Abstract
Human placenta amniotic membrane-derived mesenchymal stem cells (AMSCs) regulate immune responses, and this property can be exploited to treat stroke patients via cell therapy. We investigated the expression profile of AMSCs cultured under hypoxic conditions and observed interesting expression changes in various genes involved in immune regulation. CD200, an anti-inflammatory factor and positive regulator of TGF-β, was more highly expressed under hypoxic conditions than normoxic conditions. Furthermore, AMSCs exhibited inhibition of pro-inflammatory cytokine expression in co-cultures with LPS-primed BV2 microglia, and this effect was decreased in CD200-silenced AMSCs. The AMSCs transplanted into the ischemic rat model of stroke dramatically inhibited the expression of pro-inflammatory cytokines and up-regulated CD200, as compared with the levels in the sham-treated group. Moreover, decreased microglia activation in the boundary region and improvements in behavior were confirmed in AMSC-treated ischemic rats. The results suggested that the highly expressed CD200 from the AMSCs in a hypoxic environment modulates levels of inflammatory cytokines and microglial activation, thus increasing the therapeutic recovery potential after hypoxic-ischemic brain injury, and further demonstrated the immunomodulatory function of AMSCs in a stroke model.
Highlights
Stroke is an important clinical neurologic disorder and the most common cause of severe adult disability
Integration of gene expression changes in amniotic membrane-derived mesenchymal stem cells (AMSCs) into the interacting genes interestingly revealed that among immune-related factors, only CD200 was significantly up-regulated in the hypoxic environment (Figure 1a). This result suggested that CD200 may trigger an anti-inflammatory process in AMSCs in the early stage of stroke characterized by hypoxic environment, probably leading to a series of downstream reactions
Hypoxic conditions enhance the proliferation of Placenta-derived MSCs (PMSCs) and hypoxic-conditioned PMSCs protect against scar formation in vivo.[47]
Summary
Stroke is an important clinical neurologic disorder and the most common cause of severe adult disability. Brain cells undergo cell death and release their cytoplasmic contents into the extracellular space, thereby evoking inflammatory cascades and amplifying tissue damage.[1,2,3] Reactive macrophages and leukocytes are recruited into hypoxia-ischemic brain injury regions These cells cooperate with resident neurons, astrocytes, and microglia and result in the generation of pro-inflammatory mediators, including enzymes, such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-1 (COX-1), and cytokines and chemokines, such as interleukin-1 (IL-1), IL-6, IL-8, tumor necrosis factor-alpha (TNF-α) and monocyte chemoattractant protein-1 (MCP-1).[2,4,5] certain inflammatory conditions may have positive effects on brain repair and neurogenesis.[6,7,8], severe bouts of acute or prolonged inflammation in general can decrease neuronal viability and hinder brain regenerative processes under conditions of hypoxia-ischemia brain injury. MSCs directly inhibit the proliferation of T lymphocytes and microglial cells and modulate the cytokine secretion profile of dendritic cells and monocytes.[18,19,20,21,22] The immunosuppressive effect of transplanted MSCs has been demonstrated in Alzheimer’s disease.[23,24]
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