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Liu G, Wang D, Jia J, Hao C, Ge Q, Xu L, Zhang C, Li X, Mi Y, Wang H, Miao L, Chen Y, Zhou J, Xu X, Liu Y. Neuroprotection of Human Umbilical Cord-Derived Mesenchymal Stem Cells (hUC-MSCs) in Alleviating Ischemic Stroke-Induced Brain Injury by Regulating Inflammation and Oxidative Stress. Neurochem Res 2024; 49:2871-2887. [PMID: 39026086 DOI: 10.1007/s11064-024-04212-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 07/10/2024] [Accepted: 07/11/2024] [Indexed: 07/20/2024]
Abstract
Brain injury caused by stroke has a high rate of mortality and remains a major medical challenge worldwide. In recent years, there has been significant attention given to the use of human Umbilical cord-derived Mesenchymal Stem Cells (hUC-MSCs) for the treatment of stroke in different adult and neonate animal models of stroke. However, using hUC-MSCs by systemic administration to treat ischemic stroke has not been investigated sufficiently. In this study, we conducted various experiments to explore the neuroprotection of hUC-MSCs in rats. Our findings demonstrate that an intravenous injection of a high dose of hUC-MSCs at 2 × 10^7 cells/kg markedly ameliorated brain injury resulting from ischemic stroke. This improvement was observed one day after inducing transient middle cerebral artery occlusion (MCAO) and subsequent reperfusion in rats. Notably, the efficacy of this single administration of hUC-MSCs surpassed that of edaravone, even when the latter was used continuously over three days. Mechanistically, secretory factors derived from hUC-MSCs, such as HGF, BDNF, and TNFR1, ameliorated the levels of MDA and T-SOD to regulate oxidative stress. In particular, TNFR1 also improved the expression of NQO-1 and HO-1, important proteins associated with oxidative stress. More importantly, TNFR1 played a significant role in reducing inflammation by modulating IL-6 levels in the blood. Furthermore, TNFR1 was observed to influence the permeability of the blood-brain barrier (BBB) as demonstrated in the evan's blue experiment and protein expression of ZO-1. This study represented a breakthrough in traditional methods and provided a novel strategy for clinical medication and trials.
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Affiliation(s)
- Guangyang Liu
- Stem Cell Biology and Regenerative Medicine Institution, Beijing YiChuang Institute of Bio-Industry, Beijing, China
| | - Daohui Wang
- Stem Cell Biology and Regenerative Medicine Institution, Beijing YiChuang Institute of Bio-Industry, Beijing, China
| | - Jianru Jia
- Baoding People's Hospital, Baoding, China
| | - Chunhua Hao
- State Key Laboratory of Drug Delivery and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, China
| | - Qinggang Ge
- Department of Critical Care Medicine, Peking University Third Hospital, Beijing, China
| | - Liqiang Xu
- Stem Cell Biology and Regenerative Medicine Institution, Beijing YiChuang Institute of Bio-Industry, Beijing, China
| | - Chenliang Zhang
- Stem Cell Biology and Regenerative Medicine Institution, Beijing YiChuang Institute of Bio-Industry, Beijing, China
| | - Xin Li
- Stem Cell Biology and Regenerative Medicine Institution, Beijing YiChuang Institute of Bio-Industry, Beijing, China
| | - Yi Mi
- Stem Cell Biology and Regenerative Medicine Institution, Beijing YiChuang Institute of Bio-Industry, Beijing, China
| | - Herui Wang
- Stem Cell Biology and Regenerative Medicine Institution, Beijing YiChuang Institute of Bio-Industry, Beijing, China
| | - Li Miao
- Stem Cell Biology and Regenerative Medicine Institution, Beijing YiChuang Institute of Bio-Industry, Beijing, China
| | - Yaoyao Chen
- Stem Cell Biology and Regenerative Medicine Institution, Beijing YiChuang Institute of Bio-Industry, Beijing, China
| | - Jingwen Zhou
- Stem Cell Biology and Regenerative Medicine Institution, Beijing YiChuang Institute of Bio-Industry, Beijing, China
| | - Xiaodan Xu
- Stem Cell Biology and Regenerative Medicine Institution, Beijing YiChuang Institute of Bio-Industry, Beijing, China
| | - Yongjun Liu
- Stem Cell Biology and Regenerative Medicine Institution, Beijing YiChuang Institute of Bio-Industry, Beijing, China.
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A-Elgadir TME, Shati AA, Alqahtani SA, Ebrahim HA, Almohaimeed HM, ShamsEldeeen AM, Haidara MA, Kamar SS, Dawood AF, El-Bidawy MH. Mesenchymal stem cells improve cardiac function in diabetic rats by reducing cardiac injury biomarkers and downregulating JAK/STAT/iNOS and iNOS/Apoptosis signaling pathways. Mol Cell Endocrinol 2024; 591:112280. [PMID: 38797354 DOI: 10.1016/j.mce.2024.112280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 05/18/2024] [Accepted: 05/24/2024] [Indexed: 05/29/2024]
Abstract
Cardiovascular complications are prevalent manifestations of type 2 diabetes mellitus (T2DM) and are usually the main cause of death. This study aims to show the underlying mechanisms of the potential therapeutic effect of mesenchymal stem cells (MSCs) on diabetic cardiac dysfunction. Twenty-four male Wistar rats were randomly assigned to one of three groups The control group received standard laboratory chow, and the groups with T2DM received a single dose of 45 mg/kg body weight of streptozotocin (STZ) after 3 weeks of pretreatment with a high-fat diet (HFD). Eight weeks after the diagnosis of T2DM, rats were divided into two groups: the T2DM model group and the T2DM + MSCs group. BM-MSCs were administered systemically at 2 × 106 cells/rat doses. A Significant amelioration in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and dyslipidemia was noted 2 weeks post-administration of MSCs. Administration of MSCs improved dyslipidemia, the altered cardiac injury biomarkers (p ≤ 0.0001), downregulated Janus kinase 2/signal transducer and activator of transcription 3(JAK2/STAT3)/inducible Nitric oxide synthase (iNOS) and iNOS/Apoptosis signaling pathways. This was associated with improved cardiac dysfunction (impaired left ventricular performance and decreased contractility index). Our results show that MSCs ameliorate cardiac dysfunction associated with diabetic cardiomyopathy by lowering dyslipidemia and insulin resistance, inhibiting oxidative stress, and inflammation, downregulating JAK2/STAT3/iNOS and iNOS/Apoptosis signaling pathways.
