Group Leader Príncipe Felipe Research Center (CIPF) Valencia, Comunidad Valenciana, Spain
Abstract: Astrocytes (a type of glial cell) play critical roles in numerous central nervous system (CNS) disorders, including spinal cord injury (SCI). The elongation of reactive astrocytes after SCI represents the first step in glial scar formation. Our objective is to discern the molecular mechanisms that regulate astrocyte elongation and glial scar formation that may help to develop appropriate therapeutic strategies for SCI. We demonstrate for the first time that in vitro activation of LRP1/Trk signaling enhances AKT phosphorylation and increases β-catenin levels in ependymal cells. Astrocyte elongation during in vitro scratch assays occurs in response to LRP1/Trk signaling and β-catenin activity. These effects are observed when using FM19G11 as a pharmacological tool. We report that activation of LRP1/Trk signaling influences astrocyte elongation and improves the orientation of astrocyte protrusions toward the SCI in vivo. In response to SCI, Sox9/GFAP double-positive reactive astrocytes undergo elongation, coinciding with an increase in reactive astrocyte markers (GFAP, GLT1, C3, and S100a10) two days post-injury in model mice. Additionally, the levels of the LRP1 ligand alpha-2-macroglobulin (A2M) increase in undifferentiated ependymal cells—endogenous spinal cord progenitors—during their directed differentiation into astrocytes. In vitro studies reveal that LRP1/Trk activation by A2M leads to an increase in β-catenin levels, contributing to astrocyte elongation. These effects are observed when using FM19G11 as a pharmacological tool to modulate LRP1/Trk signaling. As a potent inducer of astrocyte activation in vitro and in vivo, FM19G11 provides a means to manipulate reactive astrocyte elongation, potentially enhancing regeneration after SCI.
Funding Source: Institute of Health Carlos III (ISCIII) of the Spanish Ministry of Science and Innovation PI21/00157
