Kegg Pathway: Chondroitin sulfate biosynthesis

J Cereb Blood Flow Metab. 2009 Oct 28;
Smirkin A, Matsumoto H, Takahashi H, Inoue A, Tagawa M, Ohue S, Watanabe H, Yano H, Kumon Y, Ohnishi T, Tanaka J

In a transient 90-min middle cerebral artery occlusion (MCAO) model of rats, a large ischemic lesion is formed where macrophage-like cells massively accumulate, many of which express a macrophage marker, Iba1, and an oligodendrocyte progenitor cell marker, NG2 Chondroitin sulfate proteoglycan (NG2); therefore, the cells were termed BINCs (Brain Iba1(+)/NG2(+) Cells). A bone marrow transplantation experiment using green-fluorescent protein-transgenic rats showed that BINCs were derived from bone marrow. 5-Fluorouracil (5FU) injection at 2 days post reperfusion (2 dpr) markedly reduced the number of BINCs at 7 dpr, causing enlargement of necrotic volumes and frequent death of the rats. When isolated BINCs were transplanted into 5FU-aggravated ischemic lesion, the volume of the lesion was much reduced. Quantitative real-time RT-PCR showed that BINCs expressed mRNAs encoding bFGF, BMP2, BMP4, BMP7, GDNF, HGF, IGF-1, PDGF-A, and VEGF. In particular, BINCs expressed IGF-1 mRNA at a very high level. Immunohistochemical staining showed that IGF-1-expressing BINCs were found not only in rat but also human ischemic brain lesions. These results suggest that bone marrow-derived BINCs play a beneficial role in ischemic brain lesions, at least in part, through secretion of neuroprotective factors.Journal of Cerebral Blood Flow & Metabolism advance online publication, 28 October 2009; doi:10.1038/jcbfm.2009.233.

J Mater Sci Mater Med. 2009 Oct 13;
Wu CH, Ko CS, Huang JW, Huang HJ, Chu IM

Cartilage extracellular matrix (ECM) is composed primarily of type II collagen (COL II) and large, networks of proteoglycans (PGs) that contain glycosaminoglycans such as hyaluronic acid (HA) and Chondroitin sulfate (CS). Since cartilage shows little tendency for self-repair, injuries are kept unhealed for years and can eventually lead to further degeneration. During the past decades, many investigations have pursued techniques to stimulate articular cartilage repair or regeneration. The current study assessed the effects of exogenous glycosaminoglycans (GAGs) including CS-A, CS-B, CS-C, heparan sulfate and HA, administration on human chondrocytes in terms of proliferation and matrix synthesis, while the cells were seeded and grown on the genipin-crosslinked collagen type II (COL II) scaffold. DNA content was measured by Hoechst dye intercalation, matrix deposition was evaluated by DMMB dye. Expression of collagen II and aggrecan mRNAs was assessed by RT-PCR, followed by gel electrophoresis. In a 28-day in vitro culture, administration of 5 mug/ml CS-A, 50 mug/ml CS-B, 50 mug/ml CS-C, 5 mug/ml HS, and 500 kDa HA led to significant increase in biosynthesis rate of PGs. Gene expression of aggrecan and collagen II were upregulated by CS-A, CS-C and HA. These results showed considerable relevance of GAGs to the issue of in vitro/ex vivo neo-cartilage synthesis for tissue engineering and regenerative medical applications.

Biochem Cell Biol. 2009 Aug; 87(4): 677-86
Franco CR, Trindade ES, Rocha HA, da Silveira RB, Paludo KS, Chammas R, Veiga SS, Nader HB, Dietrich CP

Alpha5beta1 integrin from both wild-type CHO cells (CHO-K1) and deficient in proteoglycan biosynthesis (CHO-745) is post-translationally modified by glycosaminoglycan chains. We demonstrated this using [35S]sulfate metabolic labeling of the cells, enzymatic degradation, immunoprecipitation reaction with monoclonal antibody, fluorescence microscopy, and flow cytometry. The alpha5beta1 integrin heterodimer is a hybrid proteoglycan containing both Chondroitin and heparan sulfate chains. Xyloside inhibition of sulfate incorporation into alpha5beta1 integrin also supports that integrin is a proteoglycan. Also, cells grown with xyloside adhered on fibronectin with no alteration in alpha5beta1 integrin expression. However, haptotactic motility on fibronectin declined in cells grown with xyloside or chlorate as compared with controls. Thus, alpha5beta1 integrin is a proteoglycan and the glycosaminoglycan chains of the integrin influence cell motility on fibronectin. Similar glycosylation of alpha5beta1 integrin was observed in other normal and malignant cells, suggesting that this modification is conserved and important in the function of this integrin. Therefore, these glycosaminoglycan chains of alpha5beta1 integrin are involved in cellular migration on fibronectin.

