析，计算凋亡细胞的百分率。 结果：壳聚糖支架表面光滑，透明状，质地均匀，厚度0.15 mm。正常对照组和实验组在第1，3，5，7天凋亡细胞的百分率比较，差异无显著性意义(P > 0.05)。 结论：该壳聚糖支架所需材料少，制作方法简单，与许旺细胞具有良好的组织相容性。 关键词：壳聚糖；许旺细胞；组织相容性     

Contribution of bone marrow‐derived endothelial progenitor cells to neovascularization and astrogliosis following spinal cord injury

Spinal cord injury causes initial mechanical damage, followed by ischemia‐induced, secondary degeneration, worsening the tissue damage. Although endothelial progenitor cells (EPCs) have been reported to play an important role for pathophysiological neovascularization in various ischemic tissues, the EPC kinetics following spinal cord injury have never been elucidated. In this study, we therefore assessed the in vivo kinetics of bone marrow‐derived EPCs by EPC colony‐forming assay and bone marrow transplantation from Tie2/lacZ transgenic mice into wild‐type mice with spinal cord injury. The number of circulating mononuclear cells and EPC colonies formed by the mononuclear cells peaked at day 3 postspinal cord injury. Bone marrow transplantation study revealed that bone marrow‐derived EPCs recruited into the injured spinal cord markedly increased at day 7, when neovascularization and astrogliosis drastically occurred in parallel with axon growth in the damaged tissue. To elucidate further the contribution of EPCs to recovery after spinal cord injury, exogenous EPCs were systemically infused immediately after the injury. The administered EPCs were incorporated into the injured spinal cord and accelerated neovascularization and astrogliosis. These findings suggest that bone marrow‐derived EPCs may contribute to the tissue repair by augmenting neovascularization and astrogliosis following spinal cord injury. © 2012 Wiley Periodicals, Inc.     

Human bone marrow‐derived mesenchymal stem cells induce Th2‐polarized immune response and promote endogenous repair in animal models of multiple sclerosis

Cell‐based therapies are attractive approaches to promote myelin repair. Recent studies demonstrated a reduction in disease burden in mice with experimental allergic encephalomyelitis (EAE) treated with mouse mesenchymal stem cells (MSCs). Here, we demonstrated human bone marrow‐derived MSCs (BM‐hMSCs) promote functional recovery in both chronic and relapsing‐remitting models of mouse EAE, traced their migration into the injured CNS and assayed their ability to modulate disease progression and the host immune response. Injected BM‐hMSCs accumulated in the CNS, reduced the extent of damage and increased oligodendrocyte lineage cells in lesion areas. The increase in oligodendrocytes in lesions may reflect BM‐hMSC‐induced changes in neural fate determination, since neurospheres from treated animals gave rise to more oligodendrocytes and less astrocytes than nontreated neurospheres. Host immune responses were also influenced by BM‐hMSCs. Inflammatory T‐cells including interferon gamma producing Th1 cells and IL‐17 producing Th17 inflammatory cells and their associated cytokines were reduced along with concomitant increases in IL‐4 producing Th2 cells and anti‐inflammatory cytokines. Together, these data suggest that the BM‐hMSCs represent a viable option for therapeutic approaches. © 2009 Wiley‐Liss, Inc.     

Electrical stimulation induces calcium‐dependent release of NGF from cultured Schwann cells

Production of nerve growth factor (NGF) from Schwann cells (SCs) progressively declines in the distal stump, if axonal regeneration is staggered across the suture site after peripheral nerve injuries. This may be an important factor limiting the outcome of nerve injury repair. Thus far, extensive efforts are devoted to modulating NGF production in cultured SCs, but little has been achieved. In the present in vitro study, electrical stimulation (ES) was attempted to stimulate cultured SCs to release NGF. Our data showed that ES was capable of enhancing NGF release from cultured SCs. An electrical field (1 Hz, 5 V/cm) caused a 4.1‐fold increase in NGF release from cultured SCs. The ES‐induced NGF release is calcium dependent. Depletion of extracellular or/and intracellular calcium partially/ completely abolished the ES‐induced NGF release. Further pharmacological interventions showed that ES induces calcium influx through T‐type voltage‐gated calcium channels and mobilizes calcium from 1, 4, 5‐trisphosphate‐sensitive stores and caffeine/ryanodine‐sensitive stores, both of which contributed to the enhanced NGF release induced by ES. In addition, a calcium‐triggered exocytosis mechanism was involved in the ES‐induced NGF release from cultured SCs. These findings show the feasibility of using ES in stimulating SCs to release NGF, which holds great potential in promoting nerve regeneration by enhancing survival and outgrowth of damaged nerves, and is of great significance in nerve injury repair and neuronal tissue engineering. © 2009 Wiley‐Liss, Inc.     

Laminins and their receptors in Schwann cells and hereditary neuropathies

This review focuses on the influence of laminins, mediated through laminin receptors present on Schwann cells, on peripheral nerve development and pathology. Laminins influence multiple aspects of cell differentiation and tissue morphogenesis, including cell survival, proliferation, cytoskeletal rearrangements, and polarity. Peripheral nerves are no exception, as shown by the discovery that defective laminin signals contribute to the pathogenesis of diverse neuropathies such as merosin-deficient congenital muscular dystrophy and Charcot-Marie-Tooth 4F, neurofibromatosis, and leprosy. In the last 5 years, advanced molecular and cell biological techniques and conditional mutagenesis in mice began revealing the role of different laminins and receptors in developing nerves. In this way, we are starting to explain morphological and pathological observations beginning at the start of the last century. Here, we review these recent advances and show how the roles of laminins and their receptors are surprisingly varied in both time and place.