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Anti-inflammatory effects of bone marrow mesenchymal stem cells on mice with Alzheimer's disease.

ABSTRACT: Anti-inflammatory effects of bone marrow mesenchymal stem cells (BMSCs) on mice with Alzheimer's disease (AD) were investigated. Twenty amyloid precursor protein (APP)/presenilin-1 (PS1) double transgenic mice were randomly divided into two groups: the AD control group and the stem cell treatment group. The normal control group consisted of 10 non-transgenic mice. The stem cell treatment group was injected with BMSCs, and the two control groups were given the same volume of normal saline. The Morris water maze test was used to compare the memory function of mice, and the relative expression levels of ?-site APP cleaving enzyme 1 (BACE1) and ?-2-macroglobulin (A2M) genes were detected by fluorescence quantitative polymerase chain reaction (qPCR). Amyloid ? (A?)1-42 content in brain tissues of mice and inflammatory cytokines, interleukin (IL)-1, IL-2, IL-10, tumor necrosis factor-? (TNF-?), and interferon-? (IFN-?) were detected using enzyme-linked immunosorbent assay (ELISA). Compared with that in the AD control group, the escape latency in the water maze in the stem cell treatment group was shortened, the time of crossing the ring for the first time was decreased, but the frequency of crossing the ring was increased (P<0.05). A?1-42 content in the AD control group was higher than that in the stem cell treatment group and the normal control group (P<0.05). The relative expression level of BACE1 gene in the stem cell treatment group was lower than that in the AD control group (P<0.05), but that of A2M gene was increased (P<0.05). At 14 days after treatment, the contents of IL-1, IL-2, TNF-? and IFN-? in blood in the stem cell treatment group were lower than those in the AD control group (P<0.05). Human BMSCs can ameliorate the symptoms of AD by decreasing the levels of inflammatory cytokines and regulating the expression of A?-related genes.

SUBMITTER: Wei Y

PROVIDER: S-EPMC6257159 | biostudies-other | 2018 Dec

REPOSITORIES: biostudies-other

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Anti-inflammatory effects of bone marrow mesenchymal stem cells on mice with Alzheimer's disease.

Wei Yan Y Xie Zhaohong Z Bi Jianzhong J Zhu Zhengyu Z

Experimental and therapeutic medicine 20181012 6

Anti-inflammatory effects of bone marrow mesenchymal stem cells (BMSCs) on mice with Alzheimer's disease (AD) were investigated. Twenty amyloid precursor protein (APP)/presenilin-1 (PS1) double transgenic mice were randomly divided into two groups: the AD control group and the stem cell treatment group. The normal control group consisted of 10 non-transgenic mice. The stem cell treatment group was injected with BMSCs, and the two control groups were given the same volume of normal saline. The Mo ...[more]

PMID: 30542456

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Project description:BackgroundBone marrow-derived mesenchymal stem cells (BMSCs)-derived extracellular vesicles (EVs) have shown potent anti-inflammatory function in various pathological conditions, such as osteoarthritis and neurodegenerative diseases. Since the number of EVs naturally secreted by cells is finite and they usually bear specific repertoires of bioactive molecules to perform manifold cell-cell communication, but not one particular therapeutic function as expected, their practical application is still limited. Strategies are needed to increase the production of EVs and enhance their therapeutic function. Recent studies have suggested that low-intensity pulsed ultrasound (LIPUS) is a promising non-invasive method to increase the secretion of EVs and promote their anti-inflammatory effects. However, the effect of LIPUS stimulation of BMSCs on EVs derived from the cells remains unclear. The objective of this study was to investigate whether LIPUS stimulation on BMSCs could increase the secretion of EVs and enhance their anti-inflammatory effects.MethodsBMSCs were exposed to LIPUS (300 mW/cm2) for 15 min and EVs were isolated by ultracentrifugation. Anti-inflammatory effects of EVs were investigated on RAW264.7 cells in vitro and in the allogeneic skin transplantation model. Small RNA-seq was utilized to identify components difference in EVs with/without LIPUS irradiation.ResultsIn this study, we found that LIPUS stimulation could lead to a 3.66-fold increase in the EVs release from BMSCs. Moreover, both in vitro and in vivo experimental results suggested that EVs secreted from LIPUS-treated BMSCs (LIPUS-EVs) possessed stronger anti-inflammatory function than EVs secreted from BMSCs without LIPUS stimulation (C-EVs). RNA-seq analysis revealed that miR-328-5p and miR-487b-3p were significantly up-regulated in LIPUS-EVs compare with C-EVs. The suppression of MAPK signaling pathway by these two up-regulated miRNAs could be the potential mechanism of strengthened anti-inflammatory effects of LIPUS-EVs.ConclusionLIPUS stimulation on BMSCs could significantly increase the secretion of EVs. Moreover, EVs generated from LIPUS-treated BMSCs possessed much stronger anti-inflammatory function than C-EVs. Therefore, LIPUS could be a promising non-invasive strategy to promote the production of EVs from BMSCs and augment their anti-inflammatory effects.