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Affiliation(s)
| | - Ayed A Shati
- Department of Child Health, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Saif Aboud Alqahtani
- Department of Internal Medicine, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Hasnaa A Ebrahim
- Department of Basic Medical Sciences, College of Medicine, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh, 11671, Saudi Arabia
| | - Hailah M Almohaimeed
- Department of Basic Medical Sciences, College of Medicine, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh, 11671, Saudi Arabia
| | - Asmaa M ShamsEldeeen
- Department of Physiology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mohamed A Haidara
- Department of Physiology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Samaa S Kamar
- Department of Histology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt; Department of Histology, Armed Forces College of Medicine
| | - Amal F Dawood
- Department of Basic Medical Sciences, College of Medicine, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh, 11671, Saudi Arabia.
| | - Mahmoud H El-Bidawy
- Department of Physiology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt; Department of BMS, Physiology Division, College of Medicine, Prince Sattam bin Abdulaziz University, Al-Kharj, 11942, Saudi Arabia
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Mesbah Mohamed M, Ahmed Rashed L, Ahmed El-Boghdady N, Mohamed Said M. Bone Marrow-Derived Mesenchymal Stem Cells and Pioglitazone or Exendin-4 Synergistically Improve Insulin Resistance via Multiple Modulatory Mechanisms in High-Fat Diet/Streptozotocin-Induced Diabetes in Rats. Rep Biochem Mol Biol 2023; 12:42-58. [PMID: 37724145 PMCID: PMC10505456 DOI: 10.52547/rbmb.12.1.42] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 01/18/2023] [Indexed: 09/20/2023]
Abstract
Background Diabetes mellitus (DM) is a metabolic disease, characterized by hyperglycemia resulting from defects in insulin secretion and/or insulin action. The current study was designed to assess the therapeutic potential of bone marrow-derived mesenchymal stem cells (BM-MSCs) alone and in combination with pioglitazone (Pz) or exendin-4 (Ex) in high-fat diet/streptozotocin (HFD/STZ)-induced diabetes in rats. Methods The rats were subjected to the HFD for three weeks before being injected with a single low dosage of STZ (35 mg/kg bw). The animals were assigned to different treatment groups after type II diabetes mellitus (T2DM) induction was confirmed. Results Severe insulin resistance was verified in untreated HFD/STZ T2DM rats, along with the exaggeration of oxidative stress, inflammation, apoptosis, and autophagy suppression in the adipose tissues. Monotherapy of HFD/T2DM rats with BM-MSCs and Pz or Ex alleviated diabetic complications by increasing insulin sensitivity, decreasing apoptosis and inflammation as evidenced by a decrease in serum tumor necrosis factor-alpha, caspase-3, and nuclear factor-kappa B (NF-κB) genes expression and Janus kinase (JNK) protein expression, and enhancing autophagy as revealed by upregulation in beclin and LC3, as well as peroxisome proliferator-activated receptor-γ coactivator-1 alpha (PGC-1α) genes expression in the adipose tissues. An augmented ameliorative efficacy was recorded in combined treatments. The biochemical and molecular results were confirmed by histological investigation of pancreatic tissues. Conclusions Combining Pz or Ex with BM-MSCs is a synergistic therapeutic option that reduces insulin resistance and subsequent complications in T2DM via multiple molecular mechanisms.
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Affiliation(s)
| | - Laila Ahmed Rashed
- Department of Medical Biochemistry, Faculty of Medicine, Cairo University, Cairo, Egypt.
| | | | - Mahmoud Mohamed Said
- Biochemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt.
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Mu C, Pochakom A, Reimer RA, Choudhary A, Wang M, Rho JM, Scantlebury MH, Shearer J. Addition of Prebiotics to the Ketogenic Diet Improves Metabolic Profile but Does Not Affect Seizures in a Rodent Model of Infantile Spasms Syndrome. Nutrients 2022; 14:2210. [PMID: 35684010 PMCID: PMC9182787 DOI: 10.3390/nu14112210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 05/18/2022] [Accepted: 05/19/2022] [Indexed: 12/04/2022] Open
Abstract
The ketogenic diet (KD) is an effective treatment for infantile spasms syndrome (IS). However, the KD has implications for somatic growth, development, and the gut microbiota. The impact of incorporating a prebiotic fiber (PRE, oligofructose-enriched inulin, 0.8 g/dL) into a KD diet on spasms, developmental milestones, fecal gut microbiota, metabolites, and hippocampal mitochondrial metabolism were examined. Following IS induction, animals were randomized to KD or KD + PRE diets. A third group without IS and suckled by dams was included as a normally developing reference group (R). PRE inclusion decreased ketones and increased circulating glucose levels but had no impact on spasms. In the liver, PRE increased triglyceride concentrations, decreased carnitine levels, and downregulated genes encoding enzymes responsible for ketogenesis. In the hippocampus, PRE increased glutathione levels but did not affect the maximal respiratory capacity of mitochondria. Analysis of the gut microbiota showed that KD + PRE increased microbial richness and the relative abundance of Bifidobacterium pseudolongum and Lactobacillus johnsonii. No differences in developmental milestones (i.e., surface righting, negative geotaxis, and open field behavior) were observed between KD and KD + PRE, except for ultrasonic vocalizations that were more frequent in KD + PRE. In summary, PRE did not impact spasms or developmental outcomes, but was effective in improving both metabolic parameters and gut microbiota diversity.
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Affiliation(s)
- Chunlong Mu
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada; (A.P.); (R.A.R.); (J.S.)
| | - Angela Pochakom
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada; (A.P.); (R.A.R.); (J.S.)
| | - Raylene A. Reimer
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada; (A.P.); (R.A.R.); (J.S.)
