NG2 proteoglycan is expressed exclusively by mural cells during vascular morphogenesis

Özerdem, Uğur; Grako, Kathryn A.; Dahlin-Huppe, Kimberlee; Monosov, Edward; Stallcup, William B.

doi:10.1002/dvdy.1200

Cited by 523 publications

(491 citation statements)

References 51 publications

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“…The number of Olig2ϩ cells that expressed NG2 varied with the subregion of the brain examined from a low of 8% in the SVZ to a high of 53% within white matter tracts. We found that NG2 glial cells easily could be distinguished from NG2ϩ͞Olig2Ϫ pericytes associated with blood vessels (25) on the basis of morphology; however, we could not entirely rule out that a minor population of NG2ϩ͞Olig2Ϫ cells in our counts are pericytes.…”

Section: Resultsmentioning

confidence: 60%

Development of NG2 neural progenitor cells requires Olig gene function

Ligon

Kesari

Kitada³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

188

152

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In the adult central nervous system, two distinct populations of glial cells expressing the chondroitin sulfate proteoglycan NG2 have been described: bipolar progenitor cells and more differentiated ''synantocytes.'' These cells have diverse neurological functions, including critical roles in synaptic transmission, repair, and regeneration. Despite their potential importance, the genetic factors that regulate NG2 cell development are poorly understood, and the relationship of synantocytes to the oligodendroglial lineage, in particular, remains controversial. Here, we show that >90% of embryonic and adult NG2 cells express Olig2, a basic helix-loop-helix transcription factor required for oligodendrocyte lineage specification. Analysis of mice lacking Olig function demonstrates a failure of NG2 cell development at embryonic and perinatal stages that can be rescued by addition of a transgene containing the human OLIG2 locus. These findings show a general requirement for Olig function in NG2 cell development and highlight further roles for Olig transcription factors in neural progenitor cells.Cspg4 ͉ oligodendrocyte ͉ synantocyte ͉ glia ͉ regeneration N G2 cells are central nervous system (CNS) glial cells defined by their expression of the chondroitin sulfate proteoglycan, NG2, which is also known as Cspg4 or AN2 (1-4). A significant proportion of NG2 cells actively proliferate and indeed have been characterized as the most prevalent cycling progenitor cell population in the adult CNS (5, 6). NG2 cells have diverse functions and participate in oligodendrogenesis (7) and neurogenesis (8), as well as the physiologic support of neurons and synaptic signaling (4, 9). They have also been proposed to play critical roles in brain repair and regeneration and are the primary responding neural cell type to CNS injury (10, 11).Despite their abundance as a progenitor population and potential importance in maintenance and repair of neurological function, the developmental ontogeny of NG2 cells remains controversial (4,7,12). Cytologically, they are reportedly a heterogeneous population, and two distinctive cellular morphologies have been described: bipolar progenitor cells that resemble oligodendrocyte progenitors (OLP) (1, 13) and stellate ''synantocytes.'' Most postnatal NG2 cells are synantocytes, which are defined by a complex ''differentiated'' morphologic appearance. Even so, they lack expression of most differentiated glial celltype specific markers (12). Indeed, based on these observations, several studies have suggested that the majority of postnatal NG2ϩ synantocytes comprise an independent neuroepithelial lineage distinct from neurons, astrocytes, and oligodendrocytes (4, 12, 14), a proposal that has provoked ongoing debate (15, 16).The genetic pathways, which regulate NG2 cell development, have yet to be defined, and the question of whether bipolar NG2 cells and synantocytes have fundamentally similar or different origins is unresolved. Given their early developmental expression of OLP markers, NG2 cell formation mi...

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Section: Resultsmentioning

confidence: 60%

Development of NG2 neural progenitor cells requires Olig gene function

Ligon

Kesari

Kitada³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

188

152

View full text Add to dashboard Cite

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“…Cells were incubated with rabbit anti-PDGFRb polyclonal antibodies. 5,36 After washing, cells were incubated with goat anti-rabbit IgG microbeads (Miltenyi) (4°C, 15 minutes), re-suspended, and positive selection was performed by MACS magnetic bead separation (Miltenyi). Selected cells were cultured in DMEM/F12 with 10% FBS, 1% penicillin/streptomycin, and 1% insulin-transferrinselenite (ITS), in 6-well plates precoated with 0.2% gelatin.…”

Section: Isolation and Culture Of Cells From Kidneymentioning

confidence: 99%

EphrinB2 Reverse Signaling Protects against Capillary Rarefaction and Fibrosis after Kidney Injury

