MSCs‑derived exosomes attenuate ischemia-reperfusion brain injury and inhibit microglia apoptosis via exosomal miR-26a-5p mediated suppression of CDK6

Abstract

Background: This study aims to explore the role of mesenchymal stromal cells (MSCs)-derived exosomes (MSCs-Exo) in the cerebral ischemia-reperfusion (I/R) injury.Methods: Exosomes were isolated from MSCs of adult C57BL/6J mice by the gradient centrifugation method. The expression of miR-26a-5p and CDK6 in MSCs-Exo and mice brain tissues were evaluated by qRT-PCR and western blot. MiR-26a-5p mimics and miR-NC were transfected into MSCs, and exosomes were isolated from the stably expressing MSCs. Then MSCs-Exo-miR-26a-5p mimics or MSCs-Exo-miR-NC was injected into mice through the tail vein, or added into medium to stimulate BV-2 cells. Cell viability was evaluated by CCK-8 assay. Cell apoptosis was detected by flow cytometry. The apoptosis in brain tissues was evaluated by TUNEL staining assay. Bioinformatics analysis and luciferase reporter assay were performed to determine the relationship between miR-26a-5p and CDK6. Results: MiR-26a-5p was downregulated and CDK6 was upregulated in MSCs-Exo of MCAO and OGD model. MSCs-Exo-miR-26a-5p mimics significantly reduced cell apoptosis of OGD-injured BV-2 cells. MSCs-Exo-miR-26a-5p mimics significantly reduced infarct volume of MCAO-induced mice. Luciferase reporter assay revealed that CDK-6 was a target of miR-26a-5p. In addition, MSCs-Exo-miR-26a-5p mimics significantly decreased the expression of CDK6 in both OGD-induced BV-2 cells and MCAO-treated mice brains. Conclusion: Our results indicated that MSCs‑Exo attenuated I/R injury in mice by inhibiting microglia apoptosis via exosomal miR-26a-5p mediated suppression of CDK6. Our study shed light on the application of MSC-Exo as a potential therapeutic tool for cerebral I/R injury.

Human Umbilical Cord Mesenchymal Stem Cell‐Derived Exosomes Attenuate Oxygen‐Glucose Deprivation/Reperfusion‐Induced Microglial Pyroptosis by Promoting FOXO3a‐Dependent Mitophagy

“…However, direct application of MSCs is associated with potential risks and hazards, especially in babies who are considered a fragile population [5]. Recently, MSCderived exosomes (MSC-exos) have been identified as one of the key neuroprotective mechanisms of MSCs and can effectively ameliorate ischemia/reperfusion-(I/R-) induced brain injury by promoting angiogenesis, regulating immune responses, and inhibiting neuronal apoptosis [6][7][8][9][10]. MSCexos have emerged as an attractive therapeutic alternative that holds great regenerative potential and is cell-free [11].…”

Therapeutic Mesenchymal Stem/Stromal Cells: Value, Challenges and Optimization

“…Another study using human umbilical cord-derived MSCs showed optimistic results in treating vertebral bone defects in weaned rabbits (Cui et al, 2019). Mouse BM-MSCs were shown to attenuate ischemia-reperfusion brain injury and inhibit microglial apoptosis (Cheng et al, 2021). Human umbilical cord MSCs (UC-MSCs) effectively improved renal function and inhibited inflammation and fibrosis in a rat model of diabetic nephropathy (DN) (Xiang et al, 2020).…”

Exosomes Derived From Mesenchymal Stem Cells: Novel Effects in the Treatment of Ischemic Stroke

“…MiR-29b-3p in BMSCs-Exos inhibits cell apoptosis by reducing the expression of Bax, cutting caspase3 and up-regulating Bcl-2 ( Hou et al, 2020 ), and promotes neuronal survival by promoting the anti-apoptotic signal cascades ( Zhang Y. et al, 2021 ). MiR-26a-5p in MSC-exosomes inhibits microglial apoptosis by targeting CDK6 ( Cheng et al, 2021 ). Similar to neurons, oligodendrocytes are highly sensitive to hypoxia, oxidative stress, inflammatory mediators, injuries, or injuries induced by infection.…”