- Faculty of Kinesiology, University of Calgary, 2500 University Drive NW, Calgary, AB T2N 1N4, Canada
- Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada; (A.C.); (M.W.); (M.H.S.)
| | - Anamika Choudhary
- Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada; (A.C.); (M.W.); (M.H.S.)
- Department of Pediatrics, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada
| | - Melinda Wang
- Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada; (A.C.); (M.W.); (M.H.S.)
| | - Jong M. Rho
- Departments of Neurosciences, Pediatrics and Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA;
| | - Morris H. Scantlebury
- Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada; (A.C.); (M.W.); (M.H.S.)
- Department of Pediatrics, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada
- Department of Clinical Neurosciences, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada
| | - Jane Shearer
- Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada; (A.P.); (R.A.R.); (J.S.)
- Faculty of Kinesiology, University of Calgary, 2500 University Drive NW, Calgary, AB T2N 1N4, Canada
- Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada; (A.C.); (M.W.); (M.H.S.)
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Ahmed Y, Ali ZY, Mohamed MA, Rashed LA, Mohamed EK. Impact of combined therapy of mesenchymal stem cells and sitagliptin on a metabolic syndrome rat model. J Diabetes Metab Disord 2021; 20:551-560. [PMID: 34222076 DOI: 10.1007/s40200-021-00778-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 03/20/2021] [Indexed: 12/20/2022]
Abstract
Background Emerging evidence suggests that mesenchymal stem cells (MSCs) have many anti-inflammatory and regenerative properties, which makes it a suitable candidate for the treatment of many diseases including metabolic syndrome (MetS). However, a major difficulty with stem cell therapy is to maintain cell viability, properties and function after implantation in vivo. This study aims to test the hypothesis that the combined therapy of MSCs and sitagliptin can effectively ameliorate MetS complications induced by high-fat and high-fructose diet (HFFD) in rats. Methods Rats were fed either standard diet (Control group) or HFFD. After 3 months, a group of HFFD animals was injected by a single dose of MSCs, another group received a daily oral dose of 10 mg/kg b.w. of sitagliptin, and the third group received the combined therapy of MSCs + sitagliptin for 1 month. Results Both MSCs and sitagliptin restored insulin sensitivity and reduced the HOMA-IR value in HFFD rats. The hepatic IRS-1 and Akt at both gene and protein levels, as well as the hepatic protein levels of IR and GLUT4 were improved. Downregulation of CHOP and NF-κB and upregulation of hepatic HO-1 expression and activity were also reported. Although MSCs and sitagliptin as monotherapy lead to remarkable effects, the dual application revealed the best results. Interestingly, histological findings confirmed these protective effects of the combined therapy against MetS complications. Conclusion Combined therapy of MSCs and sitagliptin can efficiently ameliorate the insulin resistance and promote the regeneration of hepatocytes in the metabolic syndrome rat model.
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Affiliation(s)
- Yossra Ahmed
- King Saud University, Riyadh, Saudi Arabia.,Faculty of Science, Al-Azhar University (Girls Branch), Cairo, Egypt
| | - Zeinab Y Ali
- National Organization of Drug Control and Research, Cairo, Egypt
| | - Mona A Mohamed
- Biochemistry Unit, Chemistry Department, Faculty of Science, Al-Azhar University (Girls Branch), Cairo, Egypt
| | - Laila A Rashed
- Biochemistry Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Ehsan K Mohamed
- National Organization of Drug Control and Research, Cairo, Egypt
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Irion CI, Martins EL, Christie MLA, de Andrade CBV, de Moraes ACN, Ferreira RP, Pimentel CF, Suhett GD, de Carvalho ACC, Lindoso RS, Vieyra A, Galina A, Goldenberg RCS. Acute Myocardial Infarction Reduces Respiration in Rat Cardiac Fibers, despite Adipose Tissue Mesenchymal Stromal Cell Transplant. Stem Cells Int 2020; 2020:4327965. [PMID: 32655647 PMCID: PMC7322589 DOI: 10.1155/2020/4327965] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 03/02/2020] [Accepted: 03/18/2020] [Indexed: 02/08/2023] Open
Abstract
Adipose-derived mesenchymal stromal cell (AD-MSC) administration improves cardiac function after acute myocardial infarction (AMI). Although the mechanisms underlying this effect remain to be elucidated, the reversal of the mitochondrial dysfunction may be associated with AMI recovery. Here, we analyzed the alterations in the respiratory capacity of cardiomyocytes in the infarcted zone (IZ) and the border zone (BZ) and evaluated if mitochondrial function improved in cardiomyocytes after AD-MSC transplantation. Female rats were subjected to AMI by permanent left anterior descending coronary (LAD) ligation and were then treated with AD-MSCs or PBS in the border zone (BZ). Cardiac fibers were analyzed 24 hours (necrotic phase) and 8 days (fibrotic phase) after AMI for mitochondrial respiration, citrate synthase (CS) activity, F0F1-ATPase activity, and transmission electron microscopy (TEM). High-resolution respirometry of permeabilized cardiac fibers showed that AMI reduced numerous mitochondrial respiration parameters in cardiac tissue, including phosphorylating and nonphosphorylating conditions, respiration coupled to ATP synthesis, and maximal respiratory capacity. CS decreased in IZ and BZ at the necrotic phase, whereas it recovered in BZ and continued to drop in IZ over time when compared to Sham. Exogenous cytochrome c doubled respiration at the necrotic phase in IZ. F0F1-ATPase activity decreased in the BZ and, to more extent, in IZ in both phases. Transmission electron microscopy showed disorganized mitochondrial cristae structure, which was more accentuated in IZ but also important in BZ. All these alterations in mitochondrial respiration were still present in the group treated with AD-MSC. In conclusion, AMI led to mitochondrial dysfunction with oxidative phosphorylation disorders, and AD-MSC improved CS temporarily but was not able to avoid alterations in mitochondria function over time.