Kida

Ieronimakis

Schrimpf

et al. 2013

Journal of the American Society of Nephrology

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Microvascular disease, a characteristic of acute and chronic kidney diseases, leads to rarefaction of peritubular capillaries (PTCs), promoting secondary ischemic injury, which may be central to disease progression. Bidirectional signaling by EphB4 receptor and ephrinB2 ligand is critical for angiogenesis during murine development, suggesting that ephrinB2 reverse signaling may have a role in renal angiogenesis induced by injury or fibrosis. Here, we found that ephrinB2 reverse signaling is activated in the kidney only after injury. In mice lacking the PDZ intracellular signaling domain of ephrinB2 (ephrinB2 DV), angiogenesis was impaired and kidney injury led to increased PTC rarefaction and fibrosis. EphrinB2 DV primary kidney pericytes migrated more than wild-type pericytes and were less able to stabilize capillary tubes in threedimensional culture and less able to stimulate synthesis of capillary basement membrane. EphrinB2 DV primary kidney microvascular endothelial cells migrated and proliferated less than wild-type microvascular endothelial cells in response to vascular endothelial growth factor A and showed less internalization and activation of vascular endothelial growth factor receptor-2. Taken together, these results suggest that PDZ domain-dependent ephrinB2 reverse signaling protects against PTC rarefaction by regulating angiogenesis and vascular stability during kidney injury. Furthermore, this signaling in kidney pericytes protects against pericyte-to-myofibroblast transition and myofibroblast activation, thereby limiting fibrogenesis.

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“…Moreover, in some regions of the tubular structures, NG2-positive cells were clearly visible ( Figure 1E). NG2 is a well-characterized marker of mural cells, 21 suggesting that mural cells surround the capillarylike structures.…”

Section: Establishment Of the Har Angiogenesis Assaymentioning

confidence: 99%

Modeling human tumor angiogenesis in a three-dimensional culture system

Seano

Chiaverina

Gagliardi

et al. 2013

Blood

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Key Points• Human arterial ring assay is an innovative system for the three-dimensional study of tumor angiogenesis.• This assay can be exploited for antiangiogenic drug screening and gene function analysis on human vessels.The intrinsic complexity of the process of vessel formation limits the efficacy of cellular assays for elucidation of its molecular and pharmacologic mechanisms. We developed an ex vivo three-dimensional (3D) assay of sprouting angiogenesis with arterial explants from human umbilical cords. In this assay, human arterial rings were embedded in basement membrane extract gel, leading to a network of capillarylike structures upon vascular endothelial growth factor (VEGF) A stimulation. The angiogenic outgrowth consisted of endothelial cells, which actively internalized acetylated-low-density lipoprotein, surrounded by pericytes. Computer-assisted quantification of this vascular network demonstrated considerable sensitivity of this assay to several angiogenic inhibitors, including kinase inhibitors and monoclonal antibodies. We also performed targeted gene knockdown on this model by directly infecting explanted umbilical arteries with lentiviruses carrying short-hairpin RNA. Downregulation of VEGFR2 resulted in a significant reduction of the sprouting capability, demonstrating the relevance of human vascular explants for functional genomics studies. Furthermore, a modification of this assay led to development of a 3D model of tumor-driven angiogenesis, in which angiogenic outgrowth was sustained by spheroids of prostate cancer cells in absence of exogenous growth factors. The human arterial ring assay bridges the gap between in vitro endothelial cell and animal model, and is a powerful system for identification of genes and drugs that regulate human angiogenesis. (Blood. 2013;121(21):e129-e137) IntroductionSignificant progress in angiogenesis research has been made after observations that a neoplastic mass does not grow above a few millimeters in diameter without recruiting new vessels. 1,2 Numerous cellular and animal models have been developed to design robust and exhaustive assays able to mechanistically decipher the angiogenic cascade and to validate new antiangiogenic drugs. Endothelial cell (EC) assays can mimic individual steps of the angiogenic cascade, such as cell migration, proliferation, and capillarylike formation. [3][4][5] However, different cell types-such as fibroblasts, pericytes, and smooth muscle cells-play a crucial role during new vessel formation by releasing soluble factors and establishing homotypic and heterotypic interactions. In addition, collective cell migration and extracellular matrix invasion are critical steps in the angiogenic process but are difficult to investigate with cultured cells. 6 Characterization of angiogenesis has therefore been established using mainly animal models. However, although powerful insights into the molecular and cellular mechanisms of angiogenesis have been elucidated by means of transgenic and knockout mouse models, 2,6 the complexity o...

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NG2 proteoglycan is expressed exclusively by mural cells during vascular morphogenesis

Cited by 523 publications

References 51 publications

Development of NG2 neural progenitor cells requires Olig gene function

Development of NG2 neural progenitor cells requires Olig gene function

EphrinB2 Reverse Signaling Protects against Capillary Rarefaction and Fibrosis after Kidney Injury

Modeling human tumor angiogenesis in a three-dimensional culture system

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