Enhancing Effect of IL-1α on Neurogenesis from Adult Human Mesenchymal Stem Cells: Implication for Inflammatory Mediators in Regenerative Medicine

Abstract

Mesenchymal stem cells (MSCs) are mesoderm-derived cells, primarily resident in adult bone marrow. MSCs show lineage specificity in generating specialized cells such as stroma, fat, and cartilage. MSCs express MHC class II and function as phagocytes and APCs. Despite these immune-enhancing properties, MSCs also exert veto functions and show evidence for allogeneic transplantation. These properties, combined with ease in isolation and expansion, demonstrate MSCs as attractive candidates for tissue repair across allogeneic barriers. MSCs have also been shown to transdifferentiate in neuronal cells. We have reported expression of the neurotransmitter gene, Tac1, in MSC-derived neuronal cells, with no evidence of translation unless cells were stimulated with IL-1α. This result led us to question the potential role of immune mediators in the field of stem cell therapy. Using Tac1 as an experimental model, IL-1α was used as a prototypical inflammatory mediator to study functions on MSC-derived neuronal cells. Undifferentiated MSCs and those induced to form neurons were studied for their response to IL-1α and other proinflammatory cytokines using production of the major Tac1 peptide, substance P (SP), as readout. Although IL-1α induced high production of SP, a similar effect was not observed for all tested cytokines. The induced SP was capable of reuptake via its high-affinity NK1R and was found to stabilize IL-1R mRNA. IL-1α also enhanced the rate of neurogenesis, based on expression of neuronal markers and cRNA microarray analyses. The results provide evidence that inflammatory mediators need to be considered when deciding the course of MSC transplantation.