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Affiliation(s)
- Camila I. Irion
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Eduarda L. Martins
- Leopoldo de Meis Institute of Medical Biochemistry, Federal University of Rio de Janeiro, 21941-902, Brazil
| | - Michelle L. A. Christie
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Cherley B. V. de Andrade
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Alan C. N. de Moraes
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Raphaela P. Ferreira
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Cibele F. Pimentel
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Grazielle D. Suhett
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Antonio Carlos C. de Carvalho
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
- National Center for Structural Biology and Bioimaging (CENABIO), Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
- National Institute of Science and Technology for Regenerative Medicine-REGENERA, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Rafael S. Lindoso
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
- National Institute of Science and Technology for Regenerative Medicine-REGENERA, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Adalberto Vieyra
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
- National Center for Structural Biology and Bioimaging (CENABIO), Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
- National Institute of Science and Technology for Regenerative Medicine-REGENERA, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
- Regenerative Medicine Program, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Antonio Galina
- Leopoldo de Meis Institute of Medical Biochemistry, Federal University of Rio de Janeiro, 21941-902, Brazil
| | - Regina C. S. Goldenberg
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
- National Institute of Science and Technology for Regenerative Medicine-REGENERA, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
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Brychtova M, Thiele JA, Lysak D, Holubova M, Kralickova M, Vistejnova L. Mesenchymal stem cells as the near future of cardiology medicine - truth or wish? Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2018; 163:8-18. [PMID: 30439932 DOI: 10.5507/bp.2018.071] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Accepted: 10/28/2018] [Indexed: 12/31/2022] Open
Abstract
Cardiac damage is one of major cause of worldwide morbidity and mortality. Despite the development in pharmacotherapy, cardiosurgery and interventional cardiology, many patients remain at increased risk of developing adverse cardiac remodeling. An alternative treatment approach is the application of stem cells. Mesenchymal stem cells are among the most promising cell types usable for cardiac regeneration. Their homing to the damaged area, differentiation into cardiomyocytes, paracrine and/or immunomodulatory effect on cardiac tissue was investigated extensively. Despite promising preclinical reports, clinical trials on human patients are not convincing. Meta-analyses of these trials open many questions and show that routine clinical application of mesenchymal stem cells as a cardiac treatment may be not as helpful as expected. This review summarizes contemporary knowledge about mesenchymal stem cells role in cardiac tissue repair and discusses the problems and perspectives of this experimental therapeutical approach.
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Affiliation(s)
- Michaela Brychtova
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Alej Svobody 76, 323 00 Pilsen, Czech Republic
| | - Jana-Aletta Thiele
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Alej Svobody 76, 323 00 Pilsen, Czech Republic
| | - Daniel Lysak
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Alej Svobody 76, 323 00 Pilsen, Czech Republic
| | - Monika Holubova
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Alej Svobody 76, 323 00 Pilsen, Czech Republic
| | - Milena Kralickova
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Alej Svobody 76, 323 00 Pilsen, Czech Republic
| | - Lucie Vistejnova
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Alej Svobody 76, 323 00 Pilsen, Czech Republic
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Deng Z, Xu H, Zhang J, Yang C, Jin L, Liu J, Song H, Chen G, Han W, Si Y. Infusion of adipose‑derived mesenchymal stem cells inhibits skeletal muscle mitsugumin 53 elevation and thereby alleviates insulin resistance in type 2 diabetic rats. Mol Med Rep 2018; 17:8466-8474. [PMID: 29693163 DOI: 10.3892/mmr.2018.8901] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Accepted: 03/08/2018] [Indexed: 11/06/2022] Open
Abstract
It is widely accepted that infusion of mesenchymal stem cells (MSCs) ameliorates hyperglycemia by alleviating insulin resistance in rats with type 2 diabetes mellitus (T2D). However, the detailed underlying mechanisms are not clearly defined. Mitsugumin 53 (MG53) is an E3 ligase that has recently been implicated in the aggravation of insulin resistance by promoting the ubiquitinoylation of insulin receptor substrate‑1 (IRS‑1) in skeletal muscles. It was therefore hypothesized that MG53 may be involved in MSC‑mediated therapeutic effects on insulin resistance. To test this hypothesis, in the present study, T2D rat models were induced by a high‑fat diet combined with streptozotocin administration and MSC infusion was performed four times (once every 2 weeks for 8 weeks). The therapeutic effects of MSC infusion on insulin resistance were evaluated and the effect on the expression of MG53 and insulin receptor signaling elements in skeletal muscle was also investigated by immunofluorescence staining and western blotting. The results demonstrated that MSC infusion ameliorated hyperglycemia and insulin resistance in T2D rats. Furthermore, MSC infusion inhibited MG53 elevation and reversed the decreases in glucose transporter type 4, insulin receptor, IRS‑1 and phosphorylated‑AKT levels in the skeletal muscle of T2D rats. These results indicated that MSC infusion has therapeutic effects in rats and that MG53 in skeletal muscle may be a promising novel therapeutic target protein for MSC‑mediated amelioration of insulin resistance in T2D.
