Combining neuropeptide Y and mesenchymal stem cells reverses remodeling after myocardial infarction

Neuropeptide Y (NPY) induced reentry of differentiated rat neonatal and adult cardiomyocytes into the cell cycle. NPY also induced differentiation of bone marrow-derived mesenchymal stem cells (MSC) into cardiomyocytes following transplantation into infarcted myocardium. Rat neonatal and adult cardiomyocytes were treated in vitro with vehicle, NPY, fibroblast growth factor (FGF; 100 ng/ml), or FGF plus NPY. DNA synthesis, mitosis, and cytokinesis were determined by immunocytochemistry. NPY-induced MSC gene expression, cell migration, tube formation, and endothelial cell differentiation were analyzed. Male rat green fluorescent protein-MSC (2 × 106), pretreated with either vehicle or NPY (10−8 M) for 72 h, were injected into the border zone of the female myocardium following left anterior descending artery ligation. On day 30, heart function was assessed, and hearts were harvested for histological and immunohistochemical analyses. NPY increased 5-bromo-2′-deoxy-uridine incorporation and promoted both cytokinesis and mitosis in rat neonatal and adult myocytes. NPY also upregulated several genes required for mitosis in MSC, including aurora B kinase, FGF-2, cycline A2, eukaryotic initiation factor 4 E, and stromal cell-derived factor-1α. NPY directly induced neonatal and adult cardiomyocyte cell-cycle reentry and enhanced the number of differentiated cardiomyocytes from MSC in the infarcted myocardium, which corresponded to improved cardiac function, reduced fibrosis, ventricular remodeling, and increased angiomyogenesis. It is concluded that a combined treatment of NPY with MSC is a novel approach for cardiac repair.

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High Glucose Affects the Cytotoxic Potential of Rapamycin, Metformin and Hydrogen Peroxide in Cultured Human Mesenchymal Stem Cells

Current Molecular Medicine ◽

10.2174/1566524019666190722115842 ◽

2019 ◽

Vol 19 (9) ◽

pp. 688-698 ◽

Cited By ~ 1

Author(s):

Azam Roohi ◽

Mahin Nikougoftar ◽

Hamed Montazeri ◽

Shadisadat Navabi ◽

Fazel Shokri ◽

...

Keyword(s):

Cell Cycle ◽

Hydrogen Peroxide ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Cell Viability ◽

High Glucose ◽

Cell Cycle Distribution ◽

Efficient Treatment ◽

Chronic Hyperglycemia ◽

Placental Mesenchymal Stem Cells

Background: Oxidative stress and chronic hyperglycemia are two major side effects of type 2 diabetes affecting all cell types including mesenchymal stem cells (MSCs). As a cell therapy choice, understanding the behavior of MSCs will provide crucial information for efficient treatment. Methods: Placental mesenchymal stem cells were treated with various concentrations of glucose, metformin, rapamycin, and hydrogen peroxide to monitor their viability and cell cycle distribution. Cellular viability was examined via the MTT assay. Cell cycle distribution was studied by propidium iodide staining and apoptosis was determined using Annexin Vpropidium iodide staining and flow cytometry. Involvement of potential signaling pathways was evaluated by Western blotting for activation of Akt, P70S6K, and AMPK. Results: The results indicated that high glucose augmented cell viability and reduced metformin toxic potential. However, the hydrogen peroxide and rapamycin toxicities were exacerbated. Conclusion: Our findings suggest that high glucose concentration has a major effect on placental mesenchymal stem cell viability in the presence of rapamycin, metformin and hydrogen peroxide in culture.

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THU0495 NOVEL UNDERSTANDING OF THE PATHOGENESIS OF JUVENILE IDIOPATHIC ARTHRITIS: FOCUS ON MESENCHYMAL STEM CELLS IMPAIRMENT, SENESCENCE AND IMMUNOREGULATORY FUNCTION

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.3845 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 483.2-484

Author(s):

L. Zaripova ◽

A. Midgley ◽

S. Christmas ◽

E. Baildam ◽

R. Oldershaw

Keyword(s):

