Conditioned Medium of BMSCs Alleviates H2O2-Induced Oxidative Damage in PC12 Cells Through the LDLR Pathway.

Abstract

Oxidative damage is pivotal in the pathogenesis and progression of a myriad of neurological disorders. The current study was designed to elucidate the therapeutic potential of conditioned medium from bone marrow-derived mesenchymal stromal cells (BMSC-CM) and to delineate the underlying mechanisms, using a neuronal oxidative injury model for this purpose. Rat pheochromocytoma PC12 cells were exposed to H₂O₂ to establish an oxidative injury model, followed by treatment with BMSC-CM or co-cultivation with BMSCs in a transwell apparatus. The oxidative stress levels pre- and post-intervention or co-cultivation were quantitatively assessed by PCR and western blot analyses. Furthermore, transcriptomic and bioinformatic analyses were used to identify pivotal genes and signaling pathways implicated in the observed effects. Both BMSC-CM treatment and BMSC co-culture decreased oxidative damage and inhibited apoptosis in PC12 cells. Transcriptomic data and enrichment analysis revealed 106 differentially expressed genes between BMSC-CM untreated and treated H₂O₂-exposed PC12 cells, including 67 downregulated and 39 upregulated genes. Notably, the significantly differentially expressed genes were predominantly those involved in lipid metabolism pathways, and the low-density lipoprotein receptor (LDLR) emerged as one statistically significant upregulated gene. The proprotein convertase subtilisin/kexin type 9, a specific inhibitor of LDLR, attenuated the positive effects of BMSC-CM treatment, corroborating that LDLR activation plays a crucial role in mitigating neuronal oxidative damage. The results of this investigation underscore the neuroprotective capacity of BMSC-CM, which we show is mediated through its ability to module lipid metabolism in neuronal cells via the LDLR. Further research into the neuroprotective properties of BMSC-CM could lead to the development of promising therapeutic avenues for neurological diseases characterized by oxidative stress.