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Regulation of oligodendrocyte progenitor cell maturation by PPARδ: effects on bone morphogenetic proteins.

Vittoria Simonini M, Polak PE, Boullerne AI, Peters JM, Richardson JC, Feinstein DL - ASN Neuro (2010)

Bottom Line: In the present study we examined effects of the PPARδ agonist GW0742 on OPCs (OL progenitor cells), and tested whether the effects involve modulation of BMPs (bone morphogenetic proteins).This was due to activation of PPARδ since process formation was reduced in PPARδ- compared with wild-type OPCs.In contrast, GW0742 reduced BMP2 and BMP4 mRNA levels in OPCs, with lesser effects in astrocytes.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, University of Illinois, Chicago, IL 60612, U.S.A.

ABSTRACT
In EAE (experimental autoimmune encephalomyelitis), agonists of PPARs (peroxisome proliferator-activated receptors) provide clinical benefit and reduce damage. In contrast with PPARγ, agonists of PPARδ are more effective when given at later stages of EAE and increase myelin gene expression, suggesting effects on OL (oligodendrocyte) maturation. In the present study we examined effects of the PPARδ agonist GW0742 on OPCs (OL progenitor cells), and tested whether the effects involve modulation of BMPs (bone morphogenetic proteins). We show that effects of GW0742 are mediated through PPARδ since no amelioration of EAE clinical scores was observed in PPARδ- mice. In OPCs derived from E13 mice (where E is embryonic day), GW0742, but not the PPARγ agonist pioglitazone, increased the number of myelin-producing OLs. This was due to activation of PPARδ since process formation was reduced in PPARδ- compared with wild-type OPCs. In both OPCs and enriched astrocyte cultures, GW0742 increased noggin protein expression; however, noggin mRNA was only increased in astrocytes. In contrast, GW0742 reduced BMP2 and BMP4 mRNA levels in OPCs, with lesser effects in astrocytes. These findings demonstrate that PPARδ plays a role in OPC maturation, mediated, in part, by regulation of BMP and BMP antagonists.

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Effect of GW0742 on PDGFRα expressionMouse E13 OPCs were plated on to PDL-coated coverslips, grown for 5 days in differentiation medium, the medium replaced with Sato–Bottenstein medium, and the cells grown for 24 h in the absence of growth factors and in the presence of vehicle (A, C and E) or 3 μM GW0742 (B, D and F). Cells were fixed, stained for PDGFRα, and cell numbers and size quantified in six fields of view taken at 20×magnification. The total number of spheres (16.8±2.5 compared with 15±1.3 spheres per field, DMSO compared with GW0742, P>0.05) was not modified by treatment. (A and B) are representative images showing the smaller average size of spheres in GW0742-treated cultures (40.7±2.1 compared with 30.4±1.6 µm diameter, P<0.0005). (C and D) are representative images showing increased numbers of PDGFRα-stained migrating cells (814±38 compared with 1135±105 cells per field, DMSO compared with GW0742, P<0.05). (E and F) are representative images showing increased number of processes on the migrating cells in the GW0742-treated cultures.
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Figure 4: Effect of GW0742 on PDGFRα expressionMouse E13 OPCs were plated on to PDL-coated coverslips, grown for 5 days in differentiation medium, the medium replaced with Sato–Bottenstein medium, and the cells grown for 24 h in the absence of growth factors and in the presence of vehicle (A, C and E) or 3 μM GW0742 (B, D and F). Cells were fixed, stained for PDGFRα, and cell numbers and size quantified in six fields of view taken at 20×magnification. The total number of spheres (16.8±2.5 compared with 15±1.3 spheres per field, DMSO compared with GW0742, P>0.05) was not modified by treatment. (A and B) are representative images showing the smaller average size of spheres in GW0742-treated cultures (40.7±2.1 compared with 30.4±1.6 µm diameter, P<0.0005). (C and D) are representative images showing increased numbers of PDGFRα-stained migrating cells (814±38 compared with 1135±105 cells per field, DMSO compared with GW0742, P<0.05). (E and F) are representative images showing increased number of processes on the migrating cells in the GW0742-treated cultures.

Mentions: Quantification of the cell numbers in Figure 2 was performed manually, and in Figures 4 and 6 performed using Zeiss Axiovision version 4.5. Comparisons between groups were made using a Student's unpaired t test. Comparisons of the number of stained cells in Figure 2 was done using χ2 analysis. Comparison of clinical signs in WT (wild-type) compared with PPARδ- mice was performed by two-way repeated measures ANOVA using data from day 25 (the start of treatment) to the end of the study (day 49). Values are means±S.E.M., and for all comparisons significance was taken at P<0.05.


