Alterations in Apoptotic Pathways and Expression of Mir-134, Mir-181, and Mir-497 Induced by Wharton's Jelly-Derived Mesenchymal Stem Cells in a Rat Model of Ischemic Brain Injury Publisher



Alizamir T^{1, 2} ; Jouzdani AF^{3, 4} ; Attari F⁵ ; Arab L⁶ ; Ashaari Z⁷ ; Komaki A⁸ ; Hassanzadeh G^{6, 9}
Source: IBRO Neuroscience Reports Published:2025

Abstract

Background: MicroRNAs (miRNAs) play crucial roles in regulating cell survival and signaling pathways. Mesenchymal stem cells (MSCs), particularly those derived from Wharton's Jelly (WJ-MSCs), have shown potential in promoting cell survival and reducing apoptosis. This study evaluates the effects of WJ-MSCs on miRNA expression and apoptosis markers in an ischemic brain injury model. Methods: Male Wistar rats (n = 30) were divided into control, sham, WJ-MSCs, Middle Cerebral Artery Occlusion (MCAO), and MCAO+WJ-MSCs groups. After 60 minutes of ischemia and 24 hours of reperfusion, WJ-MSCs were administered intracerebroventricularly. Post-surgical brain samples were analyzed using immunohistochemistry, TUNEL assay, and qRT-PCR to measure Bax/Bcl-2 ratios and miRNA (miR-497, miR-134, miR-181) expression in the cortex. Results: Immunohistochemistry revealed that the Bax/Bcl-2 ratio was significantly increased in the MCAO group, reflecting a pro-apoptotic state. In contrast, WJ-MSC treatment significantly reduced the Bax/Bcl-2 ratio in the ischemic cortex, suggesting a shift towards anti-apoptotic activity. Additionally, analysis of miRNA expression showed significantly elevated levels of miR-497, miR-134, and miR-181 in the brains of ischemic rats, which were associated with increased neuronal cell death. WJ-MSC treatment effectively modulated these miRNAs, resulting in a marked reduction in their expression. Furthermore, the TUNEL assay confirmed a substantial reduction in the number of apoptotic cells in the MCAO+WJ-MSCs group compared to the MCAO group. In the cortex, apoptotic cells were observed in WJ-MSC-treated rats, indicating enhanced neuronal survival. Conclusion: WJ-MSCs mitigate ischemic brain injury by modulating miRNA expression and apoptotic markers, promoting neuronal survival. These findings highlight their potential as a therapeutic strategy for ischemic brain injuries. © 2025