Sato Hikari, Ishii Yoko, Yamamoto Seiji, Azuma Erika, Takahashi Yoriko, Hamashima Takeru, Umezawa Akihiro, Mori Hisashi, Kuroda Satoshi, Endo Shunro, Sasahara Masakiyo
Department of Pathology, University of Toyama, Toyama, 930-0194, Japan.
Department of Neurosurgery, University of Toyama, Toyama, 930-0194, Japan.
Stem Cells. 2016 Mar;34(3):685-98. doi: 10.1002/stem.2212. Epub 2015 Oct 4.
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.
神经保护剂和内源性神经发生的诱导仍然是脑卒中治疗中亟待解决的重要问题。血小板衍生生长因子受体β（PDGFR-β）主要表达于脑内的神经干/祖细胞（NSPCs）、神经元和血管周细胞；然而，其在病理性神经发生中的作用仍不清楚。为此，我们研究了PDGFR-β在脑卒中后NSPCs迁移和增殖中的作用。将条件性Pdgfrb基因失活的小鼠制成短暂性大脑中动脉闭塞（MCAO）模型，包括N-PRβ-KO小鼠（Pdgfrb基因在除血管周细胞外的脑内大部分失活）和E-PRβ-KO小鼠（通过他莫昔芬诱导全身Pdgfrb基因失活）。与保留Pdgfrb基因的对照小鼠相比，N-PRβ-KO小鼠脑室下区DCX(+)神经母细胞向缺血核心的迁移显著增加，而E-PRβ-KO小鼠则无此现象。我们发现，对表达CXCR4的NSPCs具有强大趋化作用的CXCL12在N-PRβ-KO小鼠的缺血损伤部位上调。此外，NSPCs内在表达的整合素α3在MCAO后N-PRβ-KO小鼠中上调，整合素α3对细胞外基质依赖性迁移起关键介导作用。从N-PRβ-KO小鼠分离的NSPCs在涂有IV型胶原或纤连蛋白的表面上快速迁移，IV型胶原和纤连蛋白在血管龛和缺血核心中含量丰富。PDGFR-β可能通过调节损伤部位衍生的趋化因子以及NSPCs的内在信号，在病理性神经发生中起关键作用，我们认为对这些分子事件的协同调节可能能够改善损伤脑内的神经发生，促进进一步的功能恢复。
