Abstract
After spinal cord injury (SCI), destruction of the blood-spinal cord barrier (BSCB) results in infiltration of blood cells, such as neutrophils and macrophages, leading to permanent neurological dysfunction. Previous studies have shown that human bone marrow mesenchymal stem cell (BMSC)-derived exosomes have a beneficial neuroprotective effect in SCI models. However, whether BMSC-Exos contribute to the integrity of the BSCB has not been clarified. The purpose of this study was to investigate the mechanism of BMSC-Exo-induced changes in the permeability of the BSCB after SCI. Here, we first used BMSC-Exos to treat an SCI rat model, showing that BMSC-Exos can inhibit BSCB permeability damage and improve spontaneous repair. Next, we found that tissue inhibitors of matrix metalloproteinase 2 (TIMP2) have been shown to play an important role in the function of BMSC-Exos by inhibiting the matrix metalloproteinase (MMP) pathway, thereby reducing the reduction of cell junction proteins. Therefore, we constructed siTIMP2 to knock out TIMP2 in BMSC-Exos, which caused the activity of BMSC-Exos to be significantly weakened. Finally, we constructed an in vitro model of BSCB with HBMECs and verified that TIMP2 in BMSC-Exos in vitro can also alleviate BSCB damage. This proof-of-principle study demonstrates that BMSC-Exos can preserve the integrity of the BSCB and improve functional recovery after SCI through the TIMP2/MMP signaling pathway.
Highlights
Spinal cord injury (SCI) is a serious health problem that usually leads to permanent disability and causes a cascade of events[1]
We showed that bone marrow mesenchymal stem cell (BMSC)-Exos alleviate neurological deficits by preventing the destruction of the blood spinal cord barrier (BSCB) in rats after SCI
Through siRNA transfection, we confirmed that tissue inhibitors of matrix metalloproteinases 2 (TIMP2) in BMSC-Exos inhibits the matrix metalloproteinase (MMP) pathway, thereby alleviating the destruction of cell junctions after SCI, which contributes to BSCB repair
Summary
Spinal cord injury (SCI) is a serious health problem that usually leads to permanent disability and causes a cascade of events[1]. The blood spinal cord barrier (BSCB) plays an important role in the recovery of central nervous system diseases after SCI[3]. It can restrict and regulate the entry of external substances into the central nervous system and maintain the homeostasis of the microenvironment and has a considerable effect on the pathophysiological process of various neurological diseases[4]. The destruction of the BSCB leads to inflammatory infiltration and produces neurotoxic products that disrupt the function of neurons and synapses, which results in "programmed death" of glia and neurons, causing permanent neurological deficits[8]. Early recovery of the BSCB plays a vital role in the treatment of SCI
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