Peroxisome proliferator-activated receptor γ ligands regulate neural stem cell proliferation and differentiation in vitro and in vivo.
Peroxisome proliferator-activated receptor gamma (PPARγ) belongs to a family of ligand-activated nuclear receptors and its ligands are known to control many physiological and pathological situations. Its role in the central nervous system has been under intense analysis during the last years. Here we show a novel function for PPARγ in controlling stem cell expansion in the adult mammalian brain. Adult rats treated with pioglitazone, a specific ligand of PPARγ, had elevated numbers of proliferating progenitor cells in the subventricular zone and the rostral migratory stream. Electron microscopy analysis also showed important changes in the subventricular zone ultrastructure of pioglitazone-treated animals including an increased number of migratory cell chains. These results were further confirmed in vitro. Neurosphere assays revealed significant increases in the number of neurosphere forming cells from pioglitazone- and rosiglitazone (two specific ligands of PPARγ receptor)-treated cultures that exhibited enhanced capacity for cell migration and differentiation. The effects of pioglitazone were blocked by the PPARγ receptor antagonists GW9662 and T0070907, suggesting that its effects are mediated by a mechanism dependent on PPARγ activation. These results indicate for the first time that activation of PPARγ receptor directly regulates proliferation, differentiation, and migration of neural stem cells in vivo.
Instituto de Investigaciones Biomédicas, CSIC-UAM, Arturo Duperier 4, 28029-Madrid, Spain.
Jose A
JA
Morales-Garcia
Rosario
R
Luna-Medina
Clara
C
Alfaro-Cervello
Marta
M
Cortes-Canteli
Angel
A
Santos
Jose M
JM
Garcia-Verdugo
Ana
A
Perez-Castillo
D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000378:metabolism; D053687:Adult Stem Cells / Q000187:drug effects / Q000648:ultrastructure; D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002552:Cerebral Ventricles / Q000166:cytology; D000089622:Doublecortin Domain Proteins; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008297:Male; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D039842:Neural Cell Adhesion Molecule L1 / Q000378:metabolism; D058953:Neural Stem Cells / Q000187:drug effects* / Q000648:ultrastructure; D009479:Neuropeptides / Q000378:metabolism; D009830:Olfactory Bulb / Q000166:cytology; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D051381:Rats; D017208:Rats, Wistar; D000077154:Rosiglitazone; D012794:Sialic Acids / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*
D000089622:Doublecortin Domain Proteins; D005904:Glial Fibrillary Acidic Protein; C489787:MAP2 protein, rat; D008869:Microtubule-Associated Proteins; D039842:Neural Cell Adhesion Molecule L1; D009479:Neuropeptides; D047495:PPAR gamma; D012794:Sialic Acids; D045162:Thiazolidinediones; C103469:polysialyl neural cell adhesion molecule; D000077154:Rosiglitazone; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases; D053148:Caspase 3; D001973:Bromodeoxyuridine; D000077205:Pioglitazone