Mechanical stretch induces myelin protein loss in oligodendrocytes by activating Erk1/2 in a calcium-dependent manner

Myelin loss in the brain is a common occurrence in traumatic brain injury (TBI) that results from impact-induced acceleration forces to the head. Fast and abrupt head motions, either resulting from violent blows and/or jolts, cause rapid stretching of the brain tissue, and the long axons within the white matter tracts are especially vulnerable to such mechanical strain. Recent studies have shown that mechanotransduction plays an important role in regulating oligodendrocyte progenitors cell differentiation into oligodendrocytes. However, little is known about the impact of mechanical strain on mature oligodendrocytes and the stability of their associated myelin sheaths. We used an in vitro cellular stretch device to address these questions, as well as characterize a mechanotransduction mechanism that mediates oligodendrocyte responses. Mechanical stretch caused a transient and reversible myelin protein loss in oligodendrocytes. Cell death was not observed. Myelin protein loss was accompanied by an increase in intracellular Ca²⁺ and Erk1/2 activation. Chelating Ca²⁺ or inhibiting Erk1/2 activation was sufficient to block the stretch-induced loss of myelin protein. Further biochemical analyses revealed that the stretch-induced myelin protein loss was mediated by the release of Ca²⁺ from the endoplasmic reticulum (ER) and subsequent Ca²⁺-dependent activation of Erk1/2. Altogether, our findings characterize an Erk1/2-dependent mechanotransduction mechanism in mature oligodendrocytes that de-stabilizes the myelination program.     

HIFα Regulates Developmental Myelination Independent of Autocrine Wnt Signaling

The developing CNS is exposed to physiological hypoxia, under which hypoxia-inducible factor α (HIFα) is stabilized and plays a crucial role in regulating neural development. The cellular and molecular mechanisms of HIFα in developmental myelination remain incompletely understood. A previous concept proposes that HIFα regulates CNS developmental myelination by activating the autocrine Wnt/β-catenin signaling in oligodendrocyte progenitor cells (OPCs). Here, by analyzing a battery of genetic mice of both sexes, we presented in vivo evidence supporting an alternative understanding of oligodendroglial HIFα-regulated developmental myelination. At the cellular level, we found that HIFα was required for developmental myelination by transiently controlling upstream OPC differentiation but not downstream oligodendrocyte maturation and that HIFα dysregulation in OPCs but not oligodendrocytes disturbed normal developmental myelination. We demonstrated that HIFα played a minor, if any, role in regulating canonical Wnt signaling in the oligodendroglial lineage or in the CNS. At the molecular level, blocking autocrine Wnt signaling did not affect HIFα-regulated OPC differentiation and myelination. We further identified HIFα–Sox9 regulatory axis as an underlying molecular mechanism in HIFα-regulated OPC differentiation. Our findings support a concept shift in our mechanistic understanding of HIFα-regulated CNS myelination from the previous Wnt-dependent view to a Wnt-independent one and unveil a previously unappreciated HIFα–Sox9 pathway in regulating OPC differentiation.SIGNIFICANCE STATEMENT Promoting disturbed developmental myelination is a promising option in treating diffuse white matter injury, previously called periventricular leukomalacia, a major form of brain injury affecting premature infants. In the developing CNS, hypoxia-inducible factor α (HIFα) is a key regulator that adapts neural cells to physiological and pathologic hypoxic cues. The role and mechanism of HIFα in oligodendroglial myelination, which is severely disturbed in preterm infants affected with diffuse white matter injury, is incompletely understood. Our findings presented here represent a concept shift in our mechanistic understanding of HIFα-regulated developmental myelination and suggest the potential of intervening with an oligodendroglial HIFα-mediated signaling pathway to mitigate disturbed myelination in premature white matter injury.     

抗精神病药喹硫平对少突胶质细胞周期的影响及其作用机制研究

目的 探讨抗精神病药喹硫平对少突胶质细胞周期的影响及其作用机制。方法 采用血小板源性生长因子（PDGF）10 ng/ml、喹硫平10 μmol/L及两者混合物处理少突胶质前体细胞（OPCs）48 h,比较各组细胞周期、细胞周期退出指数及细胞分化情况。检测喹硫平干预后小鼠前额皮质8个细胞周期相关mRNA相对表达量。通过RNA干扰下调p21的表达,并分析其对细胞增殖和分化的影响。结果 PDGF可诱导G0/G1期细胞百分比下降（P <0.05）,S期和G2期细胞百分比升高（P <0.05）;喹硫平可抑制PDGF诱导的S期或G2期细胞百分比升高,并阻止G0/G1期细胞百分比降低（P <0.05）。PDGF抑制细胞周期退出（P <0.05）;喹硫平促进细胞周期退出（P <0.05）,并阻断PDGF对细胞周期退出的影响（P <0.05）。喹硫平可提高OPCs细胞的成熟率,降低低分化细胞数（P <0.05）。喹硫平干预后p21表达升高（P <0.05）;下调p21可增加S期细胞百分比,降低G2期细胞百分比（P <0.05）,增加溴脱氧尿苷阳性细胞数（P <0.05）,减少髓鞘碱性蛋白阳性细胞（P <0.05）。结论 喹硫平可能通过调节少突胶质细胞的细胞周期来调节细胞分化。     

