Abstract
The resident microglial and infiltrating cells from peripheral circulation are involved in the pathological processes of ischemia stroke and may be regulated by mesenchymal stem/stromal cell (MSC) transplantation. The present study is aimed at differentiating the neurotrophic and inflammatory roles played by microglial vs. infiltrating circulation-derived cells in the acute phase in rat ischemic brains and explore the influences of intravenously infused allogeneic MSCs. The ischemic brain injury was induced by distal middle cerebral artery occlusion (dMCAO) in SD rats, with or without MSC infusion in the same day following dMCAO. Circulation-derived infiltrating cells in the brain were identified by Ly6C, a majority of which were monocytes/macrophages. Without MSC transplantation, among the infiltrated Ly6C+ cells, some were positive for BDNF, IL-1β, or TNF-α. Following MSC infusion, the overall number of Ly6C+ infiltrated cells was reduced by 50%. In contrast, the proportions of infiltrated Ly6C+ cells coexpressing BDNF, IL-1β, or TNF-α were significantly enhanced. Interestingly, Ly6C+ cells in the infarct area could produce either neurotrophic factor BDNF or inflammatory cytokines (IL-1β or TNF-α), but not both. This suggests that the Ly6C+ cells may constitute heterogeneous populations which react differentially to the microenvironments in the infarct area. The changes in cellular composition in the infarct area may have contributed to the beneficial effect of MSC transplantation.
Highlights
Mesenchymal stem/stromal cells (MSCs) have a potential for treatment of neurological diseases, such as stroke
We have previously shown a rapid accumulation of ionized calcium binding adaptor molecule-1- (Iba-1-) positive microglia in the injured cerebral cortex two days after distal middle cerebral artery occlusion (dMCAO) in rats [7]
We have previously found that in the ischemic brain, brainderived neurotrophic factor (BDNF) is expressed in NeuN-positive neurons and CD68positive microglia/macrophages in the peri-infarct areas, but mainly by Iba-1-positive microglia in the infarct core [7]
Summary
Mesenchymal stem/stromal cells (MSCs) have a potential for treatment of neurological diseases, such as stroke. Bone marrow-derived MSCs (BM-MSCs) show merits in that they can be allogeneically or autologously transplanted without raising ethical or immunological problems. The therapeutic mechanisms of intravenous MSC transplantation have been mainly ascribed to the neurotrophic and anti-inflammatory effects [1]. MSCs are capable of secreting a lot of cytokines and eliciting the host to produce many kinds of neurotrophic factors, including brainderived neurotrophic factor (BDNF) [2], glial cell-derived neurotrophic factor (GDNF) [3], and insulin growth factor-1 (IGF-1) [4]. Inflammatory responses in stroke, including immune cells, cytokines, and chemokines, are important for stroke development and recovery. Local microglial cells and periphery circulation-derived cells, such as monocytes/macrophages, are important participants in stroke-induced
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