Bone marrow mesenchymal stem cell exosomes attenuate neuroinflammation after diabetic intracerebral hemorrhage via miR-129-5p/HMGB1

Abstract

Background In this study, we investigated whether mesenchymal stem cell (MSC)-derived exosomes (Exos) could regulate hyperglycemia-induced neuroinflammation by transferring microRNA-129-5p (miR-129-5p). Methods Bone marrow-derived MSC (BMSC)-Exos were isolated from media BMSCs from mice. This was followed by transfection with miR-129-5p. BMSC-Exos or miR-129-5p-overexpressing BMSC-Exos were intravitreally injected into diabetic mice with intracerebral hemorrhage (DM/ICH) for in vivo analyses and were cocultured with high glucose-affected BV2 cells for in vitro analyses. RT-PCR and western blotting were conducted to assess the levels of some inflammation factors, such as high-mobility group box 1 (HMGB1), interleukin (IL)-6, IL-1β, toll-like receptor 4 (TLR4), and tumor necrosis factor α (TNFα). Results Our results indicate that hyperglycemia considerably increased inflammation in ICH mice or in BV2 cells exposed to high glucose with hemin and increased the expression levels of hmgb1 and its downstream inflammatory factors. BMSC-Exos administration could effectively reverse this reaction. Compared with administration of BMSC-Exos, administration of miR-129-5p-overexpressing BMSC-Exos more effectively suppressed the HMGB1 signaling pathway and suppressed inflammation both in vivo and in vitro. We also observed an improvement in cerebral hematoma and cerebral edema in DM/ICH mice after administration of the miR-129-5p mimic, which reduced the permeability of the blood–brain barrier. Conclusions We demonstrated that BMSC-Exos can reduce the inflammatory response after DM/ICH, thereby improving the neurological function of the brain, and we demonstrate that their effect is achieved through the miR-129-5p/HMGB1/TLR4 regulatory axis. At present, the mechanism by which exosomes from bone marrow mesenchymal stem cells regulate neuroinflammation after diabetic cerebral hemorrhage remains unclear. The results of this study provide a theoretical basis for the recovery of neurological function after diabetic cerebral hemorrhage and may provide a new targeted therapy for neuroinflammation.

Exosome-shuttled miR-150–5p from LPS-preconditioned mesenchymal stem cells down-regulate PI3K/Akt/mTOR pathway via Irs1 to enhance M2 macrophage polarization and confer protection against sepsis

“…Among the up-regulated differentially expressed miRNAs, miR-150-5p ranked second, which was previously reported to regulate macrophages polarization. Although first detected in chronic lymphocytic leukemia, recent reports have indicated that miR-150-5p is associated with the activation and differentiation of macrophages (47)(48)(49). Indeed, we validated that miR-150-5p was highly expressed in LPS-Exo versus Exo, and transfection of miR-150-5p inhibitors into BMDMs reversed the effect of LPS-Exo on the activation and polarization of macrophages.…”

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“…Among the up-regulated differentially expressed miRNAs, miR-150-5p ranked second, which was previously reported to regulate macrophages polarization. Although first detected in chronic lymphocytic leukemia, recent reports have indicated that miR-150-5p is associated with the activation and differentiation of macrophages (47)(48)(49). Indeed, we validated that miR-150-5p was highly expressed in LPS-Exo versus Exo, and transfection of miR-150-5p inhibitors into BMDMs reversed the effect of LPS-Exo on the activation and polarization of macrophages.…”