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Affiliation(s)
- Zihui Deng
- Institute of Basic Medicine Science, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Huiyan Xu
- Department of Traditional Chinese Medicine, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Jinying Zhang
- Institute of Basic Medicine Science, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Chen Yang
- Department of Cardiology, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Liyuan Jin
- Department of Cardiology, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Jiejie Liu
- Institute of Basic Medicine Science, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Haijing Song
- Institute of Basic Medicine Science, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Guanghui Chen
- Department of Cardiology, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Weidong Han
- Institute of Basic Medicine Science, Chinese PLA General Hospital, Beijing 100853, P.R. China
| | - Yiling Si
- Institute of Basic Medicine Science, Chinese PLA General Hospital, Beijing 100853, P.R. China
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Mayorga ME, Kiedrowski M, McCallinhart P, Forudi F, Ockunzzi J, Weber K, Chilian W, Penn MS, Dong F. Role of SDF-1:CXCR4 in Impaired Post-Myocardial Infarction Cardiac Repair in Diabetes. Stem Cells Transl Med 2017; 7:115-124. [PMID: 29119710 PMCID: PMC5746149 DOI: 10.1002/sctm.17-0172] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Accepted: 10/06/2017] [Indexed: 12/13/2022] Open
Abstract
Diabetes is a risk factor for worse outcomes following acute myocardial infarction (AMI). In this study, we tested the hypothesis that SDF‐1:CXCR4 expression is compromised in post‐AMI in diabetes, and that reversal of this defect can reverse the adverse effects of diabetes. Mesenchymal stem cells (MSC) isolated from green fluorescent protein (GFP) transgenic mice (control MSC) were induced to overexpress stromal cell‐derived factor‐1 (SDF‐1). SDF‐1 expression in control MSC and SDF‐1‐overexpressing MSC (SDF‐1:MSC) were quantified using enzyme‐linked immunosorbent assay (ELISA). AMI was induced on db/db and control mice. Mice were randomly selected to receive infusion of control MSC, SDF‐1:MSC, or saline into the border zone after AMI. Serial echocardiography was used to assess cardiac function. SDF‐1 and CXCR4 mRNA expression in the infarct zone of db/db mice and control mice were quantified. Compared to control mice, SDF‐1 levels were decreased 82%, 91%, and 45% at baseline, 1 day and 3 days post‐AMI in db/db mice, respectively. CXCR4 levels are increased 233% at baseline and 54% 5 days post‐AMI in db/db mice. Administration of control MSC led to a significant improvement in ejection fraction (EF) in control mice but not in db/db mice 21 days after AMI. In contrast, administration of SDF‐1:MSC produced a significant improvement in EF in both control mice and db/db mice 21 days after AMI. The SDF‐1:CXCR4 axis is compromised in diabetes, which appears to augment the deleterious consequences of AMI. Over‐express of SDF‐1 expression in diabetes rescues cardiac function post AMI. Our results suggest that modulation of SDF‐1 may improve post‐AMI cardiac repair in diabetes. stemcellstranslationalmedicine2018;7:115–124
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Affiliation(s)
- Maritza E Mayorga
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA
| | - Matthew Kiedrowski
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA
| | - Patricia McCallinhart
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA
| | - Farhad Forudi
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA
| | - Jeremiah Ockunzzi
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA
| | - Kristal Weber
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA
| | - William Chilian
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA
| | - Marc S Penn
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA.,Summa Cardiovascular Institute, Summa Health System, Akron, Ohio, USA
| | - Feng Dong
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA
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10
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Jiang Y, Zhang W, Xu S, Lin H, Sui W, Liu H, Peng L, Fang Q, Chen L, Lou J. Transplantation of human fetal pancreatic progenitor cells ameliorates renal injury in streptozotocin-induced diabetic nephropathy. J Transl Med 2017; 15:147. [PMID: 28655312 PMCID: PMC5488369 DOI: 10.1186/s12967-017-1253-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Accepted: 06/22/2017] [Indexed: 12/16/2022] Open
Abstract
Background Diabetic nephropathy (DN) is a severe complication of diabetes mellitus (DM). Pancreas or islet transplantation has been reported to prevent the development of DN lesions and ameliorate or reverse existing glomerular lesions in animal models. Shortage of pancreas donor is a severe problem. Islets derived from stem cells may offer a potential solution to this problem. Objective To evaluate the effect of stem cell-derived islet transplantation on DN in a rat model of streptozotocin-induced DM. Methods Pancreatic progenitor cells were isolated from aborted fetuses of 8 weeks of gestation. And islets were prepared by suspension culture after a differentiation of progenitor cells in medium containing glucagon-like peptide-1 (Glp-1) and nicotinamide. Then islets were transplanted into the liver of diabetic rats via portal vein. Blood glucose, urinary volume, 24 h urinary protein and urinary albumin were measured once biweekly for 16 weeks. Graft survival was evaluated by monitoring human C-peptide level in rat sera and by immunohistochemical staining for human mitochondrial antigen and human C-peptide in liver tissue. The effect of progenitor-derived islets on filtration membrane was examined by electron microscopy and real-time polymerase chain reaction (PCR). Immunohistochemical staining, real-time PCR and western blot were employed for detecting fibronectin, protein kinase C beta (PKCβ), protein kinase A (PKA), inducible nitric oxide synthase (iNOS) and superoxide dismutase (SOD). Results Islet-like clusters derived from 8th gestational-week human fetal pancreatic progenitors survived in rat liver. And elevated serum level of human C-peptide was detected. Blood glucose, 24 h urinary protein and urinary albumin were lower in progenitor cell group than those in DN or insulin treatment group. Glomerular basement membrane thickness and fibronectin accumulation decreased significantly while podocytes improved morphologically in progenitor cell group. Furthermore, receptor of advanced glycation end products and PKCβ became down-regulated whereas PKA up-regulated by progenitor cell-derived islets. And iNOS rose while SOD declined. Conclusions DN may be reversed by transplantation of human fetal pancreatic progenitor cell-derived islets. And fetal pancreatic progenitor cells offer potential resources for cell replacement therapy. Electronic supplementary material The online version of this article (doi:10.1186/s12967-017-1253-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yongwei Jiang
- Department of Laboratory Medicine, China-Japan Friendship Hospital, Beijing, 100029, China.,Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, No. 2 Yinghua East Street, Chaoyang District, Beijing, 100029, People's Republic of China
| | - Wenjian Zhang
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, No. 2 Yinghua East Street, Chaoyang District, Beijing, 100029, People's Republic of China
| | - Shiqing Xu
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, No. 2 Yinghua East Street, Chaoyang District, Beijing, 100029, People's Republic of China
| | - Hua Lin
- Department of Gynecology and Obstetrics, China-Japan Friendship Hospital, Beijing, 100029, China
| | - Weiguo Sui
- First Kidney Transplantation Hemopurification Center of Chinese PLA, 181st Hospital of Chinese People's Liberation Army, Guilin, 541002, China
| | - Honglin Liu
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, No. 2 Yinghua East Street, Chaoyang District, Beijing, 100029, People's Republic of China
| | - Liang Peng
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, No. 2 Yinghua East Street, Chaoyang District, Beijing, 100029, People's Republic of China
| | - Qing Fang
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, No. 2 Yinghua East Street, Chaoyang District, Beijing, 100029, People's Republic of China
| | - Li Chen
- Department of Endocrinology, Qilu Hospital, Shandong University, Jinan, 250012, Shandong, China
| | - Jinning Lou
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, No. 2 Yinghua East Street, Chaoyang District, Beijing, 100029, People's Republic of China.