J Urol. 2009 Nov; 182(5): 2477-82
Hauser PJ, Buethe DA, Califano J, Sofinowski TM, Culkin DJ, Hurst RE

PURPOSE: Chondroitin sulfate (Stellar Pharmaceuticals, London, Ontario, Canada), which is less expensive and more inert than heparinoids, hyaluronan or pentosan polysulfate, has been introduced to restore the barrier function lost due to epithelial dysfunction in interstitial cystitis cases. To our knowledge Chondroitin sulfate binding to damaged bladder as a function of the urinary pH range, its efficacy in restoring the bladder permeability barrier and the capacity of the damaged bladder to bind Chondroitin sulfate have not been determined previously. MATERIALS AND METHODS: Chondroitin sulfate binding to bladder urothelium was investigated quantitatively using Chondroitin sulfate highly labeled with Texas Red(R) and quantitative fluorescence microscopy in a mouse model of urothelial acid damage. The efficacy of restoring barrier function was determined using the passage of intravesically instilled (86)Rb, a potassium ion mimetic, through the urothelium into the bloodstream in a rat model of bladder damage. The binding capacity of acid damaged bladder was determined by fluorometry. RESULTS: Chondroitin sulfate bound tightly and exclusively to the mouse bladder surface damaged by acid but showed only minimal binding to undamaged bladder. There was no systematic variation in pH. The model showed some variability in the degree of damage induced. In rats Chondroitin sulfate instillation restored permeability to (86)Rb to control levels. Binding was saturable at a mean +/- SEM 0.67 +/- 0.13 mg/cm(2) of the bladder surface. CONCLUSIONS: Chondroitin sulfate binds preferentially to damaged urothelium and restores the impermeability barrier. This suggests that the glycosaminoglycan layer is a major contributor to bladder urothelial impermeability. As determined by binding capacity, the dose applied in humans in Canada (400 mg per instillation) is sufficient to achieve maximum efficacy.

Science. 2009 Sep 4; 325(5945): 1258-61
Gogolla N, Caroni P, Lüthi A, Herry C

In adult animals, fear conditioning induces a permanent memory that is resilient to erasure by extinction. In contrast, during early postnatal development, extinction of conditioned fear leads to memory erasure, suggesting that fear memories are actively protected in adults. We show here that this protection is conferred by extracellular matrix Chondroitin sulfate proteoglycans (CSPGs) in the amygdala. The organization of CSPGs into perineuronal nets (PNNs) coincided with the developmental switch in fear memory resilience. In adults, degradation of PNNs by Chondroitinase ABC specifically rendered subsequently acquired fear memories susceptible to erasure. This result indicates that intact PNNs mediate the formation of erasure-resistant fear memories and identifies a molecular mechanism closing a postnatal critical period during which traumatic memories can be erased by extinction.

Science. 2009 Sep 4; 325(5945): 1214-5
Pizzorusso T

Glycoconj J. 2009 Sep 2;
Silbert JE

This article concerns personal reminiscences of research on proteoglycans accomplished by Jeremiah Silbert and his co-investigators over a 25-30 year period beginning in 1961. Radiolabeled substrates were prepared and incubated with subcellular particles from mast cells and cartilage to determine pathways and organization of heparin and Chondroitin glycosaminoglycan formation together with sulfation. Microsomal/Golgi fractions were examined for localization and organization of synthesis. Cell surface heparan sulfate and Chondroitin were examined for preliminary information regarding potential function, and techniques were developed to alter sulfation processes.

