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-b) 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-b 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-PRb-KO mice where the Pdgfrb-gene was mostly inactivated in the brain except that in vascular pericytes, and E-PRb-KO mice with tamoxifen-induced systemic Pdgfrb-gene inactivation. The migration of the DCX 1 neuroblasts from the subventricular zone toward the ischemic core was highly increased in N-PRb-KO, but not in E-PRb-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-PRb-KO mice. Furthermore, integrin a3 intrinsically expressed in NSPCs that critically mediates extracellular matrix-dependent migration, was upregulated in N-PRb-KO after MCAO. NSPCs isolated from N-PRb-KO rapidly migrated on the surface coated with collagen type IV or fibronectin that are abundant in vascular niche and ischemic core. PDGFR-b 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. STEM CELLS 2016;34:685-698 SIGNIFICANCE STATEMENTNeuroepithelium-specific Pdgfrb gene inactivation showed more robust ischemia-induced neurogenesis than that with Pdgfrb in Flox controls and in tamoxifen-induced ubiquitous Pdgfrb gene inactivated mice. Our results suggest that a coordinated regulation of lesion-derived migration inducing cue, CXCL12, as well as increased integrin a3 expression as an intrinsic factor of NSPCs may be able to improve neurogenesis in injured brain to further functional recovery.

A subset of cerebrovascular pericytes originates from mature macrophages in the very early phase of vascular development in CNS

“…For real-time PCR performed with an Mx3000 P (Agilent Technologies), cDNA was diluted 1:20 and PCR was performed using SYBR Premix EX Taq II (Takara). The real-time PCR program consisted of hot start enzyme activation at 95 °C for 10 sec followed by 40 cycles of amplification at 95 °C for 10 sec and 60 °C for 40 sec, as previously reported 64, 65 . Finally, to obtain the dissociation curve, a final cycle was performed at 95 °C for 1 min, 60 °C for 30 sec, and then 95 °C for 10 sec.…”

Targeting Adult Neurogenesis for Poststroke Therapy

“…In addition, many growth factors have been identified to protect NSCs and enhance neurogenesis after stroke. Basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), BDNF, bone morphogenetic protein (BMP), glial cell-derived neurotrophic factor (GDNF), transforming growth factor- (TGF-) α , ciliary neurotrophic factor (CNTF), and platelet-derived growth factor (PDGF) have all been proposed to play essential roles in the adult neurogenesis response to ischemia stroke [ 103 – 111 ]. Recently, some cytokines and hormones such as chemokine, complement, estrogen, and granulocyte-colony stimulating factor (G-CSF) have been proved to benefit against a stroke-induced brain and behavioral pathology [ 112 – 116 ].…”

The Novel Pathogenesis of Retinopathy Mediated by Multiple RTK Signals is Uncovered in Newly Developed Mouse Model

“…All mice were housed at 25 °C with a 12-h light/dark cycle with free access to pellet chow and water. Genotyping of the Pdgfrb flox/flox [ 17 ], Nestin-Cre [ 41 ], R26R-mCherry [ 23 ] and Flt1TK −/− [ 21 ] were performed by genomic PCR. The primer sequences are given in Supplementary information.…”