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Sharafifard F, Kazeminasab F, Ghanbari Rad M, Ghaedi K, Rosenkranz SK. The combined effects of high-intensity interval training and time-restricted feeding on the AKT/FOXO1/PEPCK pathway in diabetic rats. Sci Rep 2025; 15:13898. [PMID: 40263494 PMCID: PMC12015413 DOI: 10.1038/s41598-025-96703-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Accepted: 03/31/2025] [Indexed: 04/24/2025] Open
Abstract
High-intensity interval training (HIIT) and time-restricted feeding (TRF) have shown promise for improving glucose regulation by increasing insulin sensitivity, enhancing glucose uptake, reducing glucose production. Therefore, this study investigates the combined effects of HIIT and TRF on the AKT/FOXO1/PEPCK signaling pathway in the liver tissue of type 2 diabetic rats. 42 male Wistar rats (4-5 weeks of age) were included in the study. The animals were randomly divided into two groups: (1) Standard diet (SD, non-Diabetic (Non-D, n = 7) (2) High-fat diet (HFD, n = 35) for 4 weeks. To induce diabetes, 35 mg/kg of streptozotocin (STZ) was injected intraperitoneally (IP). Animals with blood glucose levels of > 250 mg/dL were considered as diabetic. Diabetic rats were randomly divided into 5 groups (n = 7): (1) Diabetes-exercise (D-EX), (2) Diabetes-TRF (D-TRF), (3) Diabetes-combined TRF and exercise (D-TRF&EX), (4) Diabetes no treatment (D-NT), (5) Diabetes with metformin (D-MET). Interventions (HIIT and TRF) were performed for 10 weeks. Rats in the Non-D group did not exercise and did not receive metformin or TRF. Periodic Acid-Schiff (PAS) staining was used to histologically analyze the liver tissue. Levels of blood glucose, insulin resistance (IR), FOXO1 protein, PEPCK, and area under the curve (AUC) following the IPGTT test, were significantly decreased in treatment groups compared to the D-NT group (p < 0.05). The AKT protein levels (p < 0.01), glycogen content (p < 0.05), and insulin sensitivity (p < 0.001) increased in the treatment groups as compared with the D-NT group. Microscopic examination of the liver tissue in general showed a better tissue arrangement in both treatment groups than in the D-NT group. Combining HIIT and TRF may be effective for improving blood glucose regulation, insulin sensitivity, in type 2 diabetes, as compared to TRF or HIIT interventions alone.
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Affiliation(s)
- Fatemeh Sharafifard
- Department of Physical Education and Sports Science, Faculty of Humanities, University of Kashan, Kashan, Iran
| | - Fatemeh Kazeminasab
- Department of Physical Education and Sports Science, Faculty of Humanities, University of Kashan, Kashan, Iran.
| | - Mahtab Ghanbari Rad
- Gerash Cellular and Molecular Research Center, Gerash University of Medical Sciences, Gerash, Iran
| | - Kamran Ghaedi
- Department of Biology, Faculty of Sciences, University of Isfahan, Isfahan, Iran
| | - Sara K Rosenkranz
- Department of Kinesiology and Nutrition Sciences, University of Nevada Las Vegas, Las Vegas, NV, USA
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Arendt W, Piekarska K, Hałas-Wiśniewska M, Izdebska M, Grzanka A, Gagat M. Downregulation and inhibition of TRPM2 calcium channel prevent oxidative stress-induced endothelial dysfunction in the EA.hy926 endothelial cells model - Preliminary studies. Adv Med Sci 2025; 70:62-78. [PMID: 39778739 DOI: 10.1016/j.advms.2025.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 07/24/2024] [Accepted: 01/03/2025] [Indexed: 01/11/2025]
Abstract
PURPOSE Proper functioning of the endothelial barrier is crucial for cardiovascular system homeostasis. Oxidative stress can lead to endothelial dysfunction (ED), damaging lipids, proteins, and DNA. Reactive oxygen species also increase cytoplasmic Ca2+ levels, activating transient receptor potential melastatin 2 (TRPM2), a membrane non-selective calcium channel. The study aimed to assess TRPM2's significance in vascular endothelial cells' response to oxidative stress and the potential use of TRPM2 direct and indirect inhibitors in the prevention of oxidative stress-induced ED. MATERIALS AND METHODS EA.hy926 endothelial cells were exposed to hydrogen peroxide for 24 h to mimic oxidative stress conditions. To assess the significance of TRPM2 in the response of EA.hy926 cells to hydrogen peroxide TRPM2 siRNA as well as direct (N-(p-Amylcinnamoyl)anthranilic acid, flufenamic acid) and indirect (3-aminobenzamide, 3,4-dihydro-5[4-(1-piperidinyl)butyl]-1(2H)-isoquinolinone) TRPM2 inhibitors were tested. RESULTS Results showed that hydrogen peroxide-induced ED is alleviated by TRPM2 downregulation. Moreover, preincubation of cells with both direct and indirect TRPM2 inhibitors for 30 min before hydrogen peroxide treatment reduces its negative effects on cell viability, cell migration, and junctional proteins. CONCLUSIONS The obtained results suggest that TRPM2 channel may be a potential target in therapy and prevention of cardiovascular diseases connected with oxidative stress-induced ED. However, further research is needed for clinical applications of direct and indirect TRPM2 inhibitors.
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Affiliation(s)
- Wioletta Arendt
- Department of Histology and Embryology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Toruń, Poland.
| | - Klaudia Piekarska
- Department of Histology and Embryology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Toruń, Poland
| | - Marta Hałas-Wiśniewska
- Department of Histology and Embryology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Toruń, Poland
| | - Magdalena Izdebska
- Department of Histology and Embryology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Toruń, Poland
| | - Alina Grzanka
- Department of Histology and Embryology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Toruń, Poland
| | - Maciej Gagat
- Department of Histology and Embryology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Toruń, Poland; Faculty of Medicine, Collegium Medicum, Mazovian Academy in Płock, Płock, Poland
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He Z, Sun J. The role of the neurovascular unit in vascular cognitive impairment: Current evidence and future perspectives. Neurobiol Dis 2025; 204:106772. [PMID: 39710068 DOI: 10.1016/j.nbd.2024.106772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 12/12/2024] [Accepted: 12/16/2024] [Indexed: 12/24/2024] Open
Abstract
Vascular cognitive impairment (VCI) is a progressive cognitive impairment caused by cerebrovascular disease or vascular risk factors. It is the second most common type of cognitive impairment after Alzheimer's disease. The pathogenesis of VCI is complex, and neurovascular unit destruction is one of its important mechanisms. The neurovascular unit (NVU) is responsible for combining blood flow with brain activity and includes endothelial cells, pericytes, astrocytes and many regulatory nerve terminals. The concept of an NVU emphasizes that interactions between different types of cells are essential for maintaining brain homeostasis. A stable NVU is the basis of normal brain function. Therefore, understanding the structure and function of the neurovascular unit and its role in VCI development is crucial for gaining insights into its pathogenesis. This article reviews the structure and function of the neurovascular unit and its contribution to VCI, providing valuable information for early diagnosis and prevention.
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Affiliation(s)
- Zhidong He
- Department of Neurosurgery, China-Japan Union Hospital of Jilin University, No. 126 Xiantai Street, Changchun 130031, Jilin, China
| | - Jing Sun
- Department of Neurology, China-Japan Union Hospital of Jilin University, No. 126 Xiantai Street, Changchun 130031, Jilin, China..
