Cao Liang, Shangguan Zeyu, Zhang Yi, Luo Zhangrong, Chen Chanjuan, Yan Haijian, Fu Xiangque, Tan Wei, Wang Chunqing, Dou Xiaowei, Zheng Chunfu, Li Qing
Department of Traumatic Orthopedics, The Affiliated Hospital of Guizhou Medical University, Guiyang, China; Department of Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Department of Traumatic Orthopedics, The Affiliated Hospital of Guizhou Medical University, Guiyang, China.
Cell Signal. 2025 Jun;130:111675. doi: 10.1016/j.cellsig.2025.111675. Epub 2025 Feb 20.
Activating adult neural stem cells (NSCs) located within the spinal cord niche is considered a promising therapeutic approach for treating spinal cord injury (SCI). Cerebrospinal fluid (CSF)-contacting neurons expressing Pkd2l1 exhibit phenotypic and molecular traits similar to those of adult NSCs. However, the mechanism responsible for regulating the activation of Pkd2l1 CSF-cNs still needs to be discovered. This research demonstrated that Pkd2l1 CSF-cNs have a high concentration of vascular endothelial growth factor receptor 3 (Vegfr3) and that SCI results in elevated Vegfr3 levels. The overexpression of Vegfr3 in Pkd2l1CSF-cNs induced potential NSC activation. Blocking Vegfr3 led to a significant reduction in the percentage of active Pkd2l1 CSF-cNs, suggesting that Vegfr3 is involved in controlling the shift from dormancy to activation in these cells. In vivo, the downregulation of Vegfr3 by SAR131475 inhibited Pkd2l1CSF-cN proliferation and maintained self-renewal. Injection of vascular endothelial growth factor C (Vegf-C) into the lateral ventricle of adult mice confirmed the involvement of Vegfr3 in activating Pkd2l1 CSF-cNs. Vegf-C administration significantly increased the number of activated Pkd2l1 CSF-cNs. Mechanistically, Vegfr3 primed quiescent Pkd2l1 CSF-cNs for cell cycle reentry by enabling the activation of PI3K/Akt signaling. The activation of Vegfr3 may enhance SCI outcomes by promoting neuronal survival and facilitating the recovery of motor function in mice. Together, our findings highlight that Vegfr3 is a crucial functional regulator of Pkd2l1 CSF-cNs, governing the transition from NSC quiescence to activation.
激活位于脊髓生态位内的成体神经干细胞（NSCs）被认为是治疗脊髓损伤（SCI）的一种有前景的治疗方法。表达Pkd2l1的脑脊液（CSF）接触神经元表现出与成体神经干细胞相似的表型和分子特征。然而，负责调节Pkd2l1 CSF-cNs激活的机制仍有待发现。本研究表明，Pkd2l1 CSF-cNs具有高浓度的血管内皮生长因子受体3（Vegfr3），并且脊髓损伤会导致Vegfr3水平升高。Vegfr3在Pkd2l1 CSF-cNs中的过表达诱导了潜在的神经干细胞激活。阻断Vegfr3导致活性Pkd2l1 CSF-cNs的百分比显著降低，表明Vegfr3参与控制这些细胞从休眠到激活的转变。在体内，SAR131475对Vegfr3的下调抑制了Pkd2l1 CSF-cN的增殖并维持了自我更新。向成年小鼠侧脑室注射血管内皮生长因子C（Vegf-C）证实了Vegfr3参与激活Pkd2l1 CSF-cNs。给予Vegf-C显著增加了激活的Pkd2l1 CSF-cNs的数量。从机制上讲，Vegfr3通过激活PI3K/Akt信号通路使静止的Pkd2l1 CSF-cNs为细胞周期重新进入做好准备。Vegfr3的激活可能通过促进神经元存活和促进小鼠运动功能恢复来改善脊髓损伤的结果。总之，我们的研究结果强调Vegfr3是Pkd2l1 CSF-cNs的关键功能调节因子，控制着神经干细胞从静止到激活的转变。
