Role of STAT3-FOXO3 Signaling in the Modulation of Neuroplasticity by PD-L1-HGF-Decorated Mesenchymal Stem Cell-Derived Exosomes in a Murine Stroke Model

• Published in: Advanced science 2024-09, Vol.11 (36), p.e2404882-n/a
• Main Authors: Lin, Syuan-Ling, Chang, Yi-Wen, Lee, Wei, Chiang, Chih-Sheng, Liu, Shih-Ping, Lee, Hsu-Tung, Jeng, Long-Bin, Shyu, Woei-Cherng
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; B7-H1 Antigen - metabolism; Cell death; Cell growth; Disease Models, Animal; exosomes; Exosomes - metabolism; Flow cytometry; Forkhead Box Protein O3 - genetics; Forkhead Box Protein O3 - metabolism; Genetic engineering; Hepatocyte Growth Factor - genetics; Hepatocyte Growth Factor - metabolism; HGF; Ischemia; Ligands; Lymphocytes; Male; Mesenchymal Stem Cells - metabolism; Mice; Mice, Inbred C57BL; MicroRNAs; Nervous system; Neurogenesis; Neuronal Plasticity; PD‐L1; Proteins; Signal Transduction; STAT3 Transcription Factor - metabolism; STAT3‐FOXO3 pathway; Stem cells; Stroke; Stroke - metabolism
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202404882

The limited therapeutic strategies available for stroke leave many patients disabled for life. This study assessed the potential of programmed death-ligand 1 (PD-L1) and hepatocyte growth factor (HGF)-engineered mesenchymal stem cell-derived exosomes (EXO-PD-L1-HGF) in enhancing neurological recovery post-stroke. EXO-PD-L1-HGF, which efficiently endocytosed into target cells, significantly diminishes the H O -induced neurotoxicity and increased the antiapoptotic proteins in vitro. EXO-PD-L1-HGF attenuates inflammation by inhibiting T-cell proliferation and increasing the number of CD8 CD122 IL-10 regulatory T cells. Intravenous injection of EXO-PD-L1-HGF could target stromal cell-derived factor-1α (SDF-1α ) cells over the peri-infarcted area of the ischemic brain through CXCR4 upregulation and accumulation in neuroglial cells post-stroke. EXO-PD-L1-HGF facilitates endogenous nestin neural progenitor cell (NPC)-induced neurogenesis via STAT3-FOXO3 signaling cascade, which plays a pivotal role in cell survival and neuroprotection, thereby mitigating infarct size and enhancing neurological recovery in a murine stroke model. Moreover, increasing populations of the immune-regulatory CD19 IL-10 and CD8 CD122 IL-10 cells, together with reducing populations of proinflammatory cells, created an anti-inflammatory microenvironment in the ischemic brain. Thus, innovative approaches employing EXO-PD-L1-HGF intervention, which targets SDF-1α expression, modulates the immune system, and enhances the activation of resident nestin NPCs, might significantly alter the brain microenvironment and create a niche conducive to inducing neuroplastic regeneration post-stroke.