Immunomodulation by Polarize MSC can Increase Hippocampal Neurogenesis and Cognitive Function in Mice

Mesenchymal Stem Cells (MSC) are known to increase hippocampal neurogenesis upon CNS engraftment via their rich secretome. Similarly, the immune system plays an important role in regulating hippocampal neurogenesis by cytokine secretion, as well as by cellular interactions. MSC are also known for their immunomodulatory properties. Akin of immune cells, MSC can polarize to pro-inflammatory MSC (MSC1) and anti-inflammatory MSC (MSC2) following activation of Toll-like receptor 4 (TLR4) and TLR3, respectively. We thus hypothesized that immune modulation by polarized MSC2 (pMSC) can promote neurogenesis indirectly as well, by modulating the immune system. To test this hypothesis, we asked whether splenocytes co-cultured with pMSC can increase neurogenesis following systemic delivery. To polarize MSC (pMSC) we treated MSC in culture with Pituitary Adenylate Cyclase Activating Peptide (PACAP). PACAP treatment increased the ratio of TLR3/TLR4 gene expression and the expression of MSC2 related cytokines. Co-culturing of splenocytes with pMSC resulted in altered cytokine expression from the splenocytes. Following systemic administration, splenocytes that were co-cultured with pMSC, increased hippocampal neurogenesis and cognitive functions in recipient mice compared with splenocytes co-cultured with naïve MSC. Increased neurogenesis was observed by increased progenitor proliferation (Ki67+) in the sub-granular zone and increased newly formed neurons (DCX+) in the granular cell layer of the dentate gyrus. Improved cognitive functions were determined by novel object localization and escape latency in the Morris water maze. Our work suggests another mechanism involved in MSC’s effect on hippocampal neurogenesis and dependent behavior and may lead to the development of novel therapeutic strategies.