Chondroitin Sulfate Proteoglycans in the Nervous System: Inhibitors to Repair

Siebert, Justin R.; Steencken, Amanda Conta; Osterhout, Donna J.

doi:10.1155/2014/845323

Cited by 126 publications

(117 citation statements)

References 166 publications

(209 reference statements)

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“…In addition, tenascin (Tnc), another upregulated gene in VM-Ast, has been reported to augment grafted DA neuron attachment and survival after brain injury and transplantation (59). CSPGs are known to inhibit axonal regeneration and neurogenesis (60). Notably, the expression of Neurocan (Cspg3) and Brevican (Cspg7) was greatly downregulated in the VM-Ast cultures compared with Ctx-Ast and control NPC cultures ( Figure 4E).…”

Section: Resultsmentioning

confidence: 97%

Cografting astrocytes improves cell therapeutic outcomes in a Parkinson’s disease model

Song¹,

Oh²,

Kwon³

et al. 2017

Journal of Clinical Investigation

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In this study, we have attempted to exploit the neurotrophic actions of astrocytes and Nurr1+Foxa2 functions in this cell type to improve the therapeutic outcomes of NPC transplantation using an animal model of PD. Our in vitro assays using a coculture system and conditioned media treatment revealed that astrocytes, especially those cultured from the ventral midbrain (VM), where HNF3β) is a potent cofactor that synergizes the Nurr1-mediated antiinflammatory roles in glia (16). Furthermore, forced coexpression of Nurr1 and Foxa2 (Nurr1+Foxa2) in glia promotes the synthesis and release of various neurotrophic factors, indicating that engineering of Nurr1 and Foxa2 in glia could become a powerful strategy for treating CNS disorders. Representative images of TH + DA neurons differentiated from VM-NPCs in the presence of Ctx-NPCs (control), Ctx-Ast, or VM-Ast. Scale bar: 100 μm. Insets, enlarged images of the boxed areas (original magnification, ×400). (C) DA neuronal yields at differentiation day 6 (D6). (D-H) Morphometric measurement of DA neuron maturity assessed by neurite outgrowth lengths (D), soma size (E), and by the Sholl test (F and G). In the Sholl analysis, the total number of neurite crossings was counted in each circle with the radius increasing in steps of 15 μm (F). The critical value (G) is the radius at which there was a maximum number of neurite crossings. *P < 0.05, significantly different from the control; # P < 0.05, significantly different from Ctx-Ast, 1-way ANOVA. n = 3-5 wells (C) and 100 (D and E) and 25-30 (F and G) TH + cells in each group.(H) Representative TH + neuronal morphologies reconstructed in 3D by Neurolucida. (I-L) Synaptic densities on TH + fibers. (I) Representative confocal images of synapsin + TH + fibers. Scale bar: 25 μm. Puncta positive for the synaptic vesicle-specific markers SV2 (J), synapsin (K), and bassoon (L) on TH + fibers were counted. *P < 0.05, significantly different from the control; # P < 0.05, significantly different from Ctx-Ast. n = 20 TH + fibers for each group. (M) Presynaptic DA release. n = 3 independent cultures. DA levels were measured in the media conditioned in the differentiated cultures for 24 hours (D13-D15) and in cultures evoked by KCl-mediated depolarization for 30 minutes. *P < 0.05; # P < 0.05, 1-way ANOVA. The Journal of Clinical Investigation R E S E A R C H A R T I C L E4 6 5 jci.org Volume 128 Number 1 January 2018 (Supplemental Figure 1B; supplemental material available online with this article; https://doi.org/10.1172/JCI93924DS1), immunocytochemical analyses revealed that major cell populations in the Ctx-and VM-astroglial cultures at day in vitro (DIV) 14 were positive for GFAP (85% and 82%), CD44 (79% and 76 %), GLT-1 (58% and 71 %), and GLAST protein (71% and 77%), respectively (Supplemental Figure 1A), except S100β (20% and 32%), a soluble protein associated with harmful reactivation of astrocytes (22). A few (0.24% ± 0.35% in Ctx-Ast and 0.43% ± 0.39% in VM-Ast, where Ast indicates astrocytes) and none of the cells in these c...

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Section: Resultsmentioning

confidence: 97%

Cografting astrocytes improves cell therapeutic outcomes in a Parkinson’s disease model

Song¹,

Oh²,

Kwon³

et al. 2017

Journal of Clinical Investigation

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“…; Siebert et al . ). These mechanisms, which were isolated in the reactive astrocyte models, include: (i) direct physical impact leading to decline in ARSB activity inhibiting the degradation of C4S; and (ii) TGF‐β1‐ mediated increases in CHST11 expression and sulfotransferase activity.…”

Section: Discussionmentioning

confidence: 97%

Decline in arylsulfatase B and Increase in chondroitin 4‐sulfotransferase combine to increase chondroitin 4‐sulfate in traumatic brain injury

Bhattacharyya

Zhang

Feferman

et al. 2015

Journal of Neurochemistry

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In an established rat model of penetrating ballistic-like brain injury (PBBI), arylsulfatase B (ARSB; N-acetylgalactosamine 4-sulfatase) activity was significantly reduced at the ipsilateral site of injury, but unaffected at the contralateral site or in sham controls. In addition, the ARSB substrate chondroitin 4-sulfate (C4S) and total sulfated glycosaminoglycans increased. The mRNA expression of chondroitin 4-sulfotransferase 1 (C4ST1; CHST11) and the sulfotransferase activity rose at the ipsilateral site of injury (PBBI-I), indicating contributions from both increased production and reduced degradation to the accumulation of C4S. In cultured, fetal rat astrocytes, following scratch injury, the ARSB activity declined and the nuclear hypoxia inducible factor (HIF)-1α increased significantly. In contrast, sulfotransferase activity and chondroitin 4-sulfotransferase expression increased following astrocyte exposure to TGF-β1, but not following scratch. These different pathways by which C4S increased in the cell preparations were both evident in the response to injury in the PBBI-I model. Hence, findings support effects of injury due to mechanical disruption inhibiting ARSB and to chemical mediation by TGF-β1 increasing CHST11 expression and sulfotransferase activity. The increase in C4S following TBI is due to contributions from impaired degradation and enhanced synthesis of C4S which combine in the pathogenesis of the glial scar.

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“…However since CSPGs buildup takes time stimulation of axonal growth under Y27632 treatment is observed until the lesion site has substantially developed (Chan et al, 2007). It can be speculated then that these contravening effects depend on time delay since lesion, temporal pattern in which individual CSPGs are produced and their location in the lesion milieu (Siebert et al, 2014). In our co-culture system application of Y27632 at 5 lM concentration for a short two-week period resulted beneficially in HNPCs developing significantly elongated GFP+/TUJ1+ processes as compared to controls.…”

Section: Discussionmentioning

confidence: 99%

Effects of ROCK inhibitor Y27632 and EGFR inhibitor PD168393 on human neural precursors co-cultured with rat auditory brainstem explant

et al. 2015

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Chondroitin Sulfate Proteoglycans in the Nervous System: Inhibitors to Repair

Cited by 126 publications

References 166 publications

Cografting astrocytes improves cell therapeutic outcomes in a Parkinson’s disease model

Cografting astrocytes improves cell therapeutic outcomes in a Parkinson’s disease model

Decline in arylsulfatase B and Increase in chondroitin 4‐sulfotransferase combine to increase chondroitin 4‐sulfate in traumatic brain injury

Effects of ROCK inhibitor Y27632 and EGFR inhibitor PD168393 on human neural precursors co-cultured with rat auditory brainstem explant

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