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11
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Zang L, Hao H, Liu J, Li Y, Han W, Mu Y. Mesenchymal stem cell therapy in type 2 diabetes mellitus. Diabetol Metab Syndr 2017; 9:36. [PMID: 28515792 PMCID: PMC5433043 DOI: 10.1186/s13098-017-0233-1] [Citation(s) in RCA: 80] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Accepted: 05/05/2017] [Indexed: 02/06/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM), which is characterized by the combination of relative insulin deficiency and insulin resistance, cannot be reversed with existing therapeutic strategies. Transplantation of insulin-producing cells (IPCs) was once thought to be the most promising strategy for treating diabetes, but the pace from the laboratory to clinical application has been obstructed due to its drawbacks. Mesenchymal stem cells (MSCs) harbor differentiation potential, immunosuppressive properties, and anti-inflammatory effects, and they are considered an ideal candidate cell type for treatment of DM. MSC-related research has demonstrated exciting therapeutic effects in glycemic control both in vivo and in vitro, and these results now have been translated into clinical practice. However, some critical potential problems have emerged from current clinical trials. Multi-center, large-scale, double-blind, and placebo-controlled studies with strict supervision are required before MSC transplantation can become a routine therapeutic approach for T2DM. We briefly review the molecular mechanism of MSC treatment for T2DM as well as the merits and drawbacks identified in current clinical trials.
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Affiliation(s)
- Li Zang
- Department of Endocrinology, Chinese PLA General Hospital, Beijing, 100853 China
| | - Haojie Hao
- Department of Molecular Biology, Institute of Basic Medicine, College of Life Science, Chinese PLA General Hospital, Beijing, 100853 China
| | - Jiejie Liu
- Department of Molecular Biology, Institute of Basic Medicine, College of Life Science, Chinese PLA General Hospital, Beijing, 100853 China
| | - Yijun Li
- Department of Endocrinology, Chinese PLA General Hospital, Beijing, 100853 China
| | - Weidong Han
- Department of Molecular Biology, Institute of Basic Medicine, College of Life Science, Chinese PLA General Hospital, Beijing, 100853 China
| | - Yiming Mu
- Department of Endocrinology, Chinese PLA General Hospital, Beijing, 100853 China
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12
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Malfitano C, de Souza Junior AL, Carbonaro M, Bolsoni-Lopes A, Figueroa D, de Souza LE, Silva KAS, Consolim-Colombo F, Curi R, Irigoyen MC. Glucose and fatty acid metabolism in infarcted heart from streptozotocin-induced diabetic rats after 2 weeks of tissue remodeling. Cardiovasc Diabetol 2015; 14:149. [PMID: 26553117 PMCID: PMC4640361 DOI: 10.1186/s12933-015-0308-y] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Accepted: 10/23/2015] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND The effects of streptozotocin (STZ)-induced diabetes on heart metabolism and function after myocardial infarction (MI) remodelling were investigated in rats. METHODS Fifteen days after STZ (50 mg/kg b.w. i.v.) injection, MI was induced by surgical occlusion of the left coronary artery. Two weeks after MI induction, contents of glycogen, ATP, free fatty acids and triacylglycerols (TG) and enzyme activities of glycolysis and Krebs cycle (hexokinase, glucose-6-phosphate dehydrogenase, phosphofructokinase, citrate synthase) and expression of carnitine palmitoyl-CoA transferase I (a key enzyme of mitochondrial fatty acid oxidation) were measured in the left ventricle (LV). Plasma glucose, free fatty acids and triacylglycerol levels were determined. Ejection fraction (EF) and shortening fraction (SF) were also measured by echocardiography. RESULTS Glycogen and TG contents were increased (p < 0.05) whereas ATP content was decreased in the LV of the non-infarcted diabetic group when compared to the control group (p < 0.05). When compared to infarcted control rats (MI), the diabetic infarcted rats (DI) showed (p < 0.05): increased plasma glucose and TG levels, elevated free fatty acid levels and increased activity of, citrate synthase and decreased ATP levels in the LV. Infarct size was smaller in the DI group when compared to MI rats (p < 0.05), and this was associated with higher EF and SF (p < 0.05). CONCLUSIONS Systolic function was preserved or recovered more efficiently in the heart from diabetic rats two weeks after MI, possibly due to the high provision of glucose and free fatty acids from both plasma and heart glycogen and triacylglycerol stores.
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Affiliation(s)
- Christiane Malfitano
- Hypertension Unit, Heart Institute (InCor), Medical School of University of São Paulo, Av. Eneas de Carvalho Aguiar, 44, 05403-000, Sao Paulo, SP, Brazil.
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
| | - Alcione Lescano de Souza Junior
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
- Nursing Department, State University of Mato Grosso, Alta Floresta, Brazil.
| | - Mariana Carbonaro
- Hypertension Unit, Heart Institute (InCor), Medical School of University of São Paulo, Av. Eneas de Carvalho Aguiar, 44, 05403-000, Sao Paulo, SP, Brazil.
| | - Andressa Bolsoni-Lopes
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
| | - Diego Figueroa
- Hypertension Unit, Heart Institute (InCor), Medical School of University of São Paulo, Av. Eneas de Carvalho Aguiar, 44, 05403-000, Sao Paulo, SP, Brazil.
| | - Leandro Ezequiel de Souza
- Hypertension Unit, Heart Institute (InCor), Medical School of University of São Paulo, Av. Eneas de Carvalho Aguiar, 44, 05403-000, Sao Paulo, SP, Brazil.
| | | | - Fernanda Consolim-Colombo
- Hypertension Unit, Heart Institute (InCor), Medical School of University of São Paulo, Av. Eneas de Carvalho Aguiar, 44, 05403-000, Sao Paulo, SP, Brazil.
