scholarly journals Mesenchymal stem cells alleviate hypoxia-induced oxidative stress and enhance the pro-survival pathways in porcine islets

2019 ◽  
Vol 244 (9) ◽  
pp. 781-788 ◽  
Author(s):  
Yixiong Tan ◽  
Wei Nie ◽  
Cheng Chen ◽  
Xuesong He ◽  
Yuzhi Xu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stem Cells ◽  
Cell Death ◽  
Mesenchymal Stem Cells ◽  
Islet Transplantation ◽  
Therapeutic Effects ◽  
Ros Production ◽  
Survival Pathways ◽  
Clinical Islet Transplantation ◽  
And Oxidative Stress

Islet transplantation is a promising treatment for selected patients with type 1 diabetes mellitus (T1DM). Hypoxia and oxidative stress are major causes of damage to transplanted islets. Mesenchymal stem cells (MSCs) have been shown to enhance cell survival mainly through paracrine secretion. However, mechanisms of action underlying the protective effects of MSCs on islets have not been fully elucidated. In this study, we investigated whether human umbilical cord-derived MSCs (huc-MSCs) could inhibit hypoxia and ROS-related cell death of neonatal porcine islet cell clusters (NICCs) and further determined the underlying molecular mechanisms. NICCs were cultured in vitro under normoxic and hypoxic (1% O2) conditions with or without MSC-conditioned medium (MSC-CM). Apoptosis of NICCs was evaluated by the AO/EB staining and Annexin V/PI flow cytometry analysis. Total and mitochondrial ROS production was detected by fluorometric assays. Western blot and the ERK pathway inhibitor, PD98059, were used to assess the possible pathways involved. The results showed that MSC-CM suppressed hypoxia-induced oxidative stress and cell death of NICCs. MSC-CM also activated several pro-survival pathways in NICCs under hypoxic conditions. Furthermore, MSC-secreted exosomes and IL-6 partially recapitulated the multifunctional benefits of MSC-CM. This study showed that huc-MSCs protected NICCs from hypoxia-induced cell death by regulating the cell redox state and cell signaling pathways. This increased understanding may enable MSCs to become a more promising adjuvant cell therapy for islet transplantation. Impact statement The utilization of mesenchymal stem cells (MSCs) is a promising approach to serve as adjuvant therapy for islet transplantation. But the inability to translate promising preclinical results into sound therapeutic effects in human subjects indicates a lack of key knowledge of MSC-islet interactions that warrant further research. Hypoxia and oxidative stress are critical factors which lead to a tremendous loss of islet grafts. However, previous studies mainly focused on other aspects of MSC protection such as inducing revascularization, enhancing insulin secretion, and reducing islet apoptosis. In this study, we aim to investigate whether MSC can protect islet cells from hypoxic damage by inhibiting ROS production and the potential underlying pathways involved. We also explore the effects of MSC-derived exosomes and IL-6 on hypoxia-injured islets. Our data provide new molecular targets for developing MSC applications, and this may ultimately promote the efficiency of clinical islet transplantation.

scholarly journals CHIP Reverses Hyperglycemia-associated PTEN Stability in Wharton's Jelly Derived Mesenchymal Stem Cells and Promotes Its Therapeutic Potential Against Diabetes-induced Cardiac Injury

2021 ◽  
Author(s):  
Ayaz Ali ◽  
Wei-Wen Kuo ◽  
Chia-Hua Kuo ◽  
Jeng-Feng Lo ◽  
Ray-Jade Chen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Cardiac Injury ◽  
Wharton’S Jelly ◽  
Therapeutic Effects ◽  
Downstream Signaling ◽  
Wharton's Jelly ◽  
Induced Apoptosis ◽  
And Oxidative Stress

