Photobiomodulation Promotes Repair Following Spinal Cord Injury by Regulating the Transformation of A1/A2 Reactive Astrocytes

Abstract

After spinal cord injury (SCI), reactive astrocytes can be classified into two distinctive phenotypes according to their different functions: neurotoxic (A1) astrocytes and neuroprotective (A2) astrocytes. Our previous studies proved that photobiomodulation (PBM) can promote motor function recovery and improve tissue repair after SCI, but little is known about the underlying mechanism. Therefore, we aimed to investigate whether PBM contributes to repair after SCI by regulating the activation of astrocytes. Male rats subjected to clip-compression SCI were treated with PBM for two consecutive weeks, and the results showed that recovery of motor function was improved, the lesion cavity size was reduced, and the number of neurons retained was increased. We determined the time course of A1/A2 astrocyte activation after SCI by RNA sequencing (RNA-Seq) and verified that PBM inhibited A1 astrocyte activation and promoted A2 astrocyte activation at 7 days postinjury (dpi) and 14 dpi. Subsequently, potential signaling pathways related to A1/A2 astrocyte activation were identified by GO function analysis and KEGG pathway analysis and then studied in animal experiments and preliminarily analyzed in cultured astrocytes. Next, we observed that the expression of basic fibroblast growth factor (bFGF) and transforming growth factor-β (TGF-β) was upregulated by PBM and that both factors contributed to the transformation of A1/A2 astrocytes in a dose-dependent manner. Finally, we found that PBM reduced the neurotoxicity of A1 astrocytes to dorsal root ganglion (DRG) neurons. In conclusion, PBM can promote better recovery after SCI, which may be related to the transformation of A1/A2 reactive astrocytes.

Modulatory effect of IL‐1 inhibition following lipopolysaccharide‐induced neuroinflammation in neonatal microglia and astrocytes

“…The increase of the A2 astrocyte marker EMP1 at 8 h could reflect an early neuroprotective response following LPS exposure. It was shown that the expression of A2 markers, including EMP1 and S100A10, was upregulated during the early phase of neurological injury, and this was followed by their repression in the long term (Fujita et al, 2018; Pan et al, 2022; Wang et al, 2021). As A2 astrocytic activation is described as neuroprotective in adult brain, the decrease in A2 markers at 24 h in our study further supports the acquisition of a detrimental phenotype acquired by LPS‐activated astrocytes (Liddelow et al, 2017; Zamanian et al, 2012).…”

Photobiomodulation promotes repair following spinal cord injury by restoring neuronal mitochondrial bioenergetics via AMPK/PGC-1α/TFAM pathway

“…Then the sugar-free medium was removed and replaced with the original medium, and the cells were cultured in an incubator with normal parameters (reoxygenation, 37°C, 5% CO 2 ) for 24 h before the next procession. The OGD + PBM group received two times of PBM for 10 min within 24 h at fixed time (9 and 21 a.m.) ( Wang et al, 2021b ), and Compound C (10 µM, 24 h) was added to the OGD + PBM + CC group to inhibit the AMPK pathway. In order to exclude the toxic effect of DMSO on cells, equal volume of DMSO was added to the OGD + DMSO group.…”

The PI3K/AKT signalling pathway in inflammation, cell death and glial scar formation after traumatic spinal cord injury: Mechanisms and therapeutic opportunities

“…Activated macrophages induce extensive retraction of dystrophic axons through direct physical interactions, whereas depletion of activated macrophages reduces axon retraction in a rat dorsal column crush lesion model 68 . Classically activated microglia are also able to induce the activation of A1‐type reactive astrocytes, which amplify inflammation and produce neurotoxic effects, causing neuronal and oligodendrocyte death and glial scar formation 69 . Chondroitin sulphate proteoglycans (CSPGs) inhibit axon growth.…”