Intravenous multipotent adult progenitor cell therapy for traumatic brain injury: Preserving the blood brain barrier via an interaction with splenocytes

Abstract

Recent investigation has shown an interaction between transplanted progenitor cells and resident splenocytes leading to modulation of the immunologic response in neurological injury. We hypothesize that the intravenous injection of multipotent adult progenitor cells (MAPC) confers neurovascular protection after traumatic brain injury through an interaction with resident splenocytes, subsequently leading to preservation of the blood brain barrier. Four groups of rats underwent controlled cortical impact injury (3 groups) or sham injury (1 group). MAPC were injected via the tail vein at two doses (2*106 MAPC/kg or 10*106 MAPC/kg) 2 and 24 hours after injury. Blood brain barrier permeability was assessed by measuring Evans blue dye extravasation (n=6/group). Additionally, splenic mass was measured (n=12/group) followed by splenocyte characterization (n=9/group) including: cell cycle analysis (n=6/group), apoptosis index (n=6/group), cell proliferation (n=6/group), and inflammatory cytokine measurements (n=6/group). Vascular architecture was determined by immunohistochemistry (n=3/group). Traumatic brain injury results in a decrease in splenic mass and increased blood brain barrier permeability. Intravenous infusion of MAPC preserved splenic mass and returned blood brain barrier permeability towards control sham injured levels. Splenocyte characterization indicated an increase in the number and proliferative rate of CD4+ T cells as well as an increase in IL-4 and IL-10 production in stimulated splenocytes isolated from the MAPC treatment groups. Immunohistochemistry demonstrated stabilization of the vascular architecture in the peri-lesion area Traumatic brain injury causes a reduction in splenic mass that correlates with an increase in circulating immune cells leading to increased blood brain barrier permeability. The intravenous injection of MAPC preserves splenic mass and the integrity of the blood brain barrier. Furthermore, the co-localization of transplanted MAPC and resident CD4+ splenocytes is associated with a global increase in IL-4 and IL-10 production and stabilization of the cerebral microvasculature tight junction proteins.

Activation of Alpha 7 Cholinergic Nicotinic Receptors Reduce Blood–Brain Barrier Permeability following Experimental Traumatic Brain Injury

“…More recent studies have implicated vagus nerve activity, especially the efferent splenic component, in reducing systemic inflammation (Borovikova et al, 2000;Rosas-Ballina et al, 2008;Olofsson et al, 2012). Consistent with this, we have previously demonstrated that splenectomy markedly decreased TBI-triggered BBB permeability, suggesting a role for spleen-mediated systemic inflammation in BBB breakdown (Walker et al, 2010). Investigation into the mechanism of the anti-inflammatory action of vagus nerve stimulation has led to the formulation of the cholinergic antiinflammatory pathway (CAP) hypothesis in which vagus nerve activation indirectly stimulates nicotinic acetylcholine receptor ␣7 (nAChRa7) subunit on splenocytes, causing decreased production of proinflammatory cytokines (Pavlov and Tracey, 2006;Rosas-Ballina et al, 2011).…”

“…A number of studies have investigated brain inflammation in response to TBI and its contribution to BBB pathology (Sanderson et al, 1999;Morganti-Kossmann et al, 2002;Titus et al, 2013;de Rivero Vaccari et al, 2016). These studies have shown a shift in microglia polarization toward the proinflammatory M1 subtype, astrocyte activation, and increased production of inflammatory cytokines in the injured tissue (Loane et al, 2014;Turtzo et al, 2014).…”

“…These studies have shown a shift in microglia polarization toward the proinflammatory M1 subtype, astrocyte activation, and increased production of inflammatory cytokines in the injured tissue (Loane et al, 2014;Turtzo et al, 2014). Although increases in circulating levels of cytokines, including interleukin (IL)-1␤, IL-6, and tissue necrosis factor-␣ (TNF-␣), have been observed after TBI, a few studies have suggested that some of these molecules are released into the circulation from the injured brain Helmy et al, 2011).…”

Administration of Umbilical Cord Blood Cells Transiently Decreased Hypoxic-Ischemic Brain Injury in Neonatal Rats

“…Modulating peripheral inflammation can be a therapeutic target. In a traumatic brain injury model, multipotent adult progenitor cells exerted a neuroprotective effect through interaction with resident splenocytes [43]. …”

Assessing Blood Brain Barrier Permeability in Traumatic Brain Injury Research

“…Of note, Pati et al demonstrated in mouse models of TBI that mesenchymal stem cells exert perivascular protective effects to the penumbral BBB via increased junctional protein (VE-cadherin and occludin) expression [60]. Walker et al showed increased localization/organization of occludins to the microvasculature [61]. The Cox lab is currently using diffusion tensor MRI imaging to evaluate the response to cell therapy in acute setting for severe TBI in pediatric and adult clinical trials (NCT01851083 and NCT 01575470 respectively).…”