Project description:Parkinson's disease (PD) is characterized by a selective loss of dopamine (DA) neurons in the human midbrain causing motor dysfunctions. The exact mechanism behind dopaminergic cell death is still not completely understood and, so far, no cure or neuroprotective treatment for PD is available. Recent studies have brought attention to the variety of bioactive molecules produced by mesenchymal stem cells (MSCs), generally referred to as the secretome. Herein, we evaluated whether human MSCs-bone marrow derived (hBMSCs) secretome would be beneficial in a PD pre-clinical model, when compared directly with cell transplantation of hBMSCs alone. We used a 6-hydroxydpomanie (6-OHDA) rat PD model, and motor behavior was evaluated at different time points after treatments (1, 4, and 7 weeks). The impact of the treatments in the recovery of DA neurons was estimated by determining TH-positive neuronal densities in the substantia nigra and fibers in the striatum, respectively, at the end of the behavioral characterization. Furthermore, we determined the effect of the hBMSCs secretome on the neuronal survival of human neural progenitors in vitro, and characterized the secretome through proteomic-based approaches. This work demonstrates that the injection of hBMSCs secretome led to the rescue of DA neurons, when compared to transplantation of hBMSCs themselves, which can explain the recovery of secretome-injected animals' behavioral performance in the staircase test. Moreover, we observed that hBMSCs secretome induces higher levels of in vitro neuronal differentiation. Finally, the proteomic analysis revealed that hBMSCs secrete important exosome-related molecules, such as those related with the ubiquitin-proteasome and histone systems. Overall, this work provided important insights on the potential use of hBMSCs secretome as a therapeutic tool for PD, and further confirms the importance of the secreted molecules rather than the transplantation of hBMSCs for the observed positive effects. These could be likely through normalization of defective processes in PD, namely proteostasis or altered gene transcription, which lately can lead to neuroprotective effects.

Project description:PURPOSE: To investigate the modulatory effect of rat bone marrow mesenchymal stem cells (MSC) on human corneal epithelial cells (HCE-T) stimulated with pro-inflammatory cytokines interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) in an in vitro co-cultured model. METHODS: HCE-T alone and co-cultured with MSC were stimulated with IFN-γ/TNF for 24 and 48 hours or left untreated. The expression of intracellular adhesion molecule (ICAM)-1, human leukocyte antigen ABC, DR and G (HLA-ABC, HLA-DR, HLA-G) were investigated by flow cytometry. Subcellular localization of nuclear factor-kappa B (NF-κB) and expression of indoleamine 2,3-dioxygenase (IDO) were assessed by immunofluorescence staining and western blot. The concentration of transforming growth factor beta 1 (TGF-β1) in the conditioned media from different cultures was evaluated by enzyme-linked immunosorbent assay. NF-κB and TGF-β1 signaling pathway blocking experiments were performed to analyze associations between the expression of cell surface molecules and the NF-κB transcription pathway, and the expression of IDO and TGF-β1 signaling pathway. RESULTS: IFN-γ/TNF treatment significantly up-regulated expression of ICAM-1, HLA-ABC, and induced de novo expression of HLA-DR and IDO on HCE-T cultured alone, while HLA-G expression remained unaffected. Up-regulation was significantly inhibited by co-culture with MSC. Increased TGF-β1 secretion was detected in 48 h IFN-γ/TNF-stimulated MSC monocultures and HCE-T/MSC co-cultures. MSC attenuated the activation of cytokine-induced NF-κB and IDO induction. Blockade of NF-κB transcription pathway by BMS-345541 significantly reduced the up-regulation of ICAM-1, HLA-ABC, HLA-DR and IDO expression, while blockade of TGF-β1 signaling pathways reversed the modulatory effect of MSC on IDO expression. CONCLUSIONS: MSC reduced the expression of adhesion and immunoregulatory molecules on pro-inflammatory cytokine-stimulated HCE-T via the NF-κB transcription pathway. MSC attenuated expression of IDO through both NF-κB transcription and TGF-β1 signaling pathways. Co-culture of HCEC with MSC therefore provides a useful in vitro model to study the anti-inflammatory properties of MSC on corneal epithelium.

Project description:Parkinson’s disease (PD) is characterized by a selective loss of dopamine (DA) neurons in the human midbrain causing motor dysfunctions. The exact mechanism behind dopaminergic cell death is still not completely understood and, so far, no cure or neuroprotective treatment for PD is available. Recent studies have brought attention to the wide array of bioactive molecules produced by mesenchymal stem cells (MSCs), generally referred to as the secretome. Herein, we evaluated whether human MSCs-bone marrow derived (hBMSCs) secretome would be beneficial in a PD pre-clinical model, when compared directly with cell transplantation of hBMSCs alone. We used a 6-hydroxydpomanie (6-OHDA) rat PD model, and motor behavior was evaluated at different time points after treatments (1, 4 and 7 weeks). The impact of the treatments in the recovery of DA neurons was estimated by determining TH-positive neuronal densities in the substantia nigra and fibers in the striatum, respectively, at the end of the behavioral characterization. Furthermore, we determined the effect of the hBMSCs secretome on the neuronal survival of human neural progenitors in vitro, and characterized the secretome through proteomic-based approaches. This work demonstrates that the injection of hBMSCs secretome potentiated the histological recovery of DA neurons, when compared to transplantation of hBMSCs themselves, a fact that probably explains the improved behavioral performance of secretome-injected animals in the staircase test. Moreover, we observed that hBMSCs secretome induces higher levels of in vitro neuronal differentiation. Finally, the proteomic analysis revealed that hBMSCs secrete a variety of important exosome-related molecules such as those related with the ubiquitin-proteasome and histone systems. Overall, this work provided important insights on the potential use of hBMSCs secretome as a therapeutic tool for PD, and further confirms the importance of the secreted molecules rather than the transplantation of hBMSCs for the observed positive effects. These could be likely through normalization of defective processes in PD, namely proteostasis or altered gene transcription, which lately can lead to neuroprotective effects.

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Anti-inflammatory effects of bone marrow mesenchymal stem cells on mice with Alzheimer's disease.

Publications

Anti-inflammatory effects of bone marrow mesenchymal stem cells on mice with Alzheimer's disease.

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