Oxidative Stress ◽

Cell Cycle ◽

Stem Cells ◽

Cell Proliferation ◽

Mesenchymal Stem Cells ◽

Juvenile Idiopathic Arthritis ◽

Metabolic Activity ◽

Healthy Controls ◽

High Level ◽

Pro Inflammatory Cytokines

Background:Juvenile idiopathic arthritis (JIA) is a well-known chronic rheumatic disease of childhood characterised by progressive joint destruction and severe systemic complications.Immune cells are known to trigger the pathophysiological cascade in JIA, but there is little information regarding the contribution made by Mesenchymal stem cells (MSCs). These cells are able to modulate the immune response and decrease the level of pro-inflammatory cytokines. With addition of regenerative property it makes MSCs potential candidates for clinical application as immunosuppressants in treatment of autoimmune diseases.Objectives:To investigate MSCs proliferation, viability and immunomodulatory function in JIA and healthy children.Methods:MSCs were separated from peripheral blood (PB) and synovial fluid (SF) of JIA patients and healthy controls. Cell proliferation rate was counted by Population doublings per day (PDD) during 9 days, in the last of which alamarBlue™ assays were performed to assess cell viability. Due to measure senescence MSCs were stained with SA-β-galactosidase. Immunofluorescence was used to examine the expression of p16, p21, p53. Oxidative stress was measured with DCFH-DA. Cell cycle analysis was evaluated with Propidium Iodide and analysed by Accuri® C6 Flow Cytometer.Commercially-available bone marrow mesenchymal stem cells (BM-MSCs) were treated with graded concentrations of pro-inflammatory cytokines (0.1-100 ng/ml) with following examination of cell viability. Mixed lymphocyte reactions (MLR) were performed to measure MSC immunomodulatory abilityin vitro.Results:The growth kinetics of JIA-MSCs were different from healthy controls. JIA-MSCs divided slowly and appeared disorganised with large cytoplasm and loads of outgrowth. They demonstrated a decrease in cell proliferation (negative PDD) and metabolic activity. Difference in growth kinetics and metabolic activity were found inside the JIA PB group with some evidence of response following biological treatment. Thus, PB-MSCs from patients treated with TNFi and anti-IL6 medications had notably higher cell proliferation and metabolic activity against JIA patients received other therapy. Considering this difference, it was hypothesised that cytokines obtained in a high amount in PB and SF of JIA patients may influence MSCs viability. To prove this BM-MSCs were treated with cytokines and demonstrated a dose-dependent decrease in metabolic activity significantly after TNFα and IL1, no significantly after treatment with IL6. Both BM-MSCs treated with cytokines and JIA-MSCs displayed high level of reactive oxygen species.Cell cycle analysis revealed that JIA-MSCs were arrested in G0/G1 phase with low number of mitotic cells. In addition, the number of senescence-associated SA-β-gal-positive cells was notably higher in JIA-MSCs. Furthermore, JIA-MSCs expressed high level of immunofluorescence for p16, p21 and p53 which played an important role in regulating the senescence progress of MSCs.Results of MLR showed the ability of BM-MSCs to decrease the percentage of activated T-helpers, T-suppressors, B-cells and natural killers proliferation, while JIA-MSCs lost this property.Conclusion:Taken together current research has demonstrated that under the influence of proinflammatory cytokines JIA-MSCs suffered from oxidative stress and disruption of metabolic activity acquire senescent morphology, shorten of telomere length, arrest in G0 phase of cell cycle and finally loss of immune regulation. We are continuing our research to determine the mechanisms that are responsible for the impaired phenotype with the aim of identifying new therapeutic strategies for the treatment of JIA.Disclosure of Interests: :None declared

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Mesenchymal Stem Cells Delivered With Alginate Hydrogel Improves Conduction at the Border Zone of Healed MI

Heart Rhythm ◽

10.1016/j.hrthm.2010.09.034 ◽

2010 ◽

Vol 7 (11) ◽

pp. 1714

Author(s):

Nikhil C. Panda ◽

Sean Zuckerman ◽

KeKe Fan ◽

Devi Gopinath ◽

David S. Rosenbaum ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Border Zone ◽

Alginate Hydrogel

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Palmitate Causes Endoplasmic Reticulum Stress and Apoptosis in Human Mesenchymal Stem Cells: Prevention by AMPK Activator

Endocrinology ◽

10.1210/en.2012-1418 ◽

2012 ◽

Vol 153 (11) ◽

pp. 5275-5284 ◽

Cited By ~ 41

Author(s):

Jun Lu ◽

Qinghua Wang ◽

Lianghu Huang ◽

Huiyue Dong ◽

Lingjing Lin ◽

...

