Ethionamide preconditioning enhances the therapeutic efficacy of human mesenchymal stromal cells in an Alzheimer’s disease model

Mesenchymal stromal cells (MSCs) are promising therapeutic candidates for neurodegenerative diseases, including Alzheimer’s disease (AD). However, their limited survival and functionality in pathological environments hinder their therapeutic efficacy. The primary objective of this study was to evaluate the therapeutic efficacy of ethionamide (ETH)-preconditioned MSCs (ETH-MSCs) in mitigating AD pathology. Wharton’s jelly-derived MSCs (WJ-MSCs) were preconditioned with ethionamide, and their therapeutic efficacy was evaluated in both in vitro and in vivo AD models. In vitro, ETH-MSCs were assessed for their ability to modulate microglial inflammation and promote amyloid-β (Aβ) clearance under AD-like conditions. For in vivo studies, ETH-MSCs were injected into the lateral ventricles of 5xFAD transgenic mice. The effects of ETH-MSC administration on glial activation (GFAP and Iba1 expression) and Aβ deposition were evaluated. In vitro, ETH-MSCs reduced pro-inflammatory cytokine secretion by microglia and enhanced Aβ clearance in neurons. In vivo, ETH-MSCs treatment significantly decreased GFAP and Iba1 expression, indicating reduced astroglial and microglial activation, and reduced amyloid plaque burden in 5xFAD mice. Repeated ETH-MSCs injections further boosted Aβ clearance, demonstrating a cumulative therapeutic benefit. Ethionamide preconditioning significantly enhances the neuroprotective and amyloid-clearing capabilities of WJ-MSCs. These findings suggest the potential of ETH-MSCs as an effective therapeutic strategy for AD, with superior efficacy compared to naïve MSCs in both in vitro and in vivo models.