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Xie Y, Zheng L, Chen W, Zeng Y, Yao K, Zhou T. Potential Signal Pathways and Therapeutic Effects of Mesenchymal Stem Cell on Oxidative Stress in Diseases. Curr Pharm Des 2025; 31:83-94. [PMID: 39257144 DOI: 10.2174/0113816128308454240823074555] [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: 04/17/2024] [Accepted: 07/25/2024] [Indexed: 09/12/2024]
Abstract
Oxidative stress is a biological stress response produced by the destruction of redox equilibrium in aerobic metabolism in organisms, which is closely related to the occurrence of many diseases. Mesenchymal stem cells (MSCs) have been found to improve oxidative stress injury in a variety of diseases, including lung injury, liver diseases, atherosclerotic diseases, diabetes and its complications, ischemia-reperfusion injury, inflammatory bowel disease. The antioxidant stress capacity of MSCs may be a breakthrough in the treatment of these diseases. This review found that MSCs have the ability to resist oxidative stress, which may be achieved through MSCs involvement in mediating the Nrf2, MAPK, NF-κB, AMPK, PI3K/AKT and Wnt4/β-catenin signaling pathways.
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Affiliation(s)
- Yina Xie
- Department of Nephrology, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, China
| | - Lingqian Zheng
- Department of Nephrology, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, China
| | - Wenmin Chen
- Department of Nephrology, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, China
| | - Yang Zeng
- Department of Nephrology, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, China
| | - Kaijin Yao
- Department of Nephrology, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, China
| | - Tianbiao Zhou
- Department of Nephrology, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, China
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Cheng X, Li YL, Wang H, Zhang RJ, Fan KY, Qi XT, Zheng GP, Dong HL. Mesenchymal stem cell therapy in atherosclerosis: A bibliometric and visual analysis. World J Stem Cells 2024; 16:1062-1085. [PMID: 39734478 PMCID: PMC11669984 DOI: 10.4252/wjsc.v16.i12.1062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 10/15/2024] [Accepted: 11/18/2024] [Indexed: 12/13/2024] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) are capable of self-renewal and differentiation, and extensive studies have demonstrated their therapeutic potential in atherosclerosis (AS). AIM To conduct a bibliometric analysis of studies on the use of MSC therapy for AS over the past two decades, assess key trends and provide insights for future research directions. METHODS We systematically searched the Web of Science Core Collection database for articles published between 1999 and 2023, yielding a total of 556 articles. Visual representation and bibliometric analysis of information and trends were facilitated using CiteSpace, the R package 'bibliometrix' and VOSviewer. RESULTS The analyzed articles were predominantly from 52 countries/regions, with prominent contributions from China and the United States. A cohort of 3057 authors contributed to these publications, with the works of Libby P distinguished by their influence and citation count. Int J Mol Sci has emerged as the journal with the highest publication volume, prominently disseminating influential papers and identifying citation outbreaks. Furthermore, our analysis identified current research hotspots within the field, focusing on vascular progenitor cells, inflammatory mechanisms, and extracellular vesicles. Emerging research frontiers, such as extracellular vesicles and oxidative stress, have been highlighted as areas of burgeoning interest. Finally, we offer perspectives on the status of research and future directions of MSC therapy in AS. CONCLUSION This comprehensive analysis provides valuable insights for advancing scientific research on MSC therapy for AS. By elucidating pivotal trends and research directions, this study aimed to foster innovation and promote the progress of disciplines in this field, thereby contributing to advancing scientific knowledge and clinical practice.
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Affiliation(s)
- Xing Cheng
- Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan 030000, Shanxi Province, China
| | - Ya-Ling Li
- Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan 030000, Shanxi Province, China
| | - Heng Wang
- Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan 030000, Shanxi Province, China
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney 2145, New South Wales, Australia
| | - Rui-Jing Zhang
- Department of Nephrology, The Second Hospital of Shanxi Medical University, Taiyuan 030000, Shanxi Province, China
| | - Ke-Yi Fan
- Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan 030000, Shanxi Province, China
| | - Xiao-Tong Qi
- Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan 030000, Shanxi Province, China
| | - Guo-Ping Zheng
- Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan 030000, Shanxi Province, China
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney 2145, New South Wales, Australia
| | - Hong-Lin Dong
- Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan 030000, Shanxi Province, China.
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Wang Y, Luo P, Wuren T. Narrative Review of Mesenchymal Stem Cell Therapy in Renal Diseases: Mechanisms, Clinical Applications, and Future Directions. Stem Cells Int 2024; 2024:8658246. [PMID: 39698513 PMCID: PMC11655143 DOI: 10.1155/sci/8658246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 11/27/2024] [Indexed: 12/20/2024] Open
Abstract
Renal diseases, particularly acute kidney injury (AKI) and chronic kidney disease (CKD), are significant global health challenges. These conditions impair kidney function and can lead to serious complications, including cardiovascular diseases, which further exacerbate the public health burden. Currently, the global AKI mortality rate is alarmingly high (20%-50%); CKD is projected to emerge as a major global health burden by 2040. Existing treatments such as hemodialysis and kidney transplantation have limited effectiveness and are often associated with adverse effects. Mesenchymal stem cells (MSCs) offer considerable potential for treating renal diseases owing to their regenerative and immunomodulatory properties. Thus, this review focuses on the application of MSCs in renal disease, discusses fundamental research findings, and evaluates their application in clinical trials. Moreover, we discuss the impact and safety of MSCs as a therapeutic option and highlight challenges and potential directions for their clinical application. We selected research articles from PubMed published within the last 5 years (from 2019), focusing on high-impact journals and clinical trial data, and included a few key studies predating 2019. Considerations included the novelty of the research, sample size, experimental design, and data reliability. With advancements in single-cell sequencing, CRISPR/Cas9 gene editing, and other cutting-edge technologies, future MSC research will explore combination therapies and personalized treatments to provide more promising, safer treatments with reduced adverse reactions and enhanced therapeutic outcomes. These advances will improve kidney disease treatment methods, enhance patient quality of life, and maximize the benefits of MSC therapies.