Matrix Biol. 2009 Aug 29;
Villanueva I, Gladem SK, Kessler J, Bryant SJ

This study aimed to elucidate the role of charge in mediating chondrocyte response to loading by employing synthetic 3D hydrogels. Specifically, neutral poly(ethylene glycol) (PEG) hydrogels were employed where negatively charged Chondroitin sulfate (ChS), one of the main extracellular matrix components of cartilage, was systematically incorporated into the PEG network at 0%, 20% or 40% to control the fixed charge density. PEG hydrogels were employed as a control environment for extracellular events which occur as a result of loading, but which are not associated with a charged matrix (e.g., cell deformation and fluid flow). Freshly isolated bovine articular chondrocytes were embedded in the hydrogels and subject to dynamic mechanical stimulation (0.3Hz, 15% amplitude strains, 6h) and assayed for nitric oxide production, cell proliferation, proteoglycan synthesis, and collagen deposition. In the absence of loading, incorporation of charge inhibited cell proliferation by ~75%, proteoglycan synthesis by ~22-50% depending on ChS content, but had no affect on collagen deposition. Dynamic loading had no effect on cellular responses in PEG hydrogels. However, dynamically loading 20% ChS gels inhibited nitrite production by 50%, cell proliferation by 40%, but stimulated proteoglycan and collagen deposition by 162% and 565%, respectively. Dynamic loading of 40% ChS hydrogels stimulated nitrite production by 62% and proteoglycan synthesis by 123%, but inhibited cell proliferation by 54% and collagen deposition by 52%. Upon removing the load and culturing under free-swelling conditions for 36h, the enhanced matrix synthesis observed in the 20% ChS gels was not maintained suggesting that loading is necessary to stimulate matrix production. In conclusion, extracellular events associated with a charged matrix have a dramatic affect on how chondrocytes respond to mechanical stimulation within these artificial 3D matrices suggesting that streaming potentials and/or dynamic changes in osmolarity may be important regulators of chondrocytes while cell deformation and fluid flow appear to have less of an effect.

J Refract Surg. 2009 Aug; 25(8): 739-46
Esquenazi S, Esquenazi I, Grunstein L, He J, Bazan H

PURPOSE: To evaluate the healing response at the flap interface in corneas with LASIK ectasia that required penetrating keratoplasty (PK). METHODS: Corneas of five patients who developed corneal ectasia after LASIK (range: 2.5 to 5 years postoperative) were collected after corneal transplant surgery. The corneas were bisected and processed for conventional histologic analysis and immunofluorescence. RESULTS: Light microscopy showed a hypocellular fibrotic scar at the wound margin compared with the adjacent corneal stroma in all eyes. All corneas had positive staining for alpha-smooth muscle actin (SMA), a myofibroblast marker. In one eye, alpha-SMA cells were located in the fibrotic scar region in the area of the semicircular ring of haze along the margin of the LASIK flap corresponding to an area of epithelial ingrowth. In all other eyes, alpha-SMA positive cells were fewer and mainly located in the superficial stroma under the epithelial wound margin surface. Type III collagen was minimal or absent in the central zone and wound margin of all corneas except for the cornea with epithelial ingrowth present in the hypercellular fibrotic scar region. Chondroitin sulfate was stronger in the periphery of the flap wound coinciding with a higher presence of alpha-SMA-positive cells in that region. Positive staining for matrix metalloproteinase 9 (MMP-9) in the paracentral wound margin scar was seen. CONCLUSIONS: A wound-healing process characterized by absence of significant fibrosis and myofibroblasts at the wound edge in the flap interface was noted in all keratectatic eyes. However, changes in the composition of collagen and the presence of MMP-9 at the wound edge several years after LASIK indicates active wound remodeling that may explain the ongoing loss of tissue and tendency of the cornea to bulge.

J Mol Biol. 2009 Oct 16; 393(1): 202-13
Khunrae P, Philip JM, Bull DR, Higgins MK

Severe malaria during pregnancy is associated with accumulation of parasite-infected erythrocytes in the placenta due to interactions between VAR2CSA protein, expressed on the surface of infected-erythrocytes, and placental Chondroitin sulfate proteoglycans (CSPG). VAR2CSA contains multiple CSPG-binding domains, including DBL3X and DBL6 epsilon. Previous structural studies of DBL3X suggested CSPG to bind to a positively charged patch and sulfate-binding site on the concave surface of the domain. Here we present the structure of the DBL6 epsilon domain from VAR2CSA. This domain displays the same overall architecture and secondary structure as that of DBL3X but differs in loop structures, disulfide bond positions and surface charge distribution. In particular, despite binding to CSPG, DBL6 epsilon lacks the key features of the CSPG-binding site of DBL3X. Instead DBL6 epsilon binds to CSPG through a positively charged surface on the distal side of subdomain 2 that is exposed in intact VAR2CSA on the erythrocyte surface. Finally, unlike intact VAR2CSA, both DBL3X and DBL6 epsilon bind to various carbohydrates, with greatest affinity for ligands with high sulfation and negative charge. These studies provide further insight into the structure of DBL domains and suggest a model for the role of individual domains in CSPG binding by VAR2CSA in placental malaria.

