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

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.

Immunosuppressant Drugs Mitigate Immune Responses Generated by Human Mesenchymal Stem Cells Transplanted into the Mouse Parenchyma

“…Human MSCs were expanded in media containing minimal essential alpha 1x medium (MEMα1x; Gibco, Waltham, MA, USA), 10% fetal bovine serum (FBS; Biowest, Riverside, MO, USA), and 0.5% gentamicin (Gibco, Waltham, MA, USA) at 37°C in a 5% CO2 incubator. As reported previously 25 , we applied a preconditioning protocol by treating hMSCs with ethionamide prior to transplantation to enhance the overall therapeutic efficacy of hMSCs. To prepare cells for transplantation, preconditioned hMSCs were harvested using 0.25% Trypsin-Ethylenediaminetetraacetic acid (EDTA) (Gibco, Waltham, MA, USA).…”

Intracerebroventricular Administration of Human Umbilical Cord Blood—Derived Mesenchymal Stem Cells Induces Transient Inflammation in a Transgenic Mouse Model and Patients with Alzheimer’s Disease

“…Observations were made up to 24 h in this study because fever subsided after 24 h in the clinical trial. Furthermore, according to studies that we have published recently, very few residual human MSCs were identified in the mouse brain one week following MSC transplantation [16,31,32]. Thus, although not extensively studied, since very few residual human MSCs were present in the mouse brain, signs of inflammatory responses may not have been detected at 1 or even 2 weeks following MSC transplantation.…”

Wharton’s Jelly-Derived Mesenchymal Stem Cells with High Aurora Kinase A Expression Show Improved Proliferation, Migration, and Therapeutic Potential

“…Lee et al [ 44 ] have demonstrated that MSCs with enhanced proliferation and migration due to ethionamide were retained longer when injected into mouse brain and were expected to show better therapeutic effect than naïve MSCs in the treatment of brain diseases. Therefore, WJ-MSCs with enhanced proliferation and migration, due to high expression of AURKA, probably showed improved apoptotic effect in the mdx mouse due to the higher number of WJ-MSCs retained in the muscle tissue than the WJ-MSCs with low expression of AURKA.…”