Abstract
IntroductionWe have demonstrated previously that the intravenous delivery of multipotent adult progenitor cells (MAPC) after traumatic brain injury affords neuroprotection via interaction with splenocytes, leading to an increase in systemic anti-inflammatory cytokines. We hypothesize that the observed modulation of the systemic inflammatory milieu is related to T regulatory cells and a subsequent increase in the locoregional neuroprotective M2 macrophage population.MethodsC57B6 mice were injected with intravenous MAPC 2 and 24 hours after controlled cortical impact injury. Animals were euthanized 24, 48, 72, and 120 hours after injury. In vivo, the proportion of CD4+/CD25+/FOXP3+ T-regulatory cells were measured in the splenocyte population and plasma. In addition, the brain CD86+ M1 and CD206+ M2 macrophage populations were quantified. A series of in vitro co-cultures were completed to investigate the need for direct MAPC:splenocyte contact as well as the effect of MAPC therapy on M1 and M2 macrophage subtype apoptosis and proliferation.ResultsSignificant increases in the splenocyte and plasma T regulatory cell populations were observed with MAPC therapy at 24 and 48 hours, respectively. In addition, MAPC therapy was associated with an increase in the brain M2/M1 macrophage ratio at 24, 48 and 120 hours after cortical injury. In vitro cultures of activated microglia with supernatant derived from MAPC:splenocyte co-cultures also demonstrated an increase in the M2/M1 ratio. The observed changes were secondary to an increase in M1 macrophage apoptosis.ConclusionsThe data show that the intravenous delivery of MAPC after cortical injury results in increases in T regulatory cells in splenocytes and plasma with a concordant increase in the locoregional M2/M1 macrophage ratio. Direct contact between the MAPC and splenocytes is required to modulate activated microglia, adding further evidence to the central role of the spleen in MAPC-mediated neuroprotection.
Highlights
We have demonstrated previously that the intravenous delivery of multipotent adult progenitor cells (MAPC) after traumatic brain injury affords neuroprotection via interaction with splenocytes, leading to an increase in systemic anti-inflammatory cytokines
Three groups of mice received 1 × 107 MAPC / kg injected via the tail vein at 2 and 24 hours after cortical impact (CCI) injury
Mice showed an increase in Blood brain barrier (BBB) permeability after CCI alone (0.98 ± 0.09) that was reversed by the intravenous injection of MAPC (0.72 ± 0.06, P
Summary
We have demonstrated previously that the intravenous delivery of multipotent adult progenitor cells (MAPC) after traumatic brain injury affords neuroprotection via interaction with splenocytes, leading to an increase in systemic anti-inflammatory cytokines. We hypothesize that the observed modulation of the systemic inflammatory milieu is related to T regulatory cells and a subsequent increase in the locoregional neuroprotective M2 macrophage population. Traumatic brain injury (TBI) affects nearly 1.5 million patients in the United States annually [1]. TBI is associated with significant long-term physical, cognitive, and psychosocial deficits leading to an annual economic impact of 60 billion dollars. One possible pathway towards neuroprotection is via modulation of the proinflammatory environment observed after TBI. Microglia (five to ten percent of the total glial population) represent the resident immune cells (akin to tissue macrophages) in the CNS [2]. Activation of microglial cells has been observed in both TBI and spinal cord injury {Chirumamilla, 2002 #27, [3], Beck, 2010 #28, [4]}
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