Abstract
Mesenchymal stem cells (MSCs) are a useful source for cell-based therapy of a variety of immune-mediated diseases, including neurodegenerative disorders. However, poor migration ability and survival rate of MSCs after brain transplantation hinder the therapeutic effects in the disease microenvironment. Therefore, we attempted to use a preconditioning strategy with pharmacological agents to improve the cell proliferation and migration of MSCs. In this study, we identified ethionamide via the screening of a drug library, which enhanced the proliferation of MSCs. Preconditioning with ethionamide promoted the proliferation of Wharton’s jelly-derived MSCs (WJ-MSCs) by activating phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase/extracellular signal-regulated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK)1/2 signaling. Preconditioning with ethionamide also enhanced the migration ability of MSCs by upregulating expression of genes associated with migration, such as C-X-C motif chemokine receptor 4 (CXCR4) and C-X-C motif chemokine ligand 12 (CXCL12). Furthermore, preconditioning with ethionamide stimulated the secretion of paracrine factors, including neurotrophic and growth factors in MSCs. Compared to naïve MSCs, ethionamide-preconditioned MSCs (ETH-MSCs) were found to survive longer in the brain after transplantation. These results suggested that enhancing the biological process of MSCs induced by ethionamide preconditioning presents itself as a promising strategy for enhancing the effectiveness of MSCs-based therapies.
Highlights
Stem cells possess self-renewing capabilities and have the potential to differentiate into multiple cell types
Our study investigated the P13k/Akt and MEK/ERK1/2 signaling pathways to study the mechanisms underlying the increase in proliferation of mesenchymal stem cells (MSCs) in vitro upon treatment with ethionamide
The level of proliferation was markedly lower in the MSCs treated with MEK/ERK1/2 inhibitors compared to that in the group treated with phosphatidylinositol 3-kinase (PI3K)/Akt inhibitors, and the restoring effect of ethionamide was lower in the MEK/ERK1/2 pathway
Summary
Stem cells possess self-renewing capabilities and have the potential to differentiate into multiple cell types. MSCs are known to exert their therapeutic effects by secreting various cytokines that promote anti-inflammation [12,13], antioxidant activities [14,15], and activation of endogenous neurogenesis [16,17], rather than differentiation into neurons or glial cells. Such therapeutic potential of MSCs can be enhanced upon rapid migration of MSCs to the target site and prolonged survival in the brain to exert these therapeutic effects
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