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Painting factor H onto mesenchymal stem cells protects the cells from complement- and neutrophil-mediated damage.

ABSTRACT: Mesenchymal stem cells (MSCs) are undergoing intensive testing in clinical trials as a promising new therapy for many inflammatory diseases and for regenerative medicine, but further optimization of current MSC-based therapies is required. In this study, we found that in addition to direct complement-mediated attack through the assembly of membrane attack complexes (MACs) that we and others have recently reported, of the released complement activation products, C5a, but not C3a, activates neutrophils in the blood to further damage MSCs through oxidative burst. In addition, we have developed a simple method for painting factor H, a native complement inhibitor, onto MSCs to locally inhibit complement activation on MSCs. MSCs painted with factor H are protected from both MAC- and neutrophil-mediated attack and are significantly more effective in inhibiting antigen-specific T cell responses than the mock-painted MSCs both in vitro and in vivo.

SUBMITTER: Li Y

PROVIDER: S-EPMC5290709 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Painting factor H onto mesenchymal stem cells protects the cells from complement- and neutrophil-mediated damage.

Li Yan Y Qiu Wen W Zhang Lingjun L Fung John J Lin Feng F

Biomaterials 20160608

Mesenchymal stem cells (MSCs) are undergoing intensive testing in clinical trials as a promising new therapy for many inflammatory diseases and for regenerative medicine, but further optimization of current MSC-based therapies is required. In this study, we found that in addition to direct complement-mediated attack through the assembly of membrane attack complexes (MACs) that we and others have recently reported, of the released complement activation products, C5a, but not C3a, activates neutro ...[more]

PMID: 27343468

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Project description:Cell-therapy modalities using mesenchymal stem (MSCs) in experimental strokes are being investigated due to the role of MSCs in neuroprotection and regeneration. It is necessary to know the sequence of events that occur during stress and how MSCs complement the rescue of neuronal cell death mediated by [Ca2+]i and reactive oxygen species (ROS). In the current study, SH-SY5Y-differentiated neuronal cells were subjected to in vitro cerebral ischemia-like stress and were experimentally rescued from cell death using an MSCs/neuronal cell coculture model. Neuronal cell death was characterized by the induction of proinflammatory tumor necrosis factor (TNF)-α, interleukin (IL)-1β and -12, up to 35-fold with corresponding downregulation of anti-inflammatory cytokine transforming growth factor (TGF)-β, IL-6 and -10 by approximately 1 to 7 fold. Increased intracellular calcium [Ca2+]i and ROS clearly reaffirmed oxidative stress-mediated apoptosis, while upregulation of nuclear factor NF-κB and cyclo-oxygenase (COX)-2 expressions, along with ~41% accumulation of early and late phase apoptotic cells, confirmed ischemic stress-mediated cell death. Stressed neuronal cells were rescued from death when cocultured with MSCs via increased expression of anti-inflammatory cytokines (TGF-β, 17%; IL-6, 4%; and IL-10, 13%), significantly downregulated NF-κB and proinflammatory COX-2 expression. Further accumulation of early and late apoptotic cells was diminished to 23%, while corresponding cell death decreased from 40% to 17%. Low superoxide dismutase 1 (SOD1) expression at the mRNA level was rescued by MSCs coculture, while no significant changes were observed with catalase (CAT) and glutathione peroxidase (GPx). Interestingly, increased serotonin release into the culture supernatant was proportionate to the elevated [Ca2+]i and corresponding ROS, which were later rescued by the MSCs coculture to near normalcy. Taken together, all of these results primarily support MSCs-mediated modulation of stressed neuronal cell survival in vitro.

Dataset Information

Painting factor H onto mesenchymal stem cells protects the cells from complement- and neutrophil-mediated damage.

Publications

Painting factor H onto mesenchymal stem cells protects the cells from complement- and neutrophil-mediated damage.

Similar Datasets

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