Liaocheng Univ, Liaocheng Peoples Hosp, Inst Tissue Engn & Regenerat Med, Liaocheng, Shandong, Peoples R China.
Shandong Univ Tradit Chinese Med, Translat Res Lab Stem Cells & Tradit Chinese Med, Jinan, Peoples R China.
Shandong Univ, Qilu Hosp Qingdao, Dept Neurol, Qingdao, Peoples R China.
Neural progenitor cells (NPCs) have great potentials in cell replacement therapy for neurodegenerative diseases, such as Alzheimer's disease (AD), by promoting neurogenesis associated with hippocampal memory improvement. Ephrin receptors and angiogenic growth factor receptors have a marked impact on the proliferation and differentiation of NPCs. Although ephrin receptor A4 (EphA4) was shown to directly interact with platelet-derived growth factor receptor beta (PDGFR beta), the functional effects of this interaction on neurogenesis in cultured NPCs and adult hippocampus have not yet been studied. Immunoprecipitation demonstrated that EphA4 directly interacted with PDGFR beta in NPCs under ligand stimulation. Ephrin-A1 and PDGF-platelet-derived growth factor BB (BB) significantly increased proliferation and neuronal differentiation of NPCs, which was further augmented by combined treatment of Ephrin-A1 and PDGF-BB. We also found that ligand-dependent proliferation and neuronal differentiation were inhibited by the dominant-negative EphA4 mutant or a PDGFR inhibitor. Most importantly, injection of ephrin-A1 and/or PDGF-BB promoted hippocampal NPC proliferation in the APP/PS1 mouse model of AD, indicating that direct interaction of EphA4 with PDGFR beta plays a functional role on neurogenesis in vivo. Finally, studies in NPCs showed that the EphA4/PDGFR beta/FGFR1/FRS2 alpha complex formed by ligand stimulation is involved in neurogenesis via ERK signaling. The present findings provided a novel insight into the functional role of direct interaction of EphA4 and PDGFR beta in neurogenesis, implicating its potential use for treating neurodegenerative diseases.收起