Kruppel-like factor 2 contributes to blood-spinal cord barrier integrity and functional recovery from spinal cord injury by augmenting autophagic flux

Abstract

Background: Increasing evidence suggests that acute traumatic spinal cord injury (SCI)-induced defects in autophagy and autophagy-lysosomal pathway (ALP) may contribute to endothelial barrier disruption following injury. Recently, Kruppel-like factor 2 (KLF2) was reported as a key molecular switch on regulating autophagy. Whether KLF2 coordinates endothelial endothelial ALP in SCI is not known. Methods: Genetic manipulations of KLF2 were performed in bEnd.3 cells and SCI model. Western blot, qRT-PCR, immunofluorescence staining and Lyso-Tracker Red staining, Evans blue dye extravasation, behavioral assessment via Basso mouse scale (BMS), electrophysiology and footprint analysis were performed. Results: In SCI, autophagy flux disruption in endothelial cells contributes to TJ proteins degradation, leading to blood-spinal cord barrier (BSCB) impairment. Furthermore, the KLF2 level was decreased in SCI, overexpression of which alleviated TJ proteins loss and BSCB damage, which improve motor function recovery in SCI mice, while knockdown of KLF2 displayed the opposite effects. At the molecular level, KLF2 overexpression alleviated the TJ proteins degradation and the endothelial permeability by tuning the ALP dysfunction caused by SCI and oxygen glucose deprivation (OGD). Conclusions: Endothelial KLF2 as one of the key contributors to SCI-mediated ALP dysfunction and BSCB disruption. KLF2 could be a promising pharmacological target for the management and treatment of SCI.

Tetramethylpyrazine-loaded electroconductive hydrogels promote tissue repair after spinal cord injury by protecting the blood–spinal cord barrier and neurons

“…3 Preventing the apoptosis of these endothelial cells following SCI is essential to maintain the structural integrity of the barrier, which is vital for promoting the survival of the neurons. 3,5,8,9 We evaluated apoptosis in endothelial cells at 7 and 28 days after injury. Our results showed different levels of cell apoptosis in the TMP and GMP groups.…”

“…5,6 Thus, it is significant to target BSCB repair at an early stage of SCI to mitigate peri-lesional cellular perturbations and thereby modulate neuronal network homeostasis. 3,7,8 Furthermore, it may provide a foundation for neuronal repair and myelinated axon growth.…”

DADLE promotes motor function recovery by inhibiting cytosolic phospholipase A2 mediated lysosomal membrane permeabilization after spinal cord injury

“…Damaged cellular organelles and necroptosis markers are normally removed through the autophagy lysosomal system; thus, restoration of lysosomal function contributes to neuron survival by enhancing autophagy (Liu et al, 2018). Many previous studies demonstrated that some molecules, such as metformin and Kruppel‐like factor 2, were able to enhance SCI‐induced blockade of autophagic flux by facilitating fusion of autophagosomes and lysosomes, and consequently contributed to motor function recovery in SCI mice (He et al, 2023; Wu et al, 2022). The characteristics of these therapeutic substances were consistent with the drug we were studying.…”

Macrophage Membrane-Coated MnO2 Nanoparticles Provide Neuroprotection by Reducing Oxidative Stress after Spinal Cord Injury

“…In SCI treatment, the presence of the blood-spinal cord barrier (BSCB) is a hurdle to therapeutic drug delivery . The BSCB prevents many types of drugs, cells, proteins, and other molecules entering the central nervous system from the blood. , Although the BSCB opens temporarily after SCI, the drugs still need further improvement due to the large variation in the degree and timing of BSCB opening. , Therefore, it is worthwhile to explore the functionalized nanoparticles across the BSCB to target aggregation at the SCI site. In recent years, biomimetic nanoparticles coatings with cell membranes have been extensively studied, and different sources of cell membranes have different nanoparticles delivery functions. − For example, cell membranes from tumor cells can encapsulate and deliver chemotherapeutic drugs to target and inhibit tumors .…”

“…21,22 Although the BSCB opens temporarily after SCI, the drugs still need further improvement due to the large variation in the degree and timing of BSCB opening. 23,24 Therefore, it is worthwhile to explore the functionalized nanoparticles across the BSCB to target aggregation at the SCI site. In recent years, biomimetic nanoparticles coatings with cell membranes have been extensively studied, and different sources of cell membranes have different nanoparticles delivery functions.…”