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Affiliation(s)
- Yanjun Wang
- Research Center for High Altitude Medicine, Qinghai University, Xining 810001, China
- High-Altitude Medicine Key Laboratory of the Ministry of Education, Xining 810001, China
- Qinghai Provincial Key Laboratory for Application of High-Altitude Medicine (Qinghai-Utah Joint Key Laboratory for Plateau Medicine), Xining 810001, China
- Nephrology Department, Affiliated Hospital of Qinghai University, Xining 810001, China
| | - Pengli Luo
- Nephrology Department, Affiliated Hospital of Qinghai University, Xining 810001, China
| | - Tana Wuren
- Research Center for High Altitude Medicine, Qinghai University, Xining 810001, China
- High-Altitude Medicine Key Laboratory of the Ministry of Education, Xining 810001, China
- Qinghai Provincial Key Laboratory for Application of High-Altitude Medicine (Qinghai-Utah Joint Key Laboratory for Plateau Medicine), Xining 810001, China
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Song J, Wang L, Wang L, Guo X, He Q, Cui C, Hu H, Zang N, Yang M, Yan F, Liang K, Wang C, Liu F, Sun Y, Sun Z, Lai H, Hou X, Chen L. Mesenchymal stromal cells ameliorate mitochondrial dysfunction in α cells and hyperglucagonemia in type 2 diabetes via SIRT1/FoxO3a signaling. Stem Cells Transl Med 2024; 13:776-790. [PMID: 38864709 PMCID: PMC11328933 DOI: 10.1093/stcltm/szae038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 04/24/2024] [Indexed: 06/13/2024] Open
Abstract
Dysregulation of α cells results in hyperglycemia and hyperglucagonemia in type 2 diabetes mellitus (T2DM). Mesenchymal stromal cell (MSC)-based therapy increases oxygen consumption of islets and enhances insulin secretion. However, the underlying mechanism for the protective role of MSCs in α-cell mitochondrial dysfunction remains unclear. Here, human umbilical cord MSCs (hucMSCs) were used to treat 2 kinds of T2DM mice and αTC1-6 cells to explore the role of hucMSCs in improving α-cell mitochondrial dysfunction and hyperglucagonemia. Plasma and supernatant glucagon were detected by enzyme-linked immunosorbent assay (ELISA). Mitochondrial function of α cells was assessed by the Seahorse Analyzer. To investigate the underlying mechanisms, Sirtuin 1 (SIRT1), Forkhead box O3a (FoxO3a), glucose transporter type1 (GLUT1), and glucokinase (GCK) were assessed by Western blotting analysis. In vivo, hucMSC infusion improved glucose and insulin tolerance, as well as hyperglycemia and hyperglucagonemia in T2DM mice. Meanwhile, hucMSC intervention rescued the islet structure and decreased α- to β-cell ratio. Glucagon secretion from αTC1-6 cells was consistently inhibited by hucMSCs in vitro. Meanwhile, hucMSC treatment activated intracellular SIRT1/FoxO3a signaling, promoted glucose uptake and activation, alleviated mitochondrial dysfunction, and enhanced ATP production. However, transfection of SIRT1 small interfering RNA (siRNA) or the application of SIRT1 inhibitor EX-527 weakened the therapeutic effects of hucMSCs on mitochondrial function and glucagon secretion. Our observations indicate that hucMSCs mitigate mitochondrial dysfunction and glucagon hypersecretion of α cells in T2DM via SIRT1/FoxO3a signaling, which provides novel evidence demonstrating the potential for hucMSCs in treating T2DM.
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Affiliation(s)
- Jia Song
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Lingshu Wang
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Liming Wang
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Xinghong Guo
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Qin He
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Chen Cui
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Huiqing Hu
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Nan Zang
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Mengmeng Yang
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Fei Yan
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Kai Liang
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Chuan Wang
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Fuqiang Liu
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Yujing Sun
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Zheng Sun
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
| | - Hong Lai
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
- Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan 250012, Shandong, People's Republic of China
- Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine and Health, Jinan 250012, Shandong, People's Republic of China
- Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan 250012, Shandong, People's Republic of China
| | - Xinguo Hou
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
- Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan 250012, Shandong, People's Republic of China
- Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine and Health, Jinan 250012, Shandong, People's Republic of China
- Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan 250012, Shandong, People's Republic of China
| | - Li Chen
- Department of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan 250012, Shandong, People's Republic of China
- Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan 250012, Shandong, People's Republic of China
- Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine and Health, Jinan 250012, Shandong, People's Republic of China
- Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan 250012, Shandong, People's Republic of China
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Chen X, Yao N, Mao Y, Xiao D, Huang Y, Zhang X, Wang Y. Activation of the Wnt/β-catenin/CYP1B1 pathway alleviates oxidative stress and protects the blood-brain barrier under cerebral ischemia/reperfusion conditions. Neural Regen Res 2024; 19:1541-1547. [PMID: 38051897 PMCID: PMC10883507 DOI: 10.4103/1673-5374.386398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 06/20/2023] [Indexed: 12/07/2023] Open
Abstract
Abstract
JOURNAL/nrgr/04.03/01300535-202407000-00033/figure1/v/2023-11-20T171125Z/r/image-tiff
Accumulating evidence suggests that oxidative stress and the Wnt/β-catenin pathway participate in stroke-induced disruption of the blood-brain barrier. However, the potential links between them following ischemic stroke remain largely unknown. The present study found that cerebral ischemia leads to oxidative stress and repression of the Wnt/β-catenin pathway. Meanwhile, Wnt/β-catenin pathway activation by the pharmacological inhibitor, TWS119, relieved oxidative stress, increased the levels of cytochrome P450 1B1 (CYP1B1) and tight junction-associated proteins (zonula occludens-1 [ZO-1], occludin and claudin-5), as well as brain microvascular density in cerebral ischemia rats. Moreover, rat brain microvascular endothelial cells that underwent oxygen glucose deprivation/reoxygenation displayed intense oxidative stress, suppression of the Wnt/β-catenin pathway, aggravated cell apoptosis, downregulated CYP1B1 and tight junction protein levels, and inhibited cell proliferation and migration. Overexpression of β-catenin or knockdown of β-catenin and CYP1B1 genes in rat brain microvascular endothelial cells at least partly ameliorated or exacerbated these effects, respectively. In addition, small interfering RNA-mediated β-catenin silencing decreased CYP1B1 expression, whereas CYP1B1 knockdown did not change the levels of glycogen synthase kinase 3β, Wnt-3a, and β-catenin proteins in rat brain microvascular endothelial cells after oxygen glucose deprivation/reoxygenation. Thus, the data suggest that CYP1B1 can be regulated by Wnt/β-catenin signaling, and activation of the Wnt/β-catenin/CYP1B1 pathway contributes to alleviation of oxidative stress, increased tight junction levels, and protection of the blood-brain barrier against ischemia/hypoxia-induced injury.
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Affiliation(s)
- Xingyong Chen
- Department of Neurology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Nannan Yao
- Department of Neurology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, China
- Department of Neurology, Cangzhou Central Hospital, Cangzhou, Hebei Province, China
| | - Yanguang Mao
- Department of Neurology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Dongyun Xiao
- Department of Neurology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Yiyi Huang
- Department of Neurology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Xu Zhang
- Department of Neurology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Yinzhou Wang
- Department of Neurology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, Fujian Province, China
- Fujian Academy of Medical Science, Fuzhou, Fujian Province, China
- Key Testing Laboratory of Fujian Province, Fuzhou, Fujian Province, China
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Yadav R, Patel B. Insights on effects of Wnt pathway modulation on insulin signaling and glucose homeostasis for the treatment of type 2 diabetes mellitus: Wnt activation or Wnt inhibition? Int J Biol Macromol 2024; 261:129634. [PMID: 38272413 DOI: 10.1016/j.ijbiomac.2024.129634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 12/27/2023] [Accepted: 01/06/2024] [Indexed: 01/27/2024]
Abstract
Type 2 diabetes mellitus (T2DM) is a major worldwide chronic disease and can lead to serious diabetic complications. Despite the availability of many anti-diabetic agents in the market, they are unable to meet the long-term treatment goals. Also, they cause many side effects which justify the need for novel class of anti-diabetic drugs with newer mechanism of action. Wnt signaling is one of such novel target pathways which can be explored for metabolic disorders. Many key components of the Wnt signaling are involved in the regulation of glucose homeostasis. Polymorphism in the Transcription factor 7-like 2 (TCF7L2) gene, and mutations in the LRP5 (LDL Receptor Related Protein 5) gene lead to disturbed glucose metabolism and obesity. Despite of several years of research in this field, there is no concrete proof of concept available on whether Wnt activation or Wnt inhibition is the beneficial approach for the treatment of T2DM. Here, we have summarized the conclusions of relevant published research studies to give structured insights into possibilities to explore Wnt modulation as a novel target pathway for the treatment of T2DM. The review also highlights the present challenges and future opportunities towards the development of anti-diabetic small molecules targeting the Wnt signaling pathway.
