title: PDGFR-β Plays a Key Role in the Ectopic Migration of Neuroblasts in Cerebral Stroke.
abstract: The neuroprotective agents and induction of endogenous neurogenesis remain to be the urgent issues to be established for the care of cerebral stroke. Platelet-derived growth factor receptor beta (PDGFR-β) is mainly expressed in neural stem/progenitor cells (NSPCs), neurons and vascular pericytes of the brain; however, the role in pathological neurogenesis remains elusive. To this end, we examined the role of PDGFR-β in the migration and proliferation of NSPCs after stroke. A transient middle cerebral-arterial occlusion (MCAO) was introduced into the mice with conditional Pdgfrb-gene inactivation, including N-PRβ-KO mice where the Pdgfrb-gene was mostly inactivated in the brain except that in vascular pericytes, and E-PRβ-KO mice with tamoxifen-induced systemic Pdgfrb-gene inactivation. The migration of the DCX(+) neuroblasts from the subventricular zone toward the ischemic core was highly increased in N-PRβ-KO, but not in E-PRβ-KO as compared to Pdgfrb-gene preserving control mice. We showed that CXCL12, a potent chemoattractant for CXCR4-expressing NSPCs, was upregulated in the ischemic lesion of N-PRβ-KO mice. Furthermore, integrin α3 intrinsically expressed in NSPCs that critically mediates extracellular matrix-dependent migration, was upregulated in N-PRβ-KO after MCAO. NSPCs isolated from N-PRβ-KO rapidly migrated on the surface coated with collagen type IV or fibronectin that are abundant in vascular niche and ischemic core. PDGFR-β was suggested to be critically involved in pathological neurogenesis through the regulation of lesion-derived chemoattractant as well as intrinsic signal of NSPCs, and we believe that a coordinated regulation of these molecular events may be able to improve neurogenesis in injured brain for further functional recovery.
authors.affiliation: Department of Pathology, University of Toyama, Toyama, 930-0194, Japan.|Department of Neurosurgery, University of Toyama, Toyama, 930-0194, Japan.
authors.forename: Hikari
authors.initials: H
authors.lastname: Sato
authors.affiliation: Department of Pathology, University of Toyama, Toyama, 930-0194, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ishii
authors.affiliation: Department of Pathology, University of Toyama, Toyama, 930-0194, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Department of Pathology, University of Toyama, Toyama, 930-0194, Japan.|Manufacturing & Engineering Lab., Astellas Pharma Inc., Tsukuba, 300-2635, Japan.
authors.forename: Erika
authors.initials: E
authors.lastname: Azuma
authors.affiliation: Department of Reproductive Biology, National Center for Child Health and Development, Tokyo, 157-8535, Japan.
authors.forename: Yoriko
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Department of Pathology, University of Toyama, Toyama, 930-0194, Japan.
authors.forename: Takeru
authors.initials: T
authors.lastname: Hamashima
authors.affiliation: Department of Reproductive Biology, National Center for Child Health and Development, Tokyo, 157-8535, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Umezawa
authors.affiliation: Department of Molecular Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Mori
authors.affiliation: Department of Neurosurgery, University of Toyama, Toyama, 930-0194, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kuroda
authors.affiliation: Department of Neurosurgery, University of Toyama, Toyama, 930-0194, Japan.
authors.forename: Shunro
authors.initials: S
authors.lastname: Endo
authors.affiliation: Department of Pathology, University of Toyama, Toyama, 930-0194, Japan.
authors.forename: Masakiyo
authors.initials: M
authors.lastname: Sasahara
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D054377:Chemokine CXCL12 / Q000096:biosynthesis / Q000235:genetics*; D000089662:Doublecortin Protein; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D018345:Mice, Knockout; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology; D055495:Neurogenesis / Q000235:genetics*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*; D015398:Signal Transduction; D020521:Stroke / Q000235:genetics* / Q000473:pathology
chemical_list: D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D020796:Receptor, Platelet-Derived Growth Factor alpha
keywords: Cell migration; Integrins; Microvasculature; Neural induction; Neural stem cell; Pericytes; SDF-1