Bone Marrow-Derived Mesenchymal Stem Cell-Derived Exosomes Containing Gli1 Alleviate Microglial Activation and Neuronal Apoptosis In Vitro and in a Mouse Parkinson Disease Model by Direct Inhibition of Sp1 Signaling.

Abstract

This study investigated possible therapeutic effect mechanisms of exosomes from bone marrow-derived mesenchymal stem cells (BMSC) in neuronal and microglial cells and in a Parkinson disease (PD) model. Neuronal SH-SY5Y cells and microglial HMC3 cells were subjected to 1-methyl-4-phenylpyridinium (MPP+) or LPS, respectively. The mRNA and protein expression was assessed using qRT-PCR, Western blotting, and enzyme-linked immunosorbent assay. Cell viability and apoptosis of SH-SY5Y cells were examined using the MTT assay and flow cytometry. Chromatin immunoprecipitation assays were performed to assess the binding relationship between glioma-associated oncogene homolog 1 (Gli1) and the Sp1 transcription factor promoter. BMSC-derived exosomes promoted cell proliferation and inhibited apoptosis in MPP+-treated SH-SY5Y cells and suppressed inflammatory markers in LPS-treated HMC3 cells. Sp1 knockdown decreased SH-SY5Y cell damage and HMC3 immune activation. Gli1 carried by BMSC exosomes directly bound with Sp1 to inhibit Sp1-mediated LRRK2 activation whereas exosomes secreted by Gli1-knockdown in BMSC did not. In a PD mouse model induced with MPTP, BMSC exosomes decreased neuron loss injury and the inflammatory response by inhibiting Sp1 signaling. Thus, BMSC-derived exosomal Gli1 alleviates inflammatory damage and neuronal apoptosis by inhibiting Sp1 in vitro and in vivo. These findings provide the basis for the potential clinical use of BMSC-derived exosomes in PD.

• Authors: Yang Cai, Ming-Ming Zhang, Ming Wang, Zhuo-Hang Jiang, Zhi-Gang Tan
• Journal: Journal of neuropathology and experimental neurology (J Neuropathol Exp Neurol) Vol. 81 Issue 7 Pg. 522-534 (06 20 2022) ISSN: 1554-6578 [Electronic] England
• PMID: 35609560 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 American Association of Neuropathologists, Inc. All rights reserved.

Chemical References

• GLI1 protein, human
• Lipopolysaccharides
• MicroRNAs
• Sp1 Transcription Factor
• Sp1 protein, human
• Zinc Finger Protein GLI1

Topics

• Animals
• Apoptosis (physiology)
• Bone Marrow (metabolism)
• Disease Models, Animal
• Exosomes (genetics)
• Humans
• Lipopolysaccharides
• Mesenchymal Stem Cells (metabolism)
• Mice
• MicroRNAs (genetics)
• Microglia (metabolism)
• Neuroblastoma (metabolism)
• Parkinson Disease (metabolism, therapy)
• Sp1 Transcription Factor (metabolism, pharmacology)
• Zinc Finger Protein GLI1 (genetics, metabolism)