- Laboratory of Translational Physiology, Universidade Nove de Julho, (UNINOVE), Sao Paulo, Brazil.
| | - Rui Curi
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
| | - Maria Claudia Irigoyen
- Hypertension Unit, Heart Institute (InCor), Medical School of University of São Paulo, Av. Eneas de Carvalho Aguiar, 44, 05403-000, Sao Paulo, SP, Brazil.
- Laboratory of Translational Physiology, Universidade Nove de Julho, (UNINOVE), Sao Paulo, Brazil.
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13
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Kim G, Jo K, Kim KJ, Lee YH, Han E, Yoon HJ, Wang HJ, Kang ES, Yun M. Visceral adiposity is associated with altered myocardial glucose uptake measured by (18)FDG-PET in 346 subjects with normal glucose tolerance, prediabetes, and type 2 diabetes. Cardiovasc Diabetol 2015; 14:148. [PMID: 26538247 PMCID: PMC4632263 DOI: 10.1186/s12933-015-0310-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2015] [Accepted: 10/24/2015] [Indexed: 12/13/2022] Open
Abstract
Background The heart requires constant sources of energy mostly from free fatty acids (FFA) and glucose. The alteration in myocardial substrate metabolism occurs in the heart of diabetic patients, but its specific association with other metabolic variables remains unclear. We aimed to evaluate glucose uptake in hearts of subjects with normal glucose tolerance (NGT), prediabetes, and type 2 diabetes mellitus (T2DM) using [18F]-fluorodeoxyglucose-positron emission tomography (18FDG-PET) in association with visceral and subcutaneous adiposity, and metabolic laboratory parameters. Methods A total of 346 individuals (NGT, n = 76; prediabetes, n = 208; T2DM, n = 62) in a health promotion center of a tertiary hospital were enrolled. The fasting myocardial glucose uptake, and visceral and subcutaneous fat areas were evaluated using 18FDG-PET and abdominal computed tomography, respectively. Results Myocardial glucose uptake was significantly decreased in subjects with T2DM compared to the NGT or prediabetes groups (p for trend = 0.001). Multivariate linear regression analyses revealed that visceral fat area (β = −0.22, p = 0.018), fasting FFA (β = −0.39, p < 0.001), and uric acid levels (β = −0.21, p = 0.007) were independent determinants of myocardial glucose uptake. Multiple logistic analyses demonstrated that decreased myocardial glucose uptake (OR 2.32; 95 % CI 1.02–5.29, p = 0.045) and visceral fat area (OR 1.02, 95 % CI 1.01–1.03, p = 0.018) were associated with T2DM. Conclusions Our findings indicate visceral adiposity is strongly associated with the alteration of myocardial glucose uptake evaluated by 18FDG-PET, and its association further relates to T2DM.
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Affiliation(s)
- Gyuri Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. .,Graduate School, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.
| | - Kwanhyeong Jo
- Graduate School, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea. .,Department of Nuclear Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
| | - Kwang Joon Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
| | - Yong-ho Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
| | - Eugene Han
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
| | - Hye-jin Yoon
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
| | - Hye Jin Wang
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.
| | - Eun Seok Kang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. .,Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.
| | - Mijin Yun
- Department of Nuclear Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
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14
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Csöbönyeiová M, Polák Š, Danišovič L. Perspectives of induced pluripotent stem cells for cardiovascular system regeneration. Exp Biol Med (Maywood) 2015; 240:549-556. [PMID: 25595188 PMCID: PMC4935267 DOI: 10.1177/1535370214565976] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2014] [Accepted: 11/06/2014] [Indexed: 01/08/2023] Open
Abstract
Induced pluripotent stem cells (iPSCs) hold great promise for basic research and regenerative medicine. They offer the same advantages as embryonic stem cells (ESCs) and moreover new perspectives for personalized medicine. iPSCs can be generated from adult somatic tissues by over-expression of a few defined transcription factors, including Oct4, Sox2, Klf4, and c-myc. For regenerative medicine in particular, the technology provides great hope for patients with incurable diseases or potentially fatal disorders such as heart failure. The endogenous regenerative potentials of adult hearts are extremely limited and insufficient to compensate for myocardial loss occurring after myocardial infarction. Recent discoveries have demonstrated that iPSCs have the potential to significantly advance future cardiovascular regenerative therapies. Moreover, iPSCs can be generated from somatic cells of patients with genetic basis for their disease. This human iPSC derivates offer tremendous potential for new disease models. This paper reviews current applications of iPSCs in cardiovascular regenerative medicine and discusses progress in modeling cardiovascular diseases using iPSCs-derived cardiac cells.
