hUMSC-Exosomes suppress TREM1-p38 MAPK signaling via HMGB1-dependent mechanisms to reprogram microglial function and promote neuroprotection in ischemic stroke

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

Background Ischemic stroke induces profound neuroinflammation, where microglial activation exacerbates secondary brain injury. Human umbilical mesenchymal stem cell-derived exosomes (hUMSC-Exos) exhibit therapeutic potential, but their mechanisms in modulating microglial responses remain incompletely understood. Results Following intranasal administration, hUMSC-Exos selectively accumulated in ischemic brain regions and were internalized by microglia. In transient middle cerebral artery occlusion (tMCAO) mice, hUMSC-Exos improved neurological outcomes, reduced neuronal apoptosis, and promoted a sustained shift in microglial polarization toward an anti-inflammatory phenotype-evidenced by suppressed pro-inflammatory and elevated anti-inflammatory markers in peri-infarct areas. These effects were replicated in LPS/IFN-γ-stimulated primary microglia and BV2 cells. Microglia-specific RNA sequencing revealed that hUMSC-Exos reversed tMCAO-induced pro-inflammatory and migratory transcriptional programs, concurrently suppressing p38 MAPK while activating immunoregulatory pathways. TREM1 emerged as a critical node, with hUMSC-Exos downregulating its expression in microglia; pharmacological TREM1 inhibition (LP17) synergistically augmented the suppression of microglial activation, migration, and proliferation. Mechanistically, hUMSC-Exos attenuated NF-κB/p38 MAPK signaling, with TREM1 fu

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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