Mol Cell Biol. 2009 Oct; 29(20): 5517-28
Maccarana M, Kalamajski S, Kongsgaard M, Magnusson SP, Oldberg A, Malmström A

Dermatan sulfate epimerase 1 (DS-epi1) and DS-epi2 convert glucuronic acid to iduronic acid in Chondroitin/dermatan sulfate biosynthesis. Here we report on the generation of DS-epi1-null mice and the resulting alterations in the Chondroitin/dermatan polysaccharide chains. The numbers of long blocks of adjacent iduronic acids are greatly decreased in skin decorin and biglycan Chondroitin/dermatan sulfate, along with a parallel decrease in iduronic-2-O-sulfated-galactosamine-4-O-sulfated structures. Both iduronic acid blocks and iduronic acids surrounded by glucuronic acids are also decreased in versican-derived chains. DS-epi1-deficient mice are smaller than their wild-type littermates but otherwise have no gross macroscopic alterations. The lack of DS-epi1 affects the Chondroitin/dermatan sulfate in many proteoglycans, and the consequences for skin collagen structure were initially analyzed. We found that the skin collagen architecture was altered, and electron microscopy showed that the DS-epi1-null fibrils have a larger diameter than the wild-type fibrils. The altered Chondroitin/dermatan sulfate chains carried by decorin in skin are likely to affect collagen fibril formation and reduce the tensile strength of DS-epi1-null skin.

J Pharmacol Sci. 2009 Aug; 110(4): 483-92
Seo TB, Baek K, Kwon KB, Lee SI, Lim JS, Seol IC, Kim YS, Seo YB, Namgung U

Shengmai-san (SMS) is a traditional Chinese medicine used to treat diverse symptoms including cardiovascular and neurological disorders. Here we investigated the effects of SMS on regenerative responses of spinal cord axons in rats that were given contusion injury at the lower thoracic level. The injury cavity was confined to a restricted area by SMS treatment, and the signals of glial scar protein Chondroitin sulphate proteoglycan (CSPG) and inflammatory cell marker protein CD11beta were heavily observed within the injury cavity in SMS-treated animals. Anterograde tracing of DiI-labeled corticospinal tract (CST) axons revealed increases in collateral arborization around and within the injury cavity and caudal elongation by SMS treatment. Furthermore, SMS treatment facilitated neurite elongation of dorsal root ganglion (DRG) sensory neurons that were co-cultured with non-neuronal cells prepared from injured spinal cord. Phospho-Erk1/2 was strongly induced in both spinal cord and motor cortical areas after spinal cord injury (SCI), and it was further unregulated in the motor cortex by SMS treatment. In contrast, upregulation of cell division cycle 2 (Cdc2) production by SMS treatment was limited to a local, SCI area. These data suggest that SMS may play an active role in regenerative responses and facilitate axonal regrowth after SCI.

Glycobiology. 2009 Nov; 19(11): 1197-203
Pacheco B, Maccarana M, Malmström A

Chondroitin/dermatan sulfate is a highly complex linear polysaccharide ubiquitously found in the extracellular matrix and at the cell surface. Several of its functions, such as binding to growth factors, are mediated by domains composed of alternating iduronic acid and 4-O-sulfated N-acetylgalactosamine residues, named 4-O-sulfated iduronic acid blocks. These domains are generated by the action of two DS-epimerases, which convert D-glucuronic acid into its epimer L-iduronic acid, in close connection with 4-O-sulfation. In this study, dermatan sulfate structure was evaluated after downregulating or increasing dermatan 4-O-sulfotransferase 1 (D4ST-1) expression. siRNA-mediated downregulation of D4ST-1 in primary human lung fibroblasts led to a drastic specific reduction of iduronic acid blocks. No change of epimerase activity was found, indicating that the influence of D4ST-1 on epimerization is not due to an altered expression level of the DS-epimerases. Analysis of the dermatan sulfate chains showed that D4ST-1 is essential for the biosynthesis of the disulfated structure iduronic acid-2-O-sulfate-N-acetylgalactosamine-4-O-sulfate, thus confirmed to be strictly connected with the iduronic acid blocks. Also the biologically important residue hexuronic acid-N-acetylgalactosamine-4,6-O-disulfate considerably decreased after D4ST-1 downregulation. In conclusion, D4ST-1 is a key enzyme and is indispensable in the formation of important functional domains in dermatan sulfate and cannot be compensated by other 4-O-sulfotransferases.

