Wu Zuomeng, Han Tianyu, Dong Yixiang, Ying Wang, Fang Huang, Liu Yunlei, Song Peiwen, Shen Cailiang
Department of Orthopedics (Spinal Surgery), The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, People's Republic of China.
Laboratory of Spinal and Spinal Cord Injury Regeneration and Repair, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, People's Republic of China.
Cell Mol Biol Lett. 2024 Dec 3;29(1):149. doi: 10.1186/s11658-024-00672-9.
Traumatic injuries to spinal cord lead to severe motor, sensory, and autonomic dysfunction. The accumulation of inhibitory compounds plays a pivotal role in the secondary damage to sparing neural tissue and the failure of axonal regeneration and remyelination. Acid-sensing ion channel-1(ASIC1A) is widely activated following neurotrauma, including spinal cord injury (SCI). However, its role in SCI remains elusive.
The effects of acidic environment on the differentiation and genes changes of neural stem cells (NSCs) were assessed by immunofluorescence staining and RNA-sequencing analysis, respectively. The expression of ASIC1A and prostaglandin endoperoxide synthase 2 (PTGS2) were detected by western blot and immunofluorescence staining. The concentration of prostaglandin E2 (PGE2) within NSC-derived extracellular vesicles were evaluated by ELISA. Small-interfering RNAs (siRNAs) were used to knock down Asic1a and Ptgs2 expression in NSCs. The myelin sheath regeneration and axonal remyelination in rats and Asic1a-KO mice were assessed by immunofluorescence staining.
Following injury to the spinal cord, ASIC1A was found to be colocalized and upregulated in NSCs. ASIC1A activation prevents the differentiation of NSCs into oligodendrocytes by upregulating PTGS2, which leads to increased production and release of PGE2 within extracellular vesicles (EVs). ASIC1A or PTGS2 deficiency in NSCs counters the ASIC1A-related effects on mediating NSC differentiation by reducing PGE2 expression within NSC-derived EVs. Furthermore, intervention in ASIC1A signaling by administration of ASIC1A inhibitors or genetic deletion of ASIC1A demonstrated a pronounced advantage in enhancing myelin sheath regeneration and axonal remyelination.
The activation of ASIC1A prevents NSC differentiation into oligodendrocytes via the transcellular NSC-to-NSC delivery of PGE2, resulting in the failure of myelin sheath regeneration and axonal remyelination following SCI. The inhibition of ASIC1A presents a promising therapeutic strategy for the treatment of SCI.
脊髓创伤会导致严重的运动、感觉及自主神经功能障碍。抑制性化合物的积累在对残留神经组织的继发性损伤以及轴突再生和髓鞘再生失败中起关键作用。酸敏感离子通道1（ASIC1A）在包括脊髓损伤（SCI）在内的神经创伤后被广泛激活。然而，其在SCI中的作用仍不清楚。
分别通过免疫荧光染色和RNA测序分析评估酸性环境对神经干细胞（NSC）分化和基因变化的影响。通过蛋白质免疫印迹和免疫荧光染色检测ASIC1A和前列腺素内过氧化物合酶2（PTGS2）的表达。通过酶联免疫吸附测定法评估NSC来源的细胞外囊泡中前列腺素E2（PGE2）的浓度。使用小干扰RNA（siRNA）敲低NSC中Asic1a和Ptgs2的表达。通过免疫荧光染色评估大鼠和Asic1a基因敲除小鼠的髓鞘再生和轴突髓鞘再生情况。
脊髓损伤后，发现ASIC1A在NSC中共定位并上调。ASIC1A的激活通过上调PTGS2来阻止NSC分化为少突胶质细胞，这导致细胞外囊泡（EV）中PGE2的产生和释放增加。NSC中ASIC1A或PTGS2的缺乏通过降低NSC来源的EV中PGE2的表达来对抗ASIC1A对介导NSC分化的相关影响。此外，通过给予ASIC1A抑制剂或基因缺失ASIC1A来干预ASIC1A信号通路，在增强髓鞘再生和轴突髓鞘再生方面显示出明显优势。
ASIC1A的激活通过PGE2从NSC到NSC的跨细胞传递阻止NSC分化为少突胶质细胞，导致SCI后髓鞘再生和轴突髓鞘再生失败。抑制ASIC1A为SCI的治疗提供了一种有前景的治疗策略。