Abstract BackgroundRecent studies indicate that umbilical cord stem cells are cytoprotective against several disorders. One critical limitation in using stem cells is reduction in their viability under stressful conditions, such as diabetes. However, the molecular intricacies responsible for diabetic conditions are not fully elucidated.MethodsEffects of HG on Wharton's jelly derived mesenchymal stem cells (WJMSCs) viability was evaluated by MTT assay and flow cytometry. The mechanism responsible for HG-induced PTEN degradation was assessed using loss and gain of function, immunofluorescence, co-immunoprecipitation, and western blot analysis. Co-culturing of CHIP-overexpressed WJMSCs with embryo derived cardiomyoblasts was performed to analyze their ameliorative effects. The therapeutic effects of CHIP expressing WJMSCs were further validated in Sprague Dawley male (eight weeks old) STZ-induced diabetic animals by echocardiography, immunohistochemistry, hematoxylin eosin, and masson’s trichrome and TUNEL staining. Multiple comparisons were accessed through one‐way ANOVA and p-Value of <0.05 was considered statistically significant. ResultsIn this study, we found that high glucose (HG) conditions induced loss of chaperone homeostasis, stabilized PTEN, triggered the downstream signaling cascade, and induced apoptosis and oxidative stress in Wharton's jelly derived mesenchymal stem cells (WJMSCs). Increased CHIP expression promoted PTEN degradation via the ubiquitin-proteasome system and shortened its half-life during HG stress. Docking studies confirmed the interaction of CHIP with PTEN and FOXO3a with the Bim promoter region. Further, it was found that the chaperone system is involved in CHIP-mediated PTEN proteasomal degradation. CHIP depletion stabilizes PTEN whereas PTEN inhibition showed an inverse effect. CHIP overactivation suppressed the binding of FOXO3a with bim. Co-culturing CHIP overexpressed WJMSCs suppressed HG-induced apoptosis and oxidative stress in cardiac cells. Finally, CHIP overexpression and PTEN inhibition minimized blood glucose levels, improved body and heart weight, and rescued hyperglycemia-induced cardiac injury in diabetic rats. ConclusionThe current study suggests that CHIP confers resistance to apoptosis and oxidative stress and modulates PTEN and the downstream signaling cascade by promoting PTEN proteasomal degradation, thereby potentially exerting therapeutic effects against diabetes-induced cardiomyopathies.

scholarly journals Adipose-Derived Mesenchymal Stem Cells Migrate and Rescue RPE in the Setting of Oxidative Stress

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Aya Barzelay ◽  
Shira Weisthal Algor ◽  
Anat Niztan ◽  
Sebastian Katz ◽  
Moshe Benhamou ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stem Cells ◽  
Cell Death ◽  
Mesenchymal Stem Cells ◽  
Conditioned Medium ◽  
Early Passage ◽  
Systemic Injection ◽  
Rpe Cells

Oxidative stress leads to the degeneration of retinal pigment epithelial (RPE) and photoreceptor cells. We evaluated the potential of adipose-derived mesenchymal stem cells (ASCs) as a therapeutic tool by studying the migration capacity of ASCs in vitro and their protective effect against RPE cell death under oxidative stress in vitro and in vivo. ASCs exhibited enhanced migration when exposed to conditioned medium of oxidative stressed RPE cells obtained by hydrogen peroxide. Migration-related axis SDF-1/CXCR4 was studied, and upregulation of SDF-1 in stressed RPE and of CXCR4 in ASCs was detected. Moreover, ASCs’ conditioned medium prevented H2O2-induced cell death of RPE cells. Early passage ASCs had high expression level of HGF, low VEGF levels, and unmodulated IL-1β levels, compared to late passage ASCs. Thus, early passage ASCs show the potential to migrate towards damaged RPE cells and protect them in a paracrine manner from cell death induced by oxidative stress. In vivo, mice received systemic injection of NaIO3, and 72 h later, ASCs were transplanted in the subretinal space. Seven days after ASC transplantation, the eyes were enucleated fixed and frozen for immunohistochemical analysis. Under such conditions, ASC-treated mice showed preservation of nuclear layers in the outer nuclear layer and stronger staining of RPE and photoreceptor layer, compared to PBS-treated mice. Taken together, our results indicate that ASCs are able to home in on damaged RPE cells and protect against damage to the RPE and PR layers caused by oxidative stress. These data imply the potential that ASCs have in regenerating RPE under oxidative stress, providing the basis for a therapeutic approach to retinal degeneration diseases related to oxidative stress that could help save the eyesight of millions of people worldwide.