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Affiliation(s)
- Ruchi Yadav
- Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat 382481, India
| | - Bhumika Patel
- Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat 382481, India.
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Liu T, Liu H, Xue S, Xiao L, Xu J, Tong S, Wei X. MiR129-5p-loaded exosomes suppress seizure-associated neurodegeneration in status epilepticus model mice by inhibiting HMGB1/TLR4-mediated neuroinflammation. Mol Biol Rep 2024; 51:292. [PMID: 38332381 PMCID: PMC10853309 DOI: 10.1007/s11033-024-09215-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Accepted: 01/04/2024] [Indexed: 02/10/2024]
Abstract
BACKGROUND Neuroinflammation contributes to both epileptogenesis and the associated neurodegeneration, so regulation of inflammatory signaling is a potential strategy for suppressing epilepsy development and pathological progression. Exosomes are enriched in microRNAs (miRNAs), considered as vital communication tools between cells, which have been proven as potential therapeutic method for neurological disease. Here, we investigated the role of miR129-5p-loaded mesenchymal stem cell (MSC)-derived exosomes in status epilepticus (SE) mice model. METHODS Mice were divided into four groups: untreated control (CON group), kainic acid (KA)-induced SE groups (KA group), control exosome injection (KA + Exo-con group), miR129-5p-loaded exosome injection (KA + Exo-miR129-5p group). Hippocampal expression levels of miR129-5p, HMGB1, and TLR4 were compared among groups. Nissl and Fluoro-jade B staining were conducted to evaluate neuronal damage. In addition, immunofluorescence staining for IBA-1 and GFAP was performed to assess glial cell activation, and inflammatory factor content was determined by ELISA. Hippocampal neurogenesis was assessed by BrdU staining. RESULTS The expression of HMGB1 was increased after KA-induced SE and peaking at 48 h, while hippocampal miR129-5p expression decreased in SE mice. Exo-miR129-5p injection reversed KA-induced upregulation of hippocampal HMGB1 and TLR4, alleviated neuronal damage in the hippocampal CA3, reduced IBA-1 + and GFAP + staining intensity, suppressed SE-associated increases in inflammatory factors, and decreased BrdU + cell number in dentate gyrus. CONCLUSIONS Exosomes loaded with miR129-5p can protect neurons against SE-mediated degeneration by inhibiting the pro-inflammatory HMGB1/TLR4 signaling axis.
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Affiliation(s)
- Tengfei Liu
- Department of Neurology, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu, China
| | - Haiyan Liu
- Department of Neurology, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu, China
| | - Siyi Xue
- School of Medical Imaging, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Lijie Xiao
- Department of Neurology, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu, China
| | - Jing Xu
- Department of Neurology, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu, China
| | - Shuyan Tong
- Department of Neurology, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu, China
| | - Xiu'e Wei
- Department of Neurology, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, Jiangsu, China.
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11
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Zheng L, Shi W, Liu B, Duan B, Sorgen P. Evaluation of Tyrosine Kinase Inhibitors Loaded Injectable Hydrogels for Improving Connexin43 Gap Junction Intercellular Communication. ACS APPLIED MATERIALS & INTERFACES 2024; 16:1985-1998. [PMID: 38175743 PMCID: PMC11061860 DOI: 10.1021/acsami.3c10923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2024]
Abstract
Myocardial infarction (MI) is one of the leading causes of death in the developed world, and the loss of cardiomyocytes plays a critical role in the pathogenesis of heart failure. Implicated in this process is a decrease in gap junction intercellular communication due to remodeling of Connexin43 (Cx43). We previously identified that intraperitoneal injection of the Pyk2 inhibitor PF4618433 reduced infarct size, maintained Cx43 at the intercalated disc in left ventricle hypertrophic myocytes, and improved cardiac function in an MI animal model of heart failure. With the emergence of injectable hydrogels as a therapeutic toward the regeneration of cardiac tissue after MI, here, we provide proof of concept that the release of tyrosine kinase inhibitors from hydrogels could have beneficial effects on cardiomyocytes. We developed an injectable hydrogel consisting of thiolated hyaluronic acid and P123-maleimide micelles that can incorporate PF4618433 as well as the Src inhibitor Saracatinib and achieved sustained release (of note, Src activates Pyk2). Using neonatal rat ventricular myocytes in the presence of a phorbol ester, endothelin-1, or phenylephrine to stimulate cardiac hypertrophy, the release of PF4618433 from the hydrogel had the same ability to decrease Cx43 tyrosine phosphorylation and maintain Cx43 localization at the plasma membrane as when directly added to the growth media. Additional beneficial effects included decreases in apoptosis, the hypertrophic marker atrial natriuretic peptide (ANP), and serine kinases upregulated in hypertrophy. Finally, the presence of both PF4618433 and Saracatinib further decreased the level of ANP and apoptosis than each inhibitor alone, suggesting that a combinatorial approach may be most beneficial. These findings provide the groundwork to test if tyrosine kinase inhibitor release from hydrogels will have a beneficial effect in an animal model of MI-induced heart failure.
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Affiliation(s)
- Li Zheng
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Wen Shi
- Mary & Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Division of Cardiology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Bo Liu
- Mary & Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Division of Cardiology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Bin Duan
- Mary & Dick Holland Regenerative Medicine Program, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Division of Cardiology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
- Department of Surgery, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Paul Sorgen
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
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12
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Liu P, Cao B, Zhou Y, Zhang H, Wang C. Human umbilical cord-derived mesenchymal stem cells alleviate oxidative stress-induced islet impairment via the Nrf2/HO-1 axis. J Mol Cell Biol 2023; 15:mjad035. [PMID: 37245063 PMCID: PMC10681279 DOI: 10.1093/jmcb/mjad035] [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: 05/11/2022] [Revised: 01/10/2023] [Accepted: 02/14/2023] [Indexed: 05/29/2023] Open
Abstract
Hyperglycaemia-induced oxidative stress may disrupt insulin secretion and β-cell survival in diabetes mellitus by overproducing reactive oxygen species. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) exhibit antioxidant properties. However, the mechanisms by which hUC-MSCs protect β-cells from high glucose-induced oxidative stress remain underexplored. In this study, we showed that intravenously injected hUC-MSCs engrafted into the injured pancreas and promoted pancreatic β-cell function in a mouse model of type 1 diabetes mellitus. The in vitro study revealed that hUC-MSCs attenuated high glucose-induced oxidative stress and prevented β-cell impairment via the Nrf2/HO-1 signalling pathway. Nrf2 knockdown partially blocked the anti-oxidative effect of hUC-MSCs, resulting in β-cell decompensation in a high-glucose environment. Overall, these findings provide novel insights into how hUC-MSCs protect β-cells from high glucose-induced oxidative stress.