Keyword(s):

Stem Cells ◽

Endoplasmic Reticulum ◽

Mesenchymal Stem Cells ◽

Protein Kinase ◽

Er Stress ◽

Human Mesenchymal Stem Cells ◽

Translation Initiation Factor ◽

Initiation Factor ◽

Human Umbilical Cord ◽

Amp Activated Protein Kinase

Abstract Elevated circulating saturated fatty acids concentration is commonly associated with poorly controlled diabetes. The highly prevalent free fatty acid palmitate could induce apoptosis in various cell types, but little is known about its effects on human mesenchymal stem cells (MSCs). Here, we report that prolonged exposure to palmitate induces human bone marrow-derived MSC (hBM-MSC) and human umbilical cord-derived MSC apoptosis. We investigated the role of endoplasmic reticulum (ER) stress, which is known to promote cell apoptosis. Palmitate activated XBP1 splicing, elF2α (eukaryotic translation initiation factor 2α) phosphorylation, and CHOP, ATF4, BiP, and GRP94 transcription in hBM-MSCs. ERK1/2 and p38 MAPK phosphorylation were also induced by palmitate in hBM-MSCs. A selective p38 inhibitor inhibited palmitate activation of the ER stress, whereas the ERK1/2 inhibitors had no effect. The AMP-activated protein kinase activator aminoimidazole carboxamide ribonucleotide blocked palmitate-induced ER stress and apoptosis. These findings suggest that palmitate induces ER stress and ERK1/2 and p38 activation in hBM-MSCs, and AMP-activated protein kinase activator prevents the deleterious effects of palmitate by inhibiting ER stress and apoptosis.

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Transdifferentiation of mesenchymal stem cells-derived adipogenic-differentiated cells into osteogenic- or chondrogenic-differentiated cells proceeds via dedifferentiation and have a correlation with cell cycle arresting and driving genes

Differentiation ◽

10.1016/j.diff.2013.02.001 ◽

2013 ◽

Vol 85 (3) ◽

pp. 78-90 ◽

Cited By ~ 30

Author(s):

Mujib Ullah ◽

Stefan Stich ◽

Michael Notter ◽

Jan Eucker ◽

Michael Sittinger ◽

...

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Differentiated Cells

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Effect of Placental Extract on Omentum Mesenchymal Stem Cells Differentiation in NMRI Mice

Journal of Molecular Biology Research ◽

10.5539/jmbr.v7n1p176 ◽

2017 ◽

Vol 7 (1) ◽

pp. 176

Author(s):

Maryam Sadat Nezhadfazel ◽

Kazem Parivar ◽

Nasim Hayati Roodbari ◽

Mitra Heydari Nasrabadi

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Flow Cytometry ◽

Endothelial Cells ◽

Mesenchymal Stem Cells ◽

Control Group ◽

Fat Cell ◽

Nmri Mice ◽

Differentiated Cells ◽

Placental Extract

Omentum mesenchymal stem cells (OMSCs) could be induced to differentiate into cell varieties under certain conditions. We studied differentiation of OMSCs induced by using placenta extract in NMRI mice. Mesenchymal stem cells (MSCs) were isolated from omentum and cultured with mice placenta extract. MSCs, were assessed after three passages by flow cytometry for CD90, CD44, CD73, CD105, CD34 markers and were recognized their ability to differentiate into bone and fat cell lines. Placenta extract dose was determined with IC50 test then OMSCs were cultured in DMEM and 20% placenta extract.The cell cycle was checked. OMSCs were assayed on 21 days after culture and differentiated cells were determined by flow cytometry and again processed for flow cytometry. CD90, CD44, CD73, CD105 markers were not expressed, only CD34 was their marker. OMSCs were morphologically observed. Differentiated cells are similar to the endothelial cells. Therefore, to identify differentiated cells, CD31 and FLK1 expression were measured. This was confirmed by its expression. G1 phase of the cell cycle shows that OMSCs compared to the control group, were in the differentiation phase. The reason for the differentiation of MSCs into endothelial cells was the sign of presence of VEGF factor in the medium too high value of as a VEGF secreting source.

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Mesenchymal stem cells with overexpression of Angiotensin-converting enzyme-2 improved the microenvironment and cardiac function in a rat model of myocardial infarction

10.1101/2020.05.03.075283 ◽

2020 ◽

Author(s):

Chao Liu ◽

Yue Fan ◽

Hong-Yi Zhu ◽

Lu zhou ◽

Yu Wang ◽

...

