Regulation of the timing of oligodendrocyte differentiation:mechanisms and perspectives

Axonal myelination is an essential process for normal functioning of the vertebrate central nervous system. Proper formation of myelin sheaths around axons depends on the timely differentiation of oligodendrocytes. This differentiation occurs on a predictable schedule both in culture and during development. However, the timing mechanisms for oligodendrocyte differentiation during normal development have not been fully uncovered. Recent studies have identified a large number of regulatory factors, including cell-intrinsic factors and extracel- lular signals, that could control the timing of oligodendrocyte differentiation. Here we provide a mechanistic and critical review of the timing control of oligodendrocyte differentiation.

Immunomodulative effects of mesenchymal stem cells derived from human embryonic stem cells in vivo and in vitro

Objective: Human embryonic stem cells (hESCs) have recently been reported as an unlimited source of mesenchymal stem cells (MSCs).The present study not only provides an identical and clinically compliant MSC source derived from hESCs (hESC-MSCs),but also describes the immunomodulative effects of hESC-MSCs in vitro and in vivo for a carbon tetrachloride (CCl4)-induced liver inflammation model.Methods: Undifferentiated hESCs were treated with Rho-associated kinase (ROCK) inhibitor and induced to fibroblast-looking cells.These cells were tested for their surface markers and multilineage differentiation capability.Further more,we analyzed their immune characteristics by mixed lymphocyte reactions (MLRs) and animal experiments.Results: hESC-MSCs show a homogenous fibroblastic morphology that resembles bone marrow-derived MSCs (BM-MSCs).The cell markers and differentiation potential of hESC-MSCs are also similar to those of BM-MSCs.Unlike their original cells,hESC-MSCs possess poor immunogenicity and can survive and be engrafted into a xenogenic immunocompetent environment.Conclusions: The hESC-MSCs demonstrate strong inhibitory effects on lymphocyte proliferation in vitro and anti-inflammatory infiltration properties in vivo.This study offers information essential to the applications of hESC-MSC-based therapies and evidence for the therapeutic mechanisms of action.

AATYK is a Novel Regulator of Oligodendrocyte Differentiation and Myelination

Oligodendrocytes（OLs） are myelinating glial cells that form myelin sheaths around axons to ensure rapid and focal conduction of action potentials. Here, we found that an axonal outgrowth regulatory molecule, AATYK（apoptosis-associated tyrosine kinase）, was up-regulated with OL differentiation and remyelination. We therefore studied its role in OL differentiation. The results showed that AATYK knockdown inhibited OL differentiation and the expression of myelin genes in vitro. Moreover, AATYKdeficiency maintained the proliferation status of OLs but did not affect their survival. Thus, AATYK is essential for the differentiation of OLs.

Serological Targeted Analysis of an ITIH4 Peptide Isoform: A Preterm Birth Biomarker and Its Associated SNP Implications

Over 11% of all pregnancies in the US result in preterm birth, greatly contributing to perinatal morbidity and mortality （Goldenberg and Rouse, 1998）. Preterm birth etiologies remain largely unknown, and effective prevention methods have yet to be developed. The use of biofluid （e.g., serum or urine） for the analysis of the naturally occurring peptidome （MW 〈 4000） as a source of biomarkers has been reported for different diseases （Villanueva et al., 2006; Ling et al., 2010a, 2010b, 2010c, 2011）. Mass spectrometry-based profiling of naturally occurring peptides can provide an extensive in- ventory of serum peptides derived from either high-abundant endogenous circulating proteins or cell and tissue proteins （Liotta and Petricoin, 2006）.

TAPP1 Represses the Differentiation of Oligodendrocyte and its Deficiency Accelerates Myelin Regeneration after Demyelinating Injuries

Dear Editor,Myelin,the lipid-rich insulation that supports the integrity of axons,enables rapid conduction of nerve impulses and information flow to distant brain areas[1].Oligodendrocytes(OLs)are glial cells that myelinate axons with specialized lipid membrane extensions[2].OL progenitor cells(OPCs)arise from neural stem cells[3],and undergo proliferation before terminal differentiation and eventual myelination.Impairment at any stage of OL development can affect myelin formation.

Dose-dependent regulation of oligodendrocyte specification by β-catenin signaling

Dear Editor, Although various components of the Wnt/β-catenin pathway have been investigated, there are conflicting reports on the roles of Wnt/β-catenin signaling in oligodendrogenesis and differentiation. For instance, the △Exon3 mutation of β-catenin[14], which stabilizes β-catenin by deletion of the phosphorylation site for the destruction complex, significantly inhibits the differentiation of oligodendrocytes, but knockout of β-catenin also delays it.

TAPP1 inhibits the differentiation of oligodendrocyte precursor cells via suppressing the Mek/Erk pathway

Oligodendrocytes（OLs） are glial cells that form myelin sheaths around axons in the central nervous system（CNS）.Loss of the myelin sheath in demyelinating and neurodegenerative diseases can lead to severe impairment of movement.Understanding the extracellular signals and intracellular factors that regulate OL differentiation and myelination during development can help to develop novel strategies for enhancing myelin repair in neurological disorders.Here,we report that TAPP1 was selectively expressed in differentiating OL precursor cells（OPCs）.TAPP1 knockdown promoted OL differentiation and myelin gene expression in culture.Conversely,over-expression of TAPP1 in immature OPCs suppressed their differentiation.Moreover,TAPP1 inhibition in OPCs altered the expression of Erk1/2 but not AKT.Taken together,our results identify TAPP1 as an important negative regulator of OPC differentiation through the Mek/Erk signaling pathway.

Myelin in development and disease

Myelin is an evolutionarUy novel and important structure for the proper functioning of the vertebrate nervous system. In the central nervous system （CNS）, the myelin sheath is elaborated by oligodendrocytes, and is composed of multiple layers of specialized cell membrane wrapping around axons with periodic interruptions at the nodes of Ranvier. The major function of the myelin sheath is to provide ionic insulation to ensure rapid and saltatory conduction of electrical pulses along axons. In addition, myelin provides neurotrophic support for axons, as they become increasingly dependent on myelin-derived signals for survival. Despite the importance of myelin in the functioning of the CNS, oligodendrocytes are particularly susceptible to genetic and environmental perturbations, and demyelination can be triggered by many pathological conditions including traumatic injury, autoimmune disease （multiple sclerosis, MS）, heavy metal toxicity, and hypoxia. Loss of myelin sheaths in the CNS not only results in the compromised conduction of electrical signals, but also causes progressive degeneration of axons and ultimately neuronal loss. Spontaneous myelin repair from immature oligodendrocyte progenitor cells （OPCs） is not effective in demyelinating lesions, due either to the absence of stimulatory developmental signals that are no longer produced in the adult environment, or to the presence of inhibitory factors peculiar to this environment.