Evidence that the central canal lining of the spinal cord contributes to oligodendrogenesis during postnatal development and adulthood in intact rats

Two waves of oligodendrogenesis in the ventricular zone of the spinal cord (SC‐VZ) during rat development, which take place between embryonic days 14 and 18 (E14–E18) and E20–E21, have been described. In the VZ of the brain, unlike the SC‐VZ, a third wave of oligodendrogenesis occurs during the first weeks of postnatal development. Using immunofluorescence staining of intact rat SC tissue, we noticed the presence of small numbers of Olig2⁺/Sox‐10⁺ cells inside the lining of the central canal (CC) during postnatal development and adulthood. Olig2⁺/Sox‐10⁺ cells appeared inside the lining of the CC shortly after birth, and their number reached a maximum of approximately 0.65 ± 0.14 cell/40‐μm section during the second postnatal week. After the latter development, the number of Olig2⁺/Sox‐10⁺ cells decreased to 0.21 ± 0.07 (P36) and 0.18 ± 0.1 cell/section (P120). At P21, Olig2⁺/Sox‐10⁺ cells inside the CC lining started to express other oligodendroglial markers such as CNPase, RIP, and APC. Olig2⁺/Sox‐10⁺ cells usually did not proliferate inside the CC lining and were only rarely found to be immunoreactive against oligodendrocyte progenitor markers such as NG2 or PDGFRα. Using 5‐bromo‐2‐deoxyuridine administration at P2, P11, P22, or P120–P125, we revealed that these cells arose in the CC lining during postnatal development and adulthood. Our findings confirmed that the CC lining is the source of a small number of cells with an oligodendroglial phenotype during postnatal development and adulthood in the SC of intact rats. J. Comp. Neurol. 522:3194–3207, 2014. © 2014 Wiley Periodicals, Inc.     

Polydendrocytes in development and myelin repair

Polydendrocytes (NG2 cells) are a distinct type of glia that populate the developing and adult central nervous systems (CNS). In the adult CNS, they retain mitotic activity and represent the largest proliferating cell population. Genetic and epigenetic mechanisms regulate the fate of polydendrocytes, which give rise to both oligodendrocytes and astrocytes. In addition, polydendrocytes actively differentiate into myelin-forming oligodendrocytes in response to demyelination. This review summarizes the current knowledge regarding polydendrocyte development, which provides an important basis for understanding the mechanisms that lead to the remyelination of demyelinated lesions.     

S1P1 deletion in oligodendroglial lineage cells: Effect on differentiation and myelination

Sphingosine 1‐phosphate (S1P) receptors are G protein‐coupled receptors expressed by many cell types, including cells of oligodendrocyte (OLG) lineage. We had previously shown that targeted deletion of S1P₁ in OLG lineage cells did not result in obvious clinical phenotype or altered number of OLGs at 3 months, but there were subtle abnormalities in myelin. In this study, we examined the role of S1P₁ in developmental myelination and cell survival, focusing on age 3 weeks. We found that S1P₁ deficiency led to delayed differentiation of OLG progenitors (OPCs) into OLGs that is independent of p38 phosphorylation. This was accompanied by decreased levels of myelin basic protein (MBP) but not of myelin‐OLG glycoprotein (MOG), and slight decrease in myelin thickness in the corpus callosum of S1P₁ conditional knockout (CKO) mice. S1P₁‐deficient OLGs exhibited slower process extension, which was associated with attenuated phosphorylation of extracellular signal regulated kinases (ERKs) and p21‐activated kinases (PAKs), and with upregulation of tropomodulin1. Basal levels of pAkt were not affected, though expectedly, no response to a selective S1P₁ agonist SEW2871 was observed. S1P₁‐deficient OLGs did not exhibit increased cell death in response to cuprizone, tumor necrosis factor‐α, or deprivation of nutrients and growth factors. We conclude that S1P₁ signaling regulates OLG development, morphological maturation and early myelination. GLIA 2016;64:570–582     

Scaffold-Mediated Sustained,Non-viral Delivery of miR-219/miR-338 Promotes CNS Remyelination

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