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Affiliation(s)
- Peng Liu
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Baige Cao
- Department of Endocrinology & Metabolism, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China
| | - Yang Zhou
- Translational Medical Center for Stem Cell Therapy, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200092, China
| | - Huina Zhang
- Stem Cell Translational Research Center, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China
| | - Congrong Wang
- Department of Endocrinology & Metabolism, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China
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Song J, Liu J, Cui C, Hu H, Zang N, Yang M, Yang J, Zou Y, Li J, Wang L, He Q, Guo X, Zhao R, Yan F, Liu F, Hou X, Sun Z, Chen L. Mesenchymal stromal cells ameliorate diabetes-induced muscle atrophy through exosomes by enhancing AMPK/ULK1-mediated autophagy. J Cachexia Sarcopenia Muscle 2023; 14:915-929. [PMID: 36708027 PMCID: PMC10067482 DOI: 10.1002/jcsm.13177] [Citation(s) in RCA: 51] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 11/21/2022] [Accepted: 01/02/2023] [Indexed: 01/29/2023] Open
Abstract
BACKGROUND Diabetes and obesity are associated with muscle atrophy that reduces life quality and lacks effective treatment. Mesenchymal stromal cell (MSC)-based therapy can ameliorate high fat-diet (HFD) and immobilization (IM)-induced muscle atrophy in mice. However, the effect of MSCs on muscle atrophy in type 2 diabetes mellitus (T2DM) and the potential mechanism is unclear. Here, we evaluated the efficacy and explored molecular mechanisms of human umbilical cord MSCs (hucMSCs) and hucMSC-derived exosomes (MSC-EXO) on diabetes- and obesity-induced muscle atrophy. METHODS Diabetic db/db mice, mice fed with high-fat diet (HFD), mice with hindlimb immobilization (IM), and C2C12 myotubes were used to explore the effect of hucMSCs or MSC-EXO in alleviating muscle atrophy. Grip strength test and treadmill running were used to measure skeletal muscle strength and performance. Body composition, muscle weight, and muscle fibre cross-sectional area (CSA) was used to evaluate muscle mass. RNA-seq analysis of tibialis anterior (TA) muscle and Western blot analysis of muscle atrophy signalling, including MuRF1 and Atrogin 1, were performed to investigate the underlying mechanisms. RESULTS hucMSCs increased grip strength (P = 0.0256 in db/db mice, P = 0.012 in HFD mice, P = 0.0097 in IM mice), running endurance (P = 0.0154 in HFD mice, P = 0.0006 in IM mice), and muscle mass (P = 0.0004 in db/db mice, P = 0.0076 in HFD mice, P = 0.0144 in IM mice) in all models tested, with elevated CSA of muscle fibres (P < 0.0001 in db/db mice and HFD mice, P = 0.0088 in IM mice) and reduced Atrogin1 (P = 0.0459 in db/db mice, P = 0.0088 in HFD mice, P = 0.0016 in IM mice) and MuRF1 expression (P = 0.0004 in db/db mice, P = 0.0077 in HFD mice, P = 0.0451 in IM mice). MSC-EXO replicated all these hucMSC-mediated changes (P = 0.0103 for grip strength, P = 0.013 for muscle mass, P < 0.0001 for CSA of muscle fibres, P = 0.0171 for Atrogin1 expression, and P = 0.006 for MuRF1 expression). RNA-seq revealed that hucMSCs activated the AMPK/ULK1 signalling and enhanced autophagy. Knockdown of AMPK or inhibition of autophagy with 3-methyladenine (3-MA) diminished the beneficial anti-atrophy effects of hucMSCs or MSC-EXO. CONCLUSIONS Our results suggest that human umbilical cord mesenchymal stromal cells mitigate diabetes- and obesity-induced muscle atrophy via enhancing AMPK/ULK1-mediated autophagy through exosomes, with implications of applying hucMSCs or hucMSC-derived exosomes to treat muscle atrophy.
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Affiliation(s)
- Jia Song
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Jidong Liu
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Chen Cui
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Huiqing Hu
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Nan Zang
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Mengmeng Yang
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Jingwen Yang
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Ying Zou
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Jinquan Li
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Lingshu Wang
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Qin He
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Xinghong Guo
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Ruxing Zhao
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Fei Yan
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Fuqiang Liu
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Xinguo Hou
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, Shandong, China.,Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, Shandong, China.,Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, Shandong, China.,Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan, Shandong, China
| | - Zheng Sun
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Li Chen
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, Shandong, China.,Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, Shandong, China.,Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, Shandong, China.,Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan, Shandong, China
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Ni C, Wu G, Miao T, Xu J. Wnt4 prevents apoptosis and inflammation of dental pulp cells induced by LPS by inhibiting the IKK/NF‑κB pathway. Exp Ther Med 2022; 25:75. [PMID: 36684653 PMCID: PMC9842946 DOI: 10.3892/etm.2022.11774] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 11/10/2022] [Indexed: 12/24/2022] Open
Abstract
Wnt4 has been shown to promote the recovery of odontogenic differentiation of dental pulp stem cells under inflammatory conditions, but its role in inflammation and apoptosis of pulpitis remains to be elucidated. Lipopolysaccharide (LPS) (10 µg/ml) was applied to treat the human dental pulp cells (HDPCs) for 24 h. Western blotting measured the expressions of inflammatory cytokines and apoptosis-related proteins. Cell apoptosis was measured by flow cytometry. The level of Wnt4 was evaluated by reverse transcription-quantitative PCR and western blotting. The results indicated that LPS could promote inflammatory response and apoptosis in HDPCs and downregulated Wnt4 expression was found in LPS-HDPCs. Overexpression of Wnt4 ameliorated cell inflammatory response and apoptosis, presented by reduced expressions of IL-8, IL-6, TNF-α, IL-1β, Bax, cleaved-caspase 3 and enhanced Bcl-2 expression as well as decreased apoptosis rate. Moreover, overexpression of Wnt4 reduced the phosphorylation levels of IKK2, IκBα and p65 proteins upregulated by LPS. Finally, overexpression of IKK2 reversed the effects of Wnt4 on inflammation and apoptosis of LPS-HDPCs and NF-κB inhibitor reversed the effect of IKK2 overexpression in LPS-HDPCs. Wnt4 inhibited LPS-triggered inflammation and apoptosis in HDPCs via regulating the IKK/NF-κB signaling pathway, which provided a new viewpoint for understanding the pathological mechanism of pulpitis.
