The novel role of perivascular fibroblasts in secondary injury after cervical SCI

Spinal cord injury (SCI) is a devastating condition that causes profound physical and emotional suffering, yet effective treatments remain unavailable. Developing new therapies to mitigate SCI outcomes represents a critical unmet clinical need. Disruption of the blood-spinal cord barrier (BSCB) leads to peripheral immune cell infiltration, exacerbates neuroinflammation, and worsens secondary injury, ultimately causing tissue damage and functional deficits. Protecting the damaged BSCB offers a promising strategy to limit secondary injury and improve outcomes. However, no therapies targeting BSCB dysfunction are currently available. The overall goal of this application is to investigate the previously unexplored role of perivascular fibroblasts in BSCB dysfunction and secondary injury, focusing on identifying perivascular fibroblast-derived peptidase inhibitor 16 (PI16) as a novel therapeutic target for neuroprotection after SCI. Our preliminary studies suggest that activation of the IFNγ pathway plays a key role in activating perivascular fibroblasts and promoting fibrotic scar formation. These activated fibroblasts significantly upregulate PI16 expression, which is closely associated with BSCB dysfunction and exacerbated neuroinflammation. Notably, BSCB disruption, injury size, and functional deficits were significantly reduced in PI16 knockout mice following SCI. Furthermore, a PI16-neutralizing antibody demonstrated robust neuroprotective effects when injected into the injured spinal cord. Based on these strong preliminary data, we hypothesize that upregulation of PI16 in perivascular fibroblasts via IFNγ signaling increases BSCB leakage and immune cell infiltration, exacerbating neuroinflammation and secondary injury, ultimately leading to progressive tissue damage and functional loss following SCI. Therefore, blocking PI16 activity with a neutralizing antibody could protect against tissue loss and promote functional recovery. We will test this hypothesis through three specific aims. Aim 1 will investigate the mechanisms regulating the activation of perivascular fibroblasts and PI16 upregulation after SCI. Aim 2 will validate the key role of PI16 in BSCB permeability, tissue damage, and functional deficits following SCI. Aim 3 will assess the therapeutic potential of PI16-neutralizing antibody treatment after SCI. These studies will provide valuable insights into the new role of perivascular fibroblasts in secondary injury and identify fibroblast-derived PI16 as a novel therapeutic target for SCI. Importantly, we will evaluate the therapeutic potential of a clinically translatable PI16-neutralizing antibody. These studies could pave the way for developing new treatments to improve outcomes for patients with SCI. Project Number: 1R01NS144807-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: QI LIN CAO | Institution: FLORIDA INTERNATIONAL UNIVERSITY, MIAMI, FL | Award Amount: $471,698 | Activity Code: R01 | Study Section: Clinical Neuroplasticity and Neurotransmitters Study Section[CNNT] View on NIH RePORTER: https://reporter.nih.gov/project-details/11376637