Intravenous Multipotent Adult Progenitor Cell Therapy For Traumatic Brain Injury: Modulation Of The Resident Neuronal Macrophage Population

Abstract

Introduction: Multipotent adult progenitor cells (MAPC) are bone marrow derived progenitor cells that offer neuroprotection after TBI in a rodent model. Previous work from our laboratory has demonstrated that the observed neuroprotection is dependent on MAPC interaction with resident splenocytes. Furthermore, the response of the resident microglia/macrophage to CNS injury is of interest as it appears to play a role in acute and chronic phases following injury. We hypothesize that MAPCs interact with resident splenocytes to increase the differentiation of naive T cells into T regulatory cells leading to systemic increases in anti inflammatory cytokine production and that the modulation of the systemic inflammatory response affects the resident microglial and macrophage populations leading to functional benefit. Methods: C57 Black 6 mice underwent controlled cortical impact (CCI) injury or sham injury (1 group). One group of injured animals had 10 * 106 MAPC / kg injected via the tail vein at 2 and 24 hours after CCI injury. Blood brain barrier permeability was measured via Evan's blue extravasation 72 hours after CCI injury (n=6/group). The CD4+/CD25+/FOXP3+ T regulatory cells populations were quantified in the spleen and blood at 24, 48, and 72 hours after injury (n =4/group). Additionally, the CD86+ M1 and CD206+ M2 macrophage populations were quantified using flow cytometry at 24, 48, 72, and 120 hours after CCI injury (n=6/group). Results: Mice showed an increase in BBB permeability after CCI injury that was reversed by the intravenous injection of MAPCs (p=0.009). A significant increase in T regulatory cells within the splenocyte populations of MAPC treated mice at 24 hours (p=0.003) with no difference seen at 48 or 72 hours. Additionally, a significant increase in blood T regulatory cells from MAPC treated mice was seen at 48 hours after CCI injury (p=0.006). Additionally, a significant increase in the M2/M1 macrophage ratio in MAPC treated animals at both 48 (p=0.006) and 120 hours (p=0.002) after CCI injury. Conclusions: The intravenous injection of MAPC preserves the integrity of the blood brain barrier after TBI. Furthermore, MAPC therapy increases the differentiation of T regulatory cells which are known to produce anti inflammatory cytokines. The modulation of the systemic inflammatory response could shift the microglia M2/M1 ratio accounting for the observed benefit of progenitor cell therapy for TBI.