Due to their multifactorial aspects, mesenchymal stem cells (MSCs) have been widely established as an attractive and potential candidate for the treatment of a multitude of diseases. A substantial number of studies advocate that MSCs are poorly immunogenic. In several studies, however, immune responses were observed following injections of xenogeneic donor MSCs. In this study, the aim was to examine differences in immune responses exerted based on transplantations of xenogeneic, syngeneic, and allogeneic MSCs in the wild-type mouse brain. Xenogeneic, allogeneic, and syngeneic MSCs were intracerebrally injected into C57BL/6 mice. Mice were sacrificed one week following transplantation. Based on immunohistochemical (IHC) analysis, leukocytes and neutrophils were expressed at the injection sites in the following order (highest to lowest) xenogeneic, allogeneic, and syngeneic. In contrast, microglia and macrophages were expressed in the following order (highest to lowest): syngeneic, allogeneic, and xenogeneic. Residual human MSCs in the mouse brain were barely detected after seven days. Although the discrepancy between leukocytes versus macrophages/microglia infiltration should be resolved, our results overall argue against the previous notions that MSCs are poorly immunogenic and that modulation of immune responses is a prerequisite for preclinical and clinical studies in MSC therapy of central nervous system diseases.

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.

We have recently reported on how transplantation of human mesenchymal stem cells (MSCs) into the mouse parenchyma generated immune responses. To facilitate the clinical translation of MSC-based AD therapy, the safety and efficacy of human derived MSCs (hMSCs) must be confirmed in the pre-clinical stage. Thus, it is imperative to investigate measures to reduce immune responses exerted via xenotransplantation. In this study, immunosuppressants were co-administered to mice that had received injections of hMSCs into the parenchyma. Prior to performing experiments using transgenic AD mice (5xFAD), varying immunosuppressant regimens were tested in wild-type (WT) mice and the combination of dexamethasone and tofacitinib (DexaTofa) revealed to be effective in enhancing the persistence of hMSCs. According to transcriptome sequencing and immunohistochemical analyses, administration of DexaTofa reduced immune responses generated via transplantation of hMSCs in the parenchyma of 5xFAD mice. Significant mitigation of amyloid burden, however, was not noted following transplantation of hMSCs alone or hMSCs with DexaTofa. The efficacy of the immunosuppressant regimen should be tested in multiple AD mouse models to promote its successful application and use in AD stem cell therapy.