Int J Exp Pathol. 2009 Aug; 90(4): 400-11
Ribeiro DL, Taboga SR, Góes RM

Extracellular matrix (ECM) remodelling is an important process involved in prostate cancer progression. Alterations in ECM caused by diabetes in different tissues such as kidney is well described; however, it is poorly investigated in prostate. The aim of this study was to evaluate changes in ECM of rat prostate showing gland atrophy caused by diabetes and their implications in development of malignant lesions. Diabetes was induced in Wistar rats using alloxan (45 mg/kg bw). After 90 days of diabetes onset, animals were killed and ventral prostate was removed and prepared for light microscopy following immunoreaction for fibronectin, Chondroitin sulphate and Picrossirius staining for collagen fibres. Proteoglycans (PG) were identified at transmission electron microscopy after fixation with Cuprolinic Blue. Diabetes led to a thickening of 25% in the acinar basement membrane accompanied by increase and disorganization of its proteoglycans (P1). Three additional populations of prostatic stromal PGs were identified: collagen fibril linked (P2) and interstitial (P3) and (P4) PGs. Diabetes increased P3 and mainly P4 which had higher dimension and accumulated around the smooth muscle cells. In addition, an increase in chondrotin sulphate (33%, mainly in sites where P4 were noted) and collagen (44%) was noted in diabetic rats, whereas fibronectin did not change. Atrophic changes observed in rat ventral prostate after diabetes are accompanied by stromal remodelation related to increase in collagen and Chondroitin sulphate proteoglycans. Thus, diabetes can promote a stromal microenvironment rich in elements that could favour cell migration, proliferation and pathological process.

J Biol Chem. 2009 Oct 9; 284(41): 27924-32
Ra HJ, Harju-Baker S, Zhang F, Linhardt RJ, Wilson CL, Parks WC

Matrix metalloproteinases are maintained in an inactive state by a bond between the thiol of a conserved cysteine in the prodomain and a zinc atom in the catalytic domain. Once this bond is disrupted, MMPs become active proteinases and can act on a variety of extracellular protein substrates. In vivo, matrilysin (MMP7) activates pro-alpha-defensins (procryptdins), but in vitro, processing of these peptides is slow, with about 50% conversion in 8-12 h. Similarly, autolytic activation of promatrilysin in vitro can take up to 12-24 h for 50% conversion. These inefficient reactions suggest that natural cofactors enhance the activation and activity of matrilysin. We determined that highly sulfated glycosaminoglycans (GAG), such as heparin, Chondroitin-4,6-sulfate (CS-E), and dermatan sulfate, markedly enhanced (>50-fold) the intermolecular autolytic activation of promatrilysin and the activity of fully active matrilysin to cleave specific physiologic substrates. In contrast, heparan sulfate and less sulfated forms of Chondroitin sulfate did not augment matrilysin activation or activity. Chondroitin-2,6-sulfate (CS-D) also did not enhance matrilysin activity, suggesting that the presentation of sulfates is more important than the overall degree of sulfation. Surface plasmon resonance demonstrated that promatrilysin bound heparin (K(D), 400 nm) and CS-E (K(D), 630 nm). Active matrilysin bound heparin (K(D), 150 nm) but less so to CS-E (K(D), 60 microm). Neither form bound heparan sulfate. These observations demonstrate that sulfated GAGs regulate matrilysin activation and its activity against specific substrates.

Clin Calcium. 2009 Aug; 19(8): 1149-58
Okano T, Koike T

Osteoarthritis (OA) is characterized by increased cartilage degradation and wearing. The principal disease hallmarks for assessment of OA are radiographic aspects. However, laboratory markers of joint fluid, serum or urine have received growing attention in recent years. Biomarkers should be useful for improvement of diagnosis, assessment of disease progression and evaluation of therapeutic effects in OA. Here we described the outline of biomarkers in cartilage including utility and weakness.

Rev Invest Clin. 2009 Mar-Apr; 61(2): 140-9
Díaz-Martínez NE, Velasco I

Chondroitin sulphate proteoglycans (CSPG) are components of the extracellular matrix, consisting of peptides chemically attached covalently to chains of glycosaminoglycans. There are 4 families of CSPG including lecticans, which are found mainly in the central nervous system (CNS) of vertebrates. In vitro studies have shown a negative effect of these proteoglycans on axonal growth, mediated by depolymerization of actin filaments in the neuronal cytoskeleton. In some neurodegenerative diseases, and especially after traumatic injuries of adult CNS, there are increased levels of CSPG expression. Axonal growth inhibition by CSPG has been observed also in vivo, and therefore a strategy aimed to counteract the inhibition of axonal growth might lead to new therapies designed to restore neural circuits. There is compelling in vivo evidence that CSPG degradation by Chondroitinase ABC allows both axonal growth and functional recovery in models of injury in the mammalian CNS. These data suggest that manipulation of the response to damage could result in effective ways to promote recovery of nerve functions in neurological disorders that affect humans, such as spinal cord lesions or Parkinson disease.