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Affiliation(s)
- Mária Csöbönyeiová
- Institute of Histology and Embryology, Comenius University in Bratislava, 81108 Bratislava, Slovak Republic
| | - Štefan Polák
- Institute of Histology and Embryology, Comenius University in Bratislava, 81108 Bratislava, Slovak Republic
| | - L'uboš Danišovič
- Institute of Medical Biology, Genetics and Clinical Genetics Faculty of Medicine, Comenius University in Bratislava, 81108 Bratislava, Slovak Republic
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15
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Bueno PDG, Yochite JNU, Derigge-Pisani GF, Malmegrim de Farias KCR, de Avó LRDS, Voltarelli JC, Leal ÂMDO. Metabolic and pancreatic effects of bone marrow mesenchymal stem cells transplantation in mice fed high-fat diet. PLoS One 2015; 10:e0124369. [PMID: 25923733 PMCID: PMC4414281 DOI: 10.1371/journal.pone.0124369] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2014] [Accepted: 02/27/2015] [Indexed: 12/22/2022] Open
Abstract
The purpose of this study was to investigate the effects of multiple infusions of allogeneic MSCs on glucose homeostasis and morphometry of pancreatic islets in high- fat diet (HFD) fed mice. Swiss mice were fed standard diet (C group) or HFD (HFD group). After 8 weeks, animals of HFD group received sterile phosphate-buffered saline infusions (HFD-PBS) or four infusions of MSCs one week apart (HFD-MSCs). Fasting glycemia (FG) was determined weekly and glucose (GTT) and insulin (ITT) tolerance tests were performed 4, 8, 12, and 16 weeks after the infusions of MSCs. The MSCs transplanted mice were classified as responder (FG < 180 mg/dL, 72.2% of transplanted mice) or non-responder (FG > 180mg/dL, 28.8%) Seven weeks after MSCs infusions, FG decreased in HFD-MSCs responder mice compared with the HFD-PBS group. Sixteen weeks post MSCs infusions, GTT and ITT areas under the curve (AUC) decreased in HFD-MSCs responder mice compared to HFD-PBS group. Serum insulin concentration was higher in HFD-PBS group than in control animals and was not different compared with the other groups. The relative volume of α-cells was significantly smaller in HFD-PBS group than in C group and significantly higher in HFD-MSCs-NR than in HFD-PBS and HFD-MSCs-R groups. Cell apoptosis in the islets was higher in HFD-PBS group than in C group, and lower in HFD-MSCs responder mice than in HFD-PBS group and non-responder animals. The results demonstrate the ability of multiple infusions of MSCs to promote prolonged decrease in hyperglycemia and apoptosis in pancreatic islets and increase in insulin sensitivity in HFD fed mice.
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Affiliation(s)
- Patricia de Godoy Bueno
- Department of Physiological Science, Center of Biological Sciences and Health, Federal University of São Carlos, São Carlos, São Paulo, Brazil
| | - Juliana Navarro Ueda Yochite
- Department of Biochemistry and Immunology, Ribeirao Preto Medical School, University of São Paulo, Ribeirao Preto, São Paulo, Brazil
| | - Graziela Fernanda Derigge-Pisani
- Department of Physiological Science, Center of Biological Sciences and Health, Federal University of São Carlos, São Carlos, São Paulo, Brazil
| | - Kelen Cristina Ribeiro Malmegrim de Farias
- Department of Clinical, Toxicological and Bromatological Analyses, Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirao Preto, São Paulo, Brazil
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16
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Deng B, Deng W, Xiao P, Zeng K, Zhang S, Zhang H, Deng DY, Yang Y. Nonadherent culture method downregulates stem cell antigen-1 expression in mouse bone marrow mesenchymal stem cells. Exp Ther Med 2015; 10:31-36. [PMID: 26170908 DOI: 10.3892/etm.2015.2457] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2014] [Accepted: 03/05/2015] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are primarily isolated by their adherence to plastic and their in vitro growth characteristics. Expansion of these cells from an adherent culture is the only method to obtain a sufficient number of cells for use in clinical practice and research. However, little is known with regard to the effect of adherence to plastic on the phenotype of the cells. In the present study, bone marrow CD45-CD31-CD44- stem cell antigen (Sca)-1+ MSCs were sorted by flow cytometry and expanded in adherent cultures. The expression levels of the adhesion molecule, Sca-1, in the adherent cultures were compared with those from nonadherent cultures at different time points. The flow cytometry results indicated that the expression levels of Sca-1 decreased in the MSCs in the nonadherent cultures grown in ultra-low-adherent plates. Furthermore, the result was confirmed by quantitative polymerase chain reaction at the same time points. Therefore, the results demonstrated that the loss of plastic adherence downregulated the expression of Sca-1. The observations may provide novel insights into the molecular mechanisms underlying plastic adherent culture.
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Affiliation(s)
- Baoping Deng
- Department of Cardiovascular Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Weiping Deng
- Department of Gastroenterology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Pingnan Xiao
- Center for Hematology and Regenerative Medicine (HERM), Karolinska Institute, Stockholm SE-141 86, Sweden
| | - Kuan Zeng
- Department of Cardiovascular Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Shining Zhang
- Department of Nuclear Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Hongwu Zhang
- Department of Transfer Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - David Yb Deng
- Department of Transfer Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Yanqi Yang
- Department of Cardiovascular Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, P.R. China
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17
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El'chaninov AV, Volodina MA, Arutyunyan IV, Makarov AV, Tarasova NV, Kananykhina EY, Usman NY, Marei MV, Vysokikh MY, Glinkina VV, Bol'shakova GB, Fatkhudinov TH, Sukhikh GT. Effect of multipotent stromal cells on the function of cell mitochondria in regenerating liver. Bull Exp Biol Med 2015; 158:566-572. [PMID: 25705043 DOI: 10.1007/s10517-015-2808-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2014] [Indexed: 02/07/2023]
Abstract
Intrasplenic allogeneic transplantation of multipotent stromal cells from the umbilical cord stimulates hepatocyte proliferation and promotes recovery of liver weight in rats after subtotal resection (80% organ weight). It can be hypothesized that this effect of multipotent stromal cells is due to more rapid recovery of the number of mitochondria and normalization of mitochondrial function of liver hepatocytes.
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Affiliation(s)
- A V El'chaninov
- V. I. Kulakov Research Center of Obstetrics, Gynecology, and Perinatology, Ministry of Health of the Russian Federation, Moscow, Russia
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18
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Tanabe S. Role of mesenchymal stem cells in cell life and their signaling. World J Stem Cells 2014; 6:24-32. [PMID: 24567785 PMCID: PMC3927011 DOI: 10.4252/wjsc.v6.i1.24] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2013] [Revised: 11/18/2013] [Accepted: 12/12/2013] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have various roles in the body and cellular environment, and the cellular phenotypes of MSCs changes in different conditions. MSCs support the maintenance of other cells, and the capacity of MSCs to differentiate into several cell types makes the cells unique and full of possibilities. The involvement of MSCs in the epithelial-mesenchymal transition is an important property of these cells. In this review, the role of MSCs in cell life, including their application in therapy, is first described, and the signaling mechanism of MSCs is investigated for a further understanding of these cells.
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Affiliation(s)
- Shihori Tanabe
- Shihori Tanabe, National Institute of Health Sciences, Tokyo 158-8501, Japan
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