Ethionamide Preconditioning Enhances the Proliferation and Migration of Human Wharton's Jelly-Derived Mesenchymal Stem Cells

• Published in: International journal of molecular sciences 2020-10, Vol.21 (19), p.7013
• Main Authors: Lee, Na-Hee, Myeong, Su Hyeon, Son, Hyo Jin, Hwang, Jung Won, Lee, Na Kyung, Chang, Jong Wook, Na, Duk L
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Animals; Antibiotics; Biological activity; Brain - cytology; Brain - metabolism; Cell growth; Cell Movement - drug effects; Cell proliferation; Cell Proliferation - drug effects; Chemokine receptors; CXCL12 protein; CXCR4 protein; Ethionamide; Ethionamide - pharmacology; ethionamide-preconditioned MSCs (ETH-MSCs); Extracellular signal-regulated kinase; FDA approval; Gene expression; Gene Expression Regulation - drug effects; Growth factors; Health aspects; Heterografts; Humans; Kinases; MAP kinase; MAP Kinase Signaling System - drug effects; Mesenchymal Stem Cell Transplantation; Mesenchymal stem cells; mesenchymal stem cells (MSCs); Mesenchymal Stem Cells - cytology; Mesenchymal Stem Cells - metabolism; Mice; Microenvironments; migration; Nonsteroidal anti-inflammatory drugs; paracrine factors; Paracrine signalling; Phosphorylation; Preconditioning; proliferation; Protein kinase; Proteins; Signal transduction; Stem cells; survival; Transplantation; Tuberculosis; Wound healing
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21197013

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.