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Brain to spleen stem cell migration
suggests that an immense peripheral inflammatory response follows stroke, yet investigations into stem cell therapy have not probed whether stem cells transplanted intracerebrally are capable of migrating to the periphery and alleviating systemic inflammation. Previously, we administered hBMSC intravenously in experimental rat models of stroke and the transplanted cells preferentially migrated to the spleen, demonstrated greater survival in the spleen than in the brain, and ameliorated stroke- induced neurostructural deficits and chronic inflamma- tion.19 Here, we showed that lymphatic pathways and inflammatory signals enable stem cells to migrate to the spleen after intracerebral transplantation in a stroke brain (Figure 8).
Preferential migration toward the site of pathological signals is critical for stem cell transplantation to achieve its therapeutic potential. Such deposition of systemically delivered stem cells into the spleen after stroke is accom- panied by reduced necrotic and apoptotic cell death in the brain, decreased motor and cognitive deficits, and a damp- ened splenic inflammatory response.12,30-33 This sequestra- tion of neurodegeneration by suppressing systemic inflammation originating from the spleen was previously
demonstrated in stroke animals that had their spleen removed or were transplanted with human umbilical cord cells in the acute stage of stroke.12,30
The present in vivo imaging revealed the migration of intracerebrally transplanted hBMSC to the spleen in the acute stage. The highest numbers of these cells were found on day 3 in both brain and spleen. Transient block- age of the contralateral common carotid artery caused more intense ischemia in the brain tissue of groups with severe stroke, producing much higher levels of inflamma- tory factors. This increased inflammatory response heightens the migratory action of the transplanted stem cells. In animal models of focal cerebral ischemic stroke, recruitment of multiple inflammatory cell types such as neutrophils within the ischemic brain occurs within 30 minutes to a few hours after the stroke, peaking within the first 3 days.34,35 hBMSC have immunomodulatory capacities, are multipotent, and tend to migrate to sites of tissue injury/inflammation, making them promising effec- tors for tissue regeneration.36-40
Lymphatic vessels, in addition to draining interstitial flu- ids, allow cells to travel from tissues to draining lymph nodes.41 Therefore, we examined whether the cerebral
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Figure 4. Immunofluorescent staining of inflammatory cells. (A and B) OX6-stained microglia/macrophages were frequently found in the periphery of the site of stem cell injection site in the brain (A) and around the blood vessels in the spleen (B), and the number of OX6-positive cells in the stroke groups was higher than in the sham-treated groups. Nuclei were stained with DAPI. Arrow heads indicate OX6-positive cells. Scale bars = 100 mm. Green: OX6; blue: DAPI. (C and D) In quantitative analyses of the brain (C) and the spleen (D), the stroke groups exhibited a higher number of OX6-positive cells than did the sham-treated group (**P<0.01). Significance bars: **P<0.01; ***P<0.001. (C) a: The group with mild stroke had significantly more OX6-positive cells in the brain on day 3 than on other days (P<0.01); b: the group with severe stroke had significantly more OX6-positive cells in the brain on day 3 than on other days (P<0.001). (D) a: The group with mild stroke had significantly more OX6-positive cells in the spleen on day 3 than on other days (P<0.01); b: the group with severe stroke had significantly more OX6-positive cells in the spleen on day 3 than on other days (P<0.001).
haematologica | 2019; 104(5)
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