Vegfr3 activation of Pkd2l1+ CSF-cNs triggers the neural stem cell response in spinal cord injury

Abstract

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 Pkd2l1⁺CSF-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 Pkd2l1⁺CSF-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.

Keywords: Cerebrospinal fluid-contacting neurons; Neural stem cells; PI3K/Akt signaling; Pkd2l1; Spinal cord injury; Vegfr3.