Mesenchymal stem cells inhibited the inflammation and oxidative stress in LPS-activated microglial cells through AMPK pathway

2019 ◽  
Vol 126 (12) ◽  
pp. 1589-1597 ◽  
Author(s):  
Dayong Cao ◽  
Haowen Qiao ◽  
Dejiao He ◽  
Xingping Qin ◽  
Qian Zhang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Microglial Cells ◽  
Ampk Pathway ◽  
And Oxidative Stress

scholarly journals Spleen, as an Optimal Site for Islet Transplantation and a Source of Mesenchymal Stem Cells

2018 ◽  
Author(s):  
Naoaki Sakata ◽  
Gumpei Yoshimatsu ◽  
Shohta Kodama
Keyword(s):  
Diabetes Mellitus ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Islet Transplantation ◽  
Clinical Success ◽  
Severe Diabetes ◽  
Clinical Islet Transplantation ◽  
Long Time ◽  
Optimal Site

In this review, we show the unique potential of spleen as an optimal site for islet transplantation and a source of mesenchymal stem cells. Islet transplantation is a cellular replacement therapy to treat severe diabetes mellitus, but its clinical outcome is unsatisfactory at present. One factor in clinical success of this therapy is selection of the most appropriate transplantation site. The spleen has been studied for a long time as a candidate site for islet transplantation. Its advantages include physiological insulin drainage and regulation of immunity. Recently it has also been shown that the spleen contributes to the regeneration of transplanted islets. The efficacy of transplantation is not as high as that obtained with intraportal transplantation, which is the current representative method of clinical islet transplantation. Safer and more effective methods of islet transplantation need to be established before the spleen can be effectively used in the clinic. Spleen also has an interesting aspect as a mesenchymal stem cell reservoir. The splenic mesenchymal stem cells contribute to tissue repair in damaged tissue, and thus, the infusion can be a promising therapy for autoimmune diseases, including type 1 diabetes mellitus and Sjogren&rsquo;s syndrome.

scholarly journals How the Pathological Microenvironment Affects the Behavior of Mesenchymal Stem Cells in the Idiopathic Pulmonary Fibrosis

2020 ◽  
Vol 21 (21) ◽  
pp. 8140
Author(s):  
Martina Bonifazi ◽  
Mariangela Di Vincenzo ◽  
Miriam Caffarini ◽  
Federico Mei ◽  
Michele Salati ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Chronic Disease ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Cell Types ◽  
And Control ◽  
And Oxidative Stress

Idiopathic pulmonary fibrosis (IPF) is a chronic disease characterized by fibroblasts activation, ECM accumulation, and diffused alveolar inflammation. The role of inflammation in IPF is still controversial and its involvement may follow nontraditional mechanisms. It is seen that a pathological microenvironment may affect cells, in particular mesenchymal stem cells (MSCs) that may be able to sustain the inflamed microenvironment and influence the surrounding cells. Here MSCs have been isolated from fibrotic (IPF-MSCs) and control (C-MSCs) lung tissue; first cells were characterized and compared by the expression of molecules related to ECM, inflammation, and other interdependent pathways such as hypoxia and oxidative stress. Subsequently, MSCs were co-cultured between them and with NHLF to test the effects of the cellular crosstalk. Results showed that pathological microenvironment modified the features of MSCs: IPF-MSCs, compared to C-MSCs, express higher level of molecules related to ECM, inflammation, oxidative stress, and hypoxia; notably, when co-cultured with C-MSCs and NHLF, IPF-MSCs are able to induce a pathological phenotype on the surrounding cell types. In conclusion, in IPF the pathological microenvironment affects MSCs that in turn can modulate the behavior of other cell types favoring the progression of IPF.

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