Targeting ASIC1a Promotes Neural Progenitor Cell Migration and Neurogenesis in Ischemic Stroke

神经发生 半影 酸敏离子通道 神经干细胞 祖细胞 神经科学 室下区 细胞生物学 缺血 生物 离子通道 医学 干细胞 内科学 受体
作者
Hongfei Ge,Tengyuan Zhou,Chao Zhang,Yupeng Cun,Weixiang Chen,Yang Yang,Qian Zhang,Huanhuan Li,Jun Zhong,Xuyang Zhang,Hua Feng,Rong Hu
出处
期刊:Research [AAAS00]
卷期号:6 被引量:43
标识
DOI:10.34133/research.0105
摘要

Cell replacement therapy using neural progenitor cells (NPCs) has been shown to be an effective treatment for ischemic stroke. However, the therapeutic effect is unsatisfactory due to the imbalanced homeostasis of the local microenvironment after ischemia. Microenvironmental acidosis is a common imbalanced homeostasis in the penumbra and could activate acid-sensing ion channels 1a (ASIC1a), a subunit of proton-gated cation channels following ischemic stroke. However, the role of ASIC1a in NPCs post-ischemia remains elusive. Here, our results indicated that ASIC1a was expressed in NPCs with channel functionality, which could be activated by extracellular acidification. Further evidence revealed that ASIC1a activation inhibited NPC migration and neurogenesis through RhoA signaling-mediated reorganization of filopodia formation, which could be primarily reversed by pharmacological or genetic disruption of ASIC1a. In vivo data showed that the knockout of the ASIC1a gene facilitated NPC migration and neurogenesis in the penumbra to improve behavioral recovery after stroke. Subsequently, ASIC1a gain of function partially abrogated this effect. Moreover, the administration of ASIC1a antagonists (amiloride or Psalmotoxin 1) promoted functional recovery by enhancing NPC migration and neurogenesis. Together, these results demonstrate targeting ASIC1a is a novel strategy potentiating NPC migration toward penumbra to repair lesions following ischemic stroke and even for other neurological diseases with the presence of niche acidosis.
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