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Affiliation(s)
- Chengli Ni
- College of Stomatology, Anhui Medical College, Hefei, Anhui 230601, P.R. China,Correspondence to: Ms. Chengli Ni, College of Stomatology, Anhui Medical College, 632 Furong Road, Hefei, Anhui 230601, P.R. China
| | - Gang Wu
- Shanghai Smartee Denti-Technology Co., Ltd., Shanghai 200120, P.R. China
| | - Tingting Miao
- College of Stomatology, Anhui Medical College, Hefei, Anhui 230601, P.R. China
| | - Jianguang Xu
- Key Laboratory of Oral Disease Research of Anhui Province, Department of Orthodontics, Stomatologic Hospital and College, Anhui Medical University, Hefei, Anhui 230032, P.R. China
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Naser AN, Lu Q, Chen YH. Three-Dimensional Culture of Murine Colonic Crypts to Study Intestinal Stem Cell Function Ex Vivo. J Vis Exp 2022:10.3791/64534. [PMID: 36314830 PMCID: PMC10460493 DOI: 10.3791/64534] [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] [Indexed: 08/29/2023] Open
Abstract
The intestinal epithelium regenerates every 5-7 days, and is controlled by the intestinal epithelial stem cell (IESC) population located at the bottom of the crypt region. IESCs include active stem cells, which self-renew and differentiate into various epithelial cell types, and quiescent stem cells, which serve as the reserve stem cells in the case of injury. Regeneration of the intestinal epithelium is controlled by the self-renewing and differentiating capabilities of these active IESCs. In addition, the balance of the crypt stem cell population and maintenance of the stem cell niche are essential for intestinal regeneration. Organoid culture is an important and attractive approach to studying proteins, signaling molecules, and environmental cues that regulate stem cell survival and functions. This model is less expensive, less time-consuming, and more manipulatable than animal models. Organoids also mimic the tissue microenvironment, providing in vivo relevance. The present protocol describes the isolation of colonic crypts, embedding these isolated crypt cells into a three-dimensional gel matrix system and culturing crypt cells to form colonic organoids capable of self-organization, proliferation, self-renewal, and differentiation. This model allows one to manipulate the environment-knocking out specific proteins such as claudin-7, activating/deactivating signaling pathways, etc.-to study how these effects influence the functioning of colonic stem cells. Specifically, the role of tight junction protein claudin-7 in colonic stem cell function was examined. Claudin-7 is vital for maintaining intestinal homeostasis and barrier function and integrity. Knockout of claudin-7 in mice induces an inflammatory bowel disease-like phenotype exhibiting intestinal inflammation, epithelial hyperplasia, weight loss, mucosal ulcerations, epithelial cell sloughing, and adenomas. Previously, it was reported that claudin-7 is required for intestinal epithelial stem cell functions in the small intestine. In this protocol, a colonic organoid culture system is established to study the role of claudin-7 in the large intestine.
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Affiliation(s)
- Amna N Naser
- Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University;
| | - Qun Lu
- Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University
| | - Yan-Hua Chen
- Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University
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Wang Y, Zhang JW, Wang JW, Wang JL, Zhang SC, Ma RY, Zhang J, Li Y, Liu PJ, Xue WJ, Zheng J, Ding XM. BMSCs overexpressed ISL1 reduces the apoptosis of islet cells through ANLN carrying exosome, INHBA, and caffeine. Cell Mol Life Sci 2022; 79:538. [PMID: 36190571 PMCID: PMC11802980 DOI: 10.1007/s00018-022-04571-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Revised: 08/28/2022] [Accepted: 09/22/2022] [Indexed: 11/24/2022]
Abstract
Early apoptosis of grafted islets is one of the main factors affecting the efficacy of islet transplantation. The combined transplantation of islet cells and bone marrow mesenchymal stem cells (BMSCs) can significantly improve the survival rate of grafted islets. Transcription factor insulin gene enhancer binding protein 1 (ISL1) is shown to promote the angiogenesis of grafted islets and the paracrine function of mesenchymal stem cells during the co-transplantation, yet the regulatory mechanism remains unclear. By using ISL1-overexpressing BMSCs and the subtherapeutic doses of islets for co-transplantation, we managed to reduce the apoptosis and improve the survival rate of the grafts. Our metabolomics and proteomics data suggested that ISL1 upregulates aniline (ANLN) and Inhibin beta A chain (INHBA), and stimulated the release of caffeine in the BMSCs. We then demonstrated that the upregulation of ANLN and INHBA was achieved by the binding of ISL1 to the promoter regions of the two genes. In addition, ISL1 could also promote BMSCs to release exosomes with high expression of ANLN, secrete INHBA and caffeine, and reduce streptozocin (STZ)-induced islets apoptosis. Thus, our study provides mechanical insight into the islet/BMSCs co-transplantation and paves the foundation for using conditioned medium to mimic the ISL1-overexpressing BMSCs co-transplantation.
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Affiliation(s)
- Ying Wang
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta Western Rd, Xi'an 710061, Shaanxi, China
| | - Jiang-Wei Zhang
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta Western Rd, Xi'an 710061, Shaanxi, China
| | - Jing-Wen Wang
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta Western Rd, Xi'an 710061, Shaanxi, China
| | - Jia-Le Wang
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta Western Rd, Xi'an 710061, Shaanxi, China
| | - Shu-Cong Zhang
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta Western Rd, Xi'an 710061, Shaanxi, China
| | - Rui-Yang Ma
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta Western Rd, Xi'an 710061, Shaanxi, China
| | - Jing Zhang
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta Western Rd, Xi'an 710061, Shaanxi, China
| | - Yang Li
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta Western Rd, Xi'an 710061, Shaanxi, China
| | - Pei-Jun Liu
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta Western Rd, Xi'an, 710061, Shaanxi, China
| | - Wu-Jun Xue
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta Western Rd, Xi'an 710061, Shaanxi, China
| | - Jin Zheng
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta Western Rd, Xi'an 710061, Shaanxi, China
| | - Xiao-Ming Ding
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta Western Rd, Xi'an 710061, Shaanxi, China.
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Ma X, Wang Y, Shi Y, Li S, Liu J, Li X, Zhong W, Pan Q. Exosomal miR-132-3p from mesenchymal stromal cells improves synaptic dysfunction and cognitive decline in vascular dementia. Stem Cell Res Ther 2022; 13:315. [PMID: 35841005 PMCID: PMC9284820 DOI: 10.1186/s13287-022-02995-w] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 01/26/2022] [Indexed: 12/28/2022] Open
Abstract
Background/aims Vascular dementia (VD) results in cognition and memory deficit. Exosomes and their carried microRNAs (miRs) contribute to the neuroprotective effects of mesenchymal stromal cells, and miR-132-3p plays a key role in neuron plasticity. Here, we investigated the role and underlying mechanism of MSC EX and their miR-132-3p cargo in rescuing cognition and memory deficit in VD mice. Methods Bilateral carotid artery occlusion was used to generate a VD mouse model. MiR-132-3p and MSC EX levels in the hippocampus and cortex were measured. At 24-h post-VD induction, mice were administered with MSC EX infected with control lentivirus (EXCon), pre-miR-132-3p-expressing lentivirus (EXmiR-132-3p), or miR-132-3p antago lentivirus (EXantagomiR-132-3p) intravenously. Behavioral and cognitive tests were performed, and the mice were killed in 21 days after VD. The effects of MSC EX on neuron number, synaptic plasticity, dendritic spine density, and Aβ and p-Tau levels in the hippocampus and cortex were determined. The effects of MSC EX on oxygen–glucose deprivation (OGD)-injured neurons with respect to apoptosis, and neurite elongation and branching were determined. Finally, the expression levels of Ras, phosphorylation of Akt, GSK-3β, and Tau were also measured. Results Compared with normal mice, VD mice exhibited significantly decreased miR-132-3p and MSC EX levels in the cortex and hippocampus. Compared with EXCon treatment, the infusion of EXmiR-132-3p was more effective at improving cognitive function and increasing miR-132-3p level, neuron number, synaptic plasticity, and dendritic spine density, while decreasing Aβ and p-Tau levels in the cortex and hippocampus of VD mice. Conversely, EXantagomiR-132-3p treatment significantly decreased miR-132-3p expression in cortex and hippocampus, as well as attenuated EXmiR-132-3p treatment-induced functional improvement. In vitro, EXmiR-132-3p treatment inhibited RASA1 protein expression, but increased Ras and the phosphorylation of Akt and GSK-3β, and decreased p-Tau levels in primary neurons by delivering miR-132-3p, which resulted in reduced apoptosis, and increased neurite elongation and branching in OGD-injured neurons. Conclusions Our studies suggest that miR-132-3p cluster-enriched MSC EX promotes the recovery of cognitive function by improving neuronal and synaptic dysfunction through activation of the Ras/Akt/GSK-3β pathway induced by downregulation of RASA1. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02995-w.