J Biol Chem. 2009 Sep 25; 284(39): 26547-56
Sim H, Hu B, Viapiano MS

Malignant gliomas have a distinctive ability to infiltrate the brain parenchyma and disrupt the neural extracellular matrix that inhibits motility of axons and normal neural cells. Chondroitin sulfate proteoglycans (CSPGs) are among the major inhibitory components in the neural matrix, but surprisingly, some are up-regulated in gliomas and act as pro-invasive signals. In the normal brain, CSPGs are thought to associate with hyaluronic acid and glycoproteins such as the tenascins and link proteins to form the matrix scaffold. Here, we examined for the first time the expression of link proteins in human brain and malignant gliomas. Our results indicate that HAPLN4 and HAPLN2 are the predominant members of this family in the adult human brain but are strongly reduced in the tumor parenchyma. To test if their absence was related to a pro-invasive gain of function of CSPGs, we expressed HAPLN4 in glioma cells in combination with the CSPG brevican. Surprisingly, HAPLN4 increased glioma cell adhesion and migration and even potentiated the motogenic effect of brevican. Further characterization revealed that HAPLN4 expressed in glioma cells was largely soluble and did not reproduce the strong, hyaluronan-independent association of the native protein to brain subcellular membranes. Taken together, our results suggest that the tumor parenchyma is rich in CSPGs that are not associated to HAPLNs and could instead interact with other extracellular matrix proteins produced by glioma cells. This dissociation may contribute to changes in the matrix scaffold caused by invasive glioma cells.

J Biol Chem. 2009 Sep 18; 284(38): 25842-53
Victor XV, Nguyen TK, Ethirajan M, Tran VM, Nguyen KV, Kuberan B

Glycosaminoglycan (GAG) biosynthesis requires numerous biosynthetic enzymes and activated sulfate and sugar donors. Although the sequence of biosynthetic events is resolved using reconstituted systems, little is known about the emergence of cell-specific GAG chains (heparan sulfate, Chondroitin sulfate, and dermatan sulfate) with distinct sulfation patterns. We have utilized a library of click-xylosides that have various aglycones to decipher the mechanism of GAG biosynthesis in a cellular system. Earlier studies have shown that both the concentration of the primers and the structure of the aglycone moieties can affect the composition of the newly synthesized GAG chains. However, it is largely unknown whether structural features of aglycone affect the extent of sulfation, sulfation pattern, disaccharide composition, and chain length of GAG chains. In this study, we show that aglycones can switch not only the type of GAG chains, but also their fine structures. Our findings provide suggestive evidence for the presence of GAGOSOMES that have different combinations of enzymes and their isoforms regulating the synthesis of cell-specific combinatorial structures. We surmise that click-xylosides are differentially recognized by the GAGOSOMES to generate distinct GAG structures as observed in this study. These novel click-xylosides offer new avenues to profile the cell-specific GAG chains, elucidate the mechanism of GAG biosynthesis, and to decipher the biological actions of GAG chains in model organisms.

Brain Nerve. 2009 Jul; 61(7): 733-9
Suzuki R, Nishiyama A

Polydendrocytes or NG2 cells are the fourth major glial cell type observed in the mammalian central nervous system (CNS) that is distinct from neurons, mature oligodendrocytes, astrocytes, or microglia. They can be identified on the basis of the expression of NG2 proteoglycan and are distributed throughout the gray matter and white matter both in the developing and mature CNS. Although polydendrocytes were earlier regarded as oligodendrocyte progenitor cells, recent studies using Cre/loxP fate mapping provided the first direct evidence that endogenous polydendrocytes give rise to oligodendrocytes in vivo. In addition, the same technique showed that polydendrocytes differentiate into a subpopulation of astrocytes in a region-specific manner. On the other hand, it is highly debatable whether polydendrocytes generate neurons. Although some studies suggest the possibility that polydendrocytes produce neurons, other studies do not support this hypothesis. The possibility that polydendrocytes contribute to the formation of gliomas has been suggested in a number of clinical and basic experimental studies. In this review, we present both classical findings (and the latest reports on the basic characteristics of this cell type).