Regulation of oligodendrocyte progenitor cell maturation by PPARδ: effects on bone morphogenetic proteins.

Vittoria Simonini M, Polak PE, Boullerne AI, Peters JM, Richardson JC, Feinstein DL - ASN Neuro (2010)

Effect of GW0742 on PDGFRα expressionMouse E13 OPCs were plated on to PDL-coated coverslips, grown for 5 days in differentiation medium, the medium replaced with Sato–Bottenstein medium, and the cells grown for 24 h in the absence of growth factors and in the presence of vehicle (A, C and E) or 3 μM GW0742 (B, D and F). Cells were fixed, stained for PDGFRα, and cell numbers and size quantified in six fields of view taken at 20×magnification. The total number of spheres (16.8±2.5 compared with 15±1.3 spheres per field, DMSO compared with GW0742, P>0.05) was not modified by treatment. (A and B) are representative images showing the smaller average size of spheres in GW0742-treated cultures (40.7±2.1 compared with 30.4±1.6 µm diameter, P<0.0005). (C and D) are representative images showing increased numbers of PDGFRα-stained migrating cells (814±38 compared with 1135±105 cells per field, DMSO compared with GW0742, P<0.05). (E and F) are representative images showing increased number of processes on the migrating cells in the GW0742-treated cultures.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2807733&req=5

Figure 4: Effect of GW0742 on PDGFRα expressionMouse E13 OPCs were plated on to PDL-coated coverslips, grown for 5 days in differentiation medium, the medium replaced with Sato–Bottenstein medium, and the cells grown for 24 h in the absence of growth factors and in the presence of vehicle (A, C and E) or 3 μM GW0742 (B, D and F). Cells were fixed, stained for PDGFRα, and cell numbers and size quantified in six fields of view taken at 20×magnification. The total number of spheres (16.8±2.5 compared with 15±1.3 spheres per field, DMSO compared with GW0742, P>0.05) was not modified by treatment. (A and B) are representative images showing the smaller average size of spheres in GW0742-treated cultures (40.7±2.1 compared with 30.4±1.6 µm diameter, P<0.0005). (C and D) are representative images showing increased numbers of PDGFRα-stained migrating cells (814±38 compared with 1135±105 cells per field, DMSO compared with GW0742, P<0.05). (E and F) are representative images showing increased number of processes on the migrating cells in the GW0742-treated cultures.
Mentions: Quantification of the cell numbers in Figure 2 was performed manually, and in Figures 4 and 6 performed using Zeiss Axiovision version 4.5. Comparisons between groups were made using a Student's unpaired t test. Comparisons of the number of stained cells in Figure 2 was done using χ2 analysis. Comparison of clinical signs in WT (wild-type) compared with PPARδ- mice was performed by two-way repeated measures ANOVA using data from day 25 (the start of treatment) to the end of the study (day 49). Values are means±S.E.M., and for all comparisons significance was taken at P<0.05.

Bottom Line: In the present study we examined effects of the PPARδ agonist GW0742 on OPCs (OL progenitor cells), and tested whether the effects involve modulation of BMPs (bone morphogenetic proteins).This was due to activation of PPARδ since process formation was reduced in PPARδ- compared with wild-type OPCs.In contrast, GW0742 reduced BMP2 and BMP4 mRNA levels in OPCs, with lesser effects in astrocytes.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, University of Illinois, Chicago, IL 60612, U.S.A.

ABSTRACT
In EAE (experimental autoimmune encephalomyelitis), agonists of PPARs (peroxisome proliferator-activated receptors) provide clinical benefit and reduce damage. In contrast with PPARγ, agonists of PPARδ are more effective when given at later stages of EAE and increase myelin gene expression, suggesting effects on OL (oligodendrocyte) maturation. In the present study we examined effects of the PPARδ agonist GW0742 on OPCs (OL progenitor cells), and tested whether the effects involve modulation of BMPs (bone morphogenetic proteins). We show that effects of GW0742 are mediated through PPARδ since no amelioration of EAE clinical scores was observed in PPARδ- mice. In OPCs derived from E13 mice (where E is embryonic day), GW0742, but not the PPARγ agonist pioglitazone, increased the number of myelin-producing OLs. This was due to activation of PPARδ since process formation was reduced in PPARδ- compared with wild-type OPCs. In both OPCs and enriched astrocyte cultures, GW0742 increased noggin protein expression; however, noggin mRNA was only increased in astrocytes. In contrast, GW0742 reduced BMP2 and BMP4 mRNA levels in OPCs, with lesser effects in astrocytes. These findings demonstrate that PPARδ plays a role in OPC maturation, mediated, in part, by regulation of BMP and BMP antagonists.

Show MeSH
Related in: MedlinePlus