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Affiliation(s)
- Xiaotang Ma
- Department of Neurology, Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Yan Wang
- Institute of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang, 524001, China
| | - Yumeng Shi
- Department of Neurology, Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Suqing Li
- Department of Neurology, Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Jinhua Liu
- Department of Neurology, Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Xiangyong Li
- Institute of Biochemistry and Molecular Biology, Guangdong Medical University, Zhanjiang, 524001, China
| | - Wangtao Zhong
- Department of Neurology, Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China.
| | - Qunwen Pan
- Department of Neurology, Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China.
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Oxidative Stress in Ageing and Chronic Degenerative Pathologies: Molecular Mechanisms Involved in Counteracting Oxidative Stress and Chronic Inflammation. Int J Mol Sci 2022; 23:ijms23137273. [PMID: 35806275 PMCID: PMC9266760 DOI: 10.3390/ijms23137273] [Citation(s) in RCA: 148] [Impact Index Per Article: 49.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 06/24/2022] [Accepted: 06/24/2022] [Indexed: 12/17/2022] Open
Abstract
Ageing and chronic degenerative pathologies demonstrate the shared characteristics of high bioavailability of reactive oxygen species (ROS) and oxidative stress, chronic/persistent inflammation, glycation, and mitochondrial abnormalities. Excessive ROS production results in nucleic acid and protein destruction, thereby altering the cellular structure and functional outcome. To stabilise increased ROS production and modulate oxidative stress, the human body produces antioxidants, “free radical scavengers”, that inhibit or delay cell damage. Reinforcing the antioxidant defence system and/or counteracting the deleterious repercussions of immoderate reactive oxygen and nitrogen species (RONS) is critical and may curb the progression of ageing and chronic degenerative syndromes. Various therapeutic methods for ROS and oxidative stress reduction have been developed. However, scientific investigations are required to assess their efficacy. In this review, we summarise the interconnected mechanism of oxidative stress and chronic inflammation that contributes to ageing and chronic degenerative pathologies, including neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), cardiovascular diseases CVD, diabetes mellitus (DM), and chronic kidney disease (CKD). We also highlight potential counteractive measures to combat ageing and chronic degenerative diseases.
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Hu H, Zhao R, He Q, Cui C, Song J, Guo X, Zang N, Yang M, Zou Y, Yang J, Li J, Wang L, Xia L, Wang L, He F, Hou X, Yan F, Chen L. cGAS-STING mediates cytoplasmic mitochondrial-DNA-induced inflammatory signal transduction during accelerated senescence of pancreatic β-cells induced by metabolic stress. FASEB J 2022; 36:e22266. [PMID: 35357035 DOI: 10.1096/fj.202101988r] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 02/21/2022] [Accepted: 03/08/2022] [Indexed: 12/17/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is an age-related disease characterized by impaired pancreatic β cell function and insulin resistance. Recent studies have shown that the accumulation of senescent β cells under metabolic stress conditions leads to the progression of T2DM, while senolysis can improve the prognosis. However, the specific mechanism of β cell senescence is still unclear. In this study, we found that the increased load of senescence pancreatic β cells in both older mice and obese mice induced by high-fat diet (HFD) (DIO mice) was accompanied by activation of the Cyclic GMP-AMP synthase (cGAS) - stimulator of interferon genes (STING) pathway and using cGAS or STING small interfering RNA or STING inhibitor C176 to downregulate this pathway reduced the senescence-associated secretion profile (SASP) and senescence of Min6 cells treated with palmitic acid or hydrogen peroxide. C176 intervention in DIO mice also significantly reduced the inflammation and senescence of the islets, thereby protecting the function of pancreatic β cell and glucose metabolism. Our study further revealed that mitochondrial DNA (mtDNA) leakage under metabolic stress conditions was critical for the activation of the cGAS-STING pathway, which can be reversed by the mtDNA depleting agent ethidium bromide. Consistently, mtDNA leakage was more severe in older mice and was accelerated by a chronic HFD. In conclusion, we demonstrate that cytoplasmic mtDNA activates the cGAS-STING pathway to mediate SASP during the accelerated senescence of pancreatic β-cells induced by metabolic stress, and this process can be downregulated by the STING inhibitor C176.
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Affiliation(s)
- Huiqing Hu
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Ruxing Zhao
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China.,Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China.,Jinan Clinical Research Center for Endocrine and Metabolic Diseases, Jinan, China
| | - Qin He
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Chen Cui
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jia Song
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xinghong Guo
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Nan Zang
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Mengmeng Yang
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Ying Zou
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jingwen Yang
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jinquan Li
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Liming Wang
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Longqing Xia
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Lingshu Wang
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China.,Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China.,Jinan Clinical Research Center for Endocrine and Metabolic Diseases, Jinan, China
| | - Falian He
- Nuolai Biomedical Technology Co., Ltd., Taian, China
| | - Xinguo Hou
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China.,Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China.,Jinan Clinical Research Center for Endocrine and Metabolic Diseases, Jinan, China
| | - Fei Yan
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China.,Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China.,Jinan Clinical Research Center for Endocrine and Metabolic Diseases, Jinan, China
| | - Li Chen
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, China.,Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, China.,Jinan Clinical Research Center for Endocrine and Metabolic Diseases, Jinan, China.,Nuolai Biomedical Technology Co., Ltd., Taian, China
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Li X, Zhang X, Liu Y, Pan R, Liang X, Huang L, Yang C. Exosomes derived from mesenchyml stem cells ameliorate oxygen-glucose deprivation/reoxygenation-induced neuronal injury via transferring MicroRNA-194 and targeting Bach1. Tissue Cell 2021; 73:101651. [PMID: 34600339 DOI: 10.1016/j.tice.2021.101651] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 09/01/2021] [Accepted: 09/13/2021] [Indexed: 01/13/2023]
Abstract
The neuroprotective function of miR-194 on neurovascular endothelial cell injury is perceived as a novel method for clinical therapy. So are exosomes (EXs), being attractive in neurofunctional recovery. However, whether EXs derived from mesenchymal stromal cells (MSCs) perform the same efficacy by transferring miR-194 and the underlying mechanism remain vague. This study rooted in oxygen-glucose deprivation/reoxygenation (OGD/R) model. MSCs were isolated by gradient centrifugation and identified by flow cytometry. EXs were obtained through ultracentrifugation, whereas protein levels of specific markers (CD63, TGS101), together with Bach1, Nrf2 and HO-1 were measured by western blot. The relative mRNA expressions of Bach1, NOX1, AGSL4, GPX4 and miR-194 were measured by RT-qPCR assays. Cell viability was measured by cell counting kit-8, and cell migration was detected by wound healing assay. The interaction between miR-194 and Bach1 was predicted by starBase and confirmed by dual luciferase reporter assay. OGD/R dampened cell viability and miR-194 expression. Bach1 could bind with miR-194. miR-194 mimic attenuated the effect of OGD/R on cell viability and protein levels of Nrf2, HO-1 and Bach1, whereas Bach1 overexpression reversed the effect of miR-194 mimics. MSC-EXs could merge with HBMECs. Based on this, MSC-EXs loaded with miR-194 downregulated Bach1 protein level and iron content and the mRNA expressions of NOX1 and ACSL4, yet upregulated miR-194 and GPX4 expressions and Nrf2/HO-1 protein level in OGD/R-injured cells, whereas those carrying ShmiR-194 had the opposite effects. Our study suggested MSC-EXs loaded with miR-194 attenuated OGD/R-induced injury via targeting Bach1, providing a new therapeutic strategy for cerebral injuries.
