The Significance of Chondroitin Sulfate Proteoglycan 4 (CSPG4) in Human Gliomas

The most challenging aspect of secondary progressive multiple sclerosis (SPMS) is the lack of efficient regenerative response for remyelination, which is carried out by the endogenous population of adult oligoprogenitor cells (OPCs) after proper activation. OPCs must proliferate and migrate to the lesion and then differentiate into mature oligodendrocytes. To investigate the OPC cellular component in SPMS, we developed induced pluripotent stem cells (iPSCs) from SPMS-affected donors and age-matched controls (CT). We confirmed their efficient and similar OPC differentiation capacity, although we reported SPMS-OPCs were transcriptionally distinguishable from their CT counterparts. Analysis of OPC-generated conditioned media (CM) also evinced differences in protein secretion. We further confirmed SPMS-OPC CM presented a deficient capacity to stimulate OPC in vitro migration that can be compensated by exogenous addition of specific components. Our results provide an SPMS-OPC cellular model and encouraging venues to study potential cell communication deficiencies in the progressive form of multiple sclerosis (MS) for future treatment strategies.

Section: Resultsmentioning

confidence: 99%

iPS-Derived Early Oligodendrocyte Progenitor Cells from SPMS Patients Reveal Deficient In Vitro Cell Migration Stimulation

Lopez-Caraballo

Martorell-Marugán

Carmona-Sáez

et al. 2020

“…One of these is nerve/glial antigen (NG)2, also known as chondroitin sulphate proteoglycane 4 (CSPG4), high molecular weight melanoma-associated antigen (HMW-MAA) or melanoma chondroitin sulfate proteoglycane (MCSP) [ 16 , 17 , 18 ]. NG2 consists of a large, posttranslational modified extracellular domain, which interacts with β1-integrin (CD29), resulting in enhanced cell proliferation [ 19 , 20 ]. Moreover, the extracellular domain binds to collagen VI [ 21 , 22 , 23 ], and thus promotes the detachment of pericytes from the vascular wall and their migration into the surrounding tissue as a major prerequisite for angiogenic sprout formation [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

Protein Kinase CK2 Regulates Nerve/Glial Antigen (NG)2-Mediated Angiogenic Activity of Human Pericytes

Schmitt

Boewe

Becker

et al. 2020

Protein kinase CK2 is a crucial regulator of endothelial cell proliferation, migration and sprouting during angiogenesis. However, it is still unknown whether this kinase additionally affects the angiogenic activity of other vessel-associated cells. In this study, we investigated the effect of CK2 inhibition on primary human pericytes. We found that CK2 inhibition reduces the expression of nerve/glial antigen (NG)2, a crucial factor which is involved in angiogenic processes. Reporter gene assays revealed a 114 bp transcriptional active region of the human NG2 promoter, whose activity was decreased after CK2 inhibition. Functional analyses demonstrated that the pharmacological inhibition of CK2 by CX-4945 suppresses pericyte proliferation, migration, spheroid sprouting and the stabilization of endothelial tubes. Moreover, aortic rings of NG2−/− mice showed a significantly reduced vascular sprouting when compared to rings of NG2+/+ mice, indicating that NG2 is an important regulator of the angiogenic activity of pericytes. In vivo, implanted Matrigel plugs containing CX-4945-treated pericytes exhibited a lower microvessel density when compared to controls. These findings demonstrate that CK2 regulates the angiogenic activity of pericytes through NG2 gene expression. Hence, the inhibition of CK2 represents a promising anti-angiogenic strategy, because it does not only target endothelial cells, but also vessel-associated pericytes.

“…During cytogenesis, NG2/CSPG4 is expressed from a certain stage of development until terminal differentiation in adult oligodendrocytes. NG2/CSPG4-positive or NG2/CSPG4-negative tumors could originate from the transformation of precursors/progenitors at different timepoints (either before expressing NG2/CSPG4, during its expression, or after its loss) ( Figure 5 ) [ 85 ]. They could correspond to tumors with different maturation degrees, proliferation rates, and survival times, according to their early or late derivation.…”

Section: Discussionmentioning

confidence: 99%

“…During tumorigenesis, the glioma stem cell is believed to derive from the transformation of neural stem cells or from the dedifferentiation and transformation of NG2+ glial restricted progenitors, OPCs, or mature cells (astrocytes and oligodendrocytes). The arising tumor cells show potential for self-renewal and express markers associated with both stem and progenitor cell types [ 85 ].…”

Section: Figurementioning

confidence: 99%

Chondroitin Sulphate Proteoglycan 4 (NG2/CSPG4) Localization in Low- and High-Grade Gliomas

Mellai

Annovazzi

Bisogno

et al. 2020

Self Cite

Background: Neuron glial antigen 2 or chondroitin sulphate proteoglycan 4 (NG2/CSPG4) is expressed by immature precursors/progenitor cells and is possibly involved in malignant cell transformation. The aim of this study was to investigate its role on the progression and survival of sixty-one adult gliomas and nine glioblastoma (GB)-derived cell lines. Methods: NG2/CSPG4 protein expression was assessed by immunohistochemistry and immunofluorescence. Genetic and epigenetic alterations were detected by molecular genetic techniques. Results: NG2/CSPG4 was frequently expressed in IDH-mutant/1p19q-codel oligodendrogliomas (59.1%) and IDH-wild type GBs (40%) and rarely expressed in IDH-mutant or IDH-wild type astrocytomas (14.3%). Besides tumor cells, NG2/CSPG4 immunoreactivity was found in the cytoplasm and/or cell membranes of reactive astrocytes and vascular pericytes/endothelial cells. In GB-derived neurospheres, it was variably detected according to the number of passages of the in vitro culture. In GB-derived adherent cells, a diffuse positivity was found in most cells. NG2/CSPG4 expression was significantly associated with EGFR gene amplification (p = 0.0005) and poor prognosis (p = 0.016) in astrocytic tumors. Conclusion: The immunoreactivity of NG2/CSPG4 provides information on the timing of the neoplastic transformation and could have prognostic and therapeutic relevance as a promising tumor-associated antigen for antibody-based immunotherapy in patients with malignant gliomas.