Keyword(s):

Myocardial Infarction ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Angiotensin Converting Enzyme ◽

Cardiac Function ◽

Heart Function ◽

Tube Formation ◽

Border Zone ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2

AbstractBackgroundAngiotensin-converting enzyme-2 (ACE2) overexpression improves left ventricular remodeling and function in diabetic cardiomyopathy; however, the effect of ACE2-overexpressed mesenchymal stem cells (MSCs) on myocardial infarction (MI) remains unexplored. This study aimed to investigate the effect of ACE2-overexpression on the function of MSCs and the therapeutic efficacy of MSCs for MI.MethodsMSCs were transfected with Ace2 gene using lentivirus, and then transplanted into the border zone of ischemic heart. The renin-angiotensin system (RAS) expression, nitric oxide synthase (NOS) expression, paracrine factors, anti-hypoxia ability, tube formation of MSCs, and heart function were determined.ResultsMSCs expressed little ACE2. ACE2-overexpression decreased the expression of AT1 and VEGF apparently, up-regulated the paracrine of HGF, and increased the synthesis of Angiotensin 1-7 in vitro. ACE2-overexpressed MSCs showed a cytoprotective effect on cardiomyocyte, and an interesting tube formation ability, decreased the heart fibrosis and infarct size, and improved the heart function.ConclusionTherapies employing MSCs with ACE2 overexpression may represent an effective treatment for improving the myocardium microenvironment and the cardiac function after MI.

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Mesenchymal stem cells from human umbilical cord ameliorate testicular dysfunction in a male rat hypogonadism model

Asian Journal of Andrology ◽

10.4103/1008-682x.186186 ◽

2017 ◽

Vol 19 (5) ◽

pp. 543 ◽

Cited By ~ 5

Author(s):

Jie Sun ◽

Zhi-Yuan Zhang ◽

Xiao-Yu Xing ◽

Guan-Qun Ju ◽

Liang Zhong

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Umbilical Cord ◽

Male Rat ◽

Human Umbilical Cord ◽

Testicular Dysfunction

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Comparative characterization and osteogenic / adipogenic differentiation of mesenchymal stem cells derived from male rat hair follicles and bone marrow

Cell Regeneration ◽

10.1186/s13619-020-00051-7 ◽

2020 ◽

Vol 9 (1) ◽

Author(s):

Abdel Kader A. Zaki ◽

Tariq I. Almundarij ◽

Faten A. M. Abo-Aziza

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Stem Cell ◽

Adipogenic Differentiation ◽

Adult Stem Cell ◽

Cell Counting ◽

Population Doubling ◽

Male Rat ◽

Cell Source

AbstractClinical applications of cell therapy and tissue regeneration under different conditions need a multiplicity of adult stem cell sources. Up to date, little is available on the comparative isolation, characterization, proliferation, rapid amplification, and osteogenic/adipogenic differentiation of rat mesenchymal stem cells (MSCs) isolated from living bulge cells of the hair follicle (HF) and bone marrow (BM) from the same animal. This work hopes to use HF-MSCs as an additional adult stem cell source for research and application. After reaching 80% confluence, the cell counting, viability %, and yields of HF-MSCs and BM-MSCs were nearly similar. The viability % was 91.41 ± 2.98 and 93.11 ± 3.06 while the cells yield of initial seeding was 33.15 ± 2.76 and 34.22 ± 3.99 and of second passage was 28.76 ± 1.01 and 29.56 ± 3.11 for HF-MSCs and BM-MSCs respectively. Clusters of differentiation (CDs) analysis revealed that HF-MSCs were positively expressed CD34, CD73 and CD200 and negatively expressed CD45. BM-MSCs were positively expressed CD73 and CD200 and negatively expressed of CD34 and CD45. The proliferation of HF-MSCs and BM-MSCs was determined by means of incorporation of Brd-U, population doubling time (PDT) assays and the quantity of formazan release. The percentage of Brd-U positive cells and PDT were relatively similar in both types of cells. The proliferation, as expressed by the quantity of formazan assay in confluent cells, revealed that the quantity of release by BM-MSCs was slightly higher than HF-MSCs. Adipogenic differentiated BM-MSCs showed moderate accumulation of oil red-O stained lipid droplets when compared to that of HF-MSCs which exhibited high stain. The total lipid concentration was significantly higher in adipogenic differentiated HF-MSCs than BM-MSCs (P < 0.05). It was found that activity of bone alkaline phosphatase and calcium concentration were significantly higher (P < 0.01 and P < 0.05 respectively) in osteogenic differentiated BM-MSCs than that of HF-MSCs. The present findings demonstrate that the HF-MSCs are very similar in most tested characteristics to BM-MSCs with the exception of differentiation. Additionally; no issues have been reported during the collection of HF-MSCs. Therefore, the HF may represent a suitable and accessible source for adult stem cells and can be considered an ideal cell source for adipogenesis research.

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