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Affiliation(s)
- Xu Li
- Department of Neurosurgey, The First Affiliated Hospital of Zhejiang Chinese Medical University, China
| | - Xin Zhang
- Department of Neurosurgey, The First Affiliated Hospital of Zhejiang Chinese Medical University, China
| | - Yajun Liu
- Department of Neurosurgey, The First Affiliated Hospital of Zhejiang Chinese Medical University, China
| | - Ruihan Pan
- Department of Neurosurgey, The First Affiliated Hospital of Zhejiang Chinese Medical University, China
| | - Xiaolong Liang
- Department of Neurosurgey, The First Affiliated Hospital of Zhejiang Chinese Medical University, China
| | - Lifa Huang
- Department of Neurosurgey, The First Affiliated Hospital of Zhejiang Chinese Medical University, China
| | - Chao Yang
- Department of Neurosurgey, The First Affiliated Hospital of Zhejiang Chinese Medical University, China.
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Song J, He Q, Guo X, Wang L, Wang J, Cui C, Hu H, Yang M, Cui Y, Zang N, Yan F, Liu F, Sun Y, Liang K, Qin J, Zhao R, Wang C, Sun Z, Hou X, Li W, Chen L. Mesenchymal stem cell-conditioned medium alleviates high fat-induced hyperglucagonemia via miR-181a-5p and its target PTEN/AKT signaling. Mol Cell Endocrinol 2021; 537:111445. [PMID: 34464683 DOI: 10.1016/j.mce.2021.111445] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 08/08/2021] [Accepted: 08/25/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND α-cell dysregulation gives rise to fasting and postprandial hyperglycemia in type 2 diabetes mellitus(T2DM). Administration of Mesenchymal stem cells (MSCs) or their conditioned medium can improve islet function and enhance insulin secretion. However, studies showing the direct effect of MSCs on islet α-cell dysfunction are limited. METHODS In this study, we used high-fat diet (HFD)-induced mice and α-cell line exposure to palmitate (PA) to determine the effects of bone marrow-derived MSC-conditioned medium (bmMSC-CM) on glucagon secretion. Plasma and supernatant glucagon were detected by enzyme-linked immunosorbent assay(ELISA). To investigate the potential signaling pathways, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), AKT and phosphorylated AKT(p-AKT) were assessed by Western blotting. RESULTS In vivo, bmMSC-CM infusion improved the glucose and insulin tolerance and protected against HFD-induced hyperglycemia and hyperglucagonemia. Meanwhile, bmMSC-CM infusion ameliorated HFD-induced islet hypertrophy and decreased α- and β-cell area. Consistently, in vitro, glucagon secretion from α-cells or primary islets was inhibited by bmMSC-CM, accompanied by reduction of intracellular PTEN expression and restoration of AKT signaling. Previous studies and the TargetScan database indicate that miR-181a and its target PTEN play vital roles in ameliorating α-cell dysfunction. We observed that miR-181a-5p was highly expressed in BM-MSCs but prominently lower in αTC1-6 cells. Overexpression or downregulation of miR-181a-5p respectively alleviated or aggravated glucagon secretion in αTC1-6 cells via the PTEN/AKT signaling pathway. CONCLUSIONS Our observations suggest that MSC-derived miR-181a-5p mitigates glucagon secretion of α-cells by regulating PTEN/AKT signaling, which provides novel evidence demonstrating the potential for MSCs in treating T2DM.
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Affiliation(s)
- Jia Song
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Qin He
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Xinghong Guo
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Lingshu Wang
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Jinbang Wang
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Chen Cui
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Huiqing Hu
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Mengmeng Yang
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Yixin Cui
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Nan Zang
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Fei Yan
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Fuqiang Liu
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Yujing Sun
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Kai Liang
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Jun Qin
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Ruxing Zhao
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Chuan Wang
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Zheng Sun
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Xinguo Hou
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China; Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, 250012, Shandong, China; Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, 250012, Shandong, China; Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan, 250012, Shandong, China
| | - Wenjuan Li
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China; Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, 250012, Shandong, China; Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, 250012, Shandong, China; Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan, 250012, Shandong, China.
| | - Li Chen
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China; Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, 250012, Shandong, China; Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, 250012, Shandong, China; Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan, 250012, Shandong, China.
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Guo X, Cui C, Song J, He Q, Zang N, Hu H, Wang X, Li D, Wang C, Hou X, Li X, Liang K, Yan F, Chen L. Mof acetyltransferase inhibition ameliorates glucose intolerance and islet dysfunction of type 2 diabetes via targeting pancreatic α-cells. Mol Cell Endocrinol 2021; 537:111425. [PMID: 34391847 DOI: 10.1016/j.mce.2021.111425] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 08/10/2021] [Accepted: 08/12/2021] [Indexed: 01/04/2023]
Abstract
BACKGROUND Previously, we reported that Mof was highly expressed in α-cells, and its knockdown led to ameliorated fasting blood glucose (FBG) and glucose tolerance in non-diabetic mice, attributed by reduced total α-cell but enhanced prohormone convertase (PC)1/3-positive α-cell mass. However, how Mof and histone 4 lysine 16 acetylation (H4K16ac) control α-cell and whether Mof inhibition improves glucose handling in type 2 diabetes (T2DM) mice remain unknown. METHODS Mof overexpression and chromatin immunoprecipitation sequence (ChIP-seq) based on H4K16ac were applied to determine the effect of Mof on α-cell transcriptional factors and underlying mechanism. Then we administrated mg149 to α-TC1-6 cell line, wild type, db/db and diet-induced obesity (DIO) mice to observe the impact of Mof inhibition in vitro and in vivo. In vitro, western blotting and TUNEL staining were used to examine α-cell apoptosis and function. In vivo, glucose tolerance, hormone levels, islet population, α-cell ratio and the co-staining of glucagon and PC1/3 or PC2 were examined. RESULTS Mof activated α-cell-specific transcriptional network. ChIP-seq results indicated that H4K16ac targeted essential genes regulating α-cell differentiation and function. Mof activity inhibition in vitro caused impaired α-cell function and enhanced apoptosis. In vivo, it contributed to ameliorated glucose intolerance and islet dysfunction, characterized by decreased fasting glucagon and elevated post-challenge insulin levels in T2DM mice. CONCLUSION Mof regulates α-cell differentiation and function via acetylating H4K16ac and H4K16ac binding to Pax6 and Foxa2 promoters. Mof inhibition may be a potential interventional target for T2DM, which led to decreased α-cell ratio but increased PC1/3-positive α-cells.
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Affiliation(s)
- Xinghong Guo
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Chen Cui
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Jia Song
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Qin He
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Nan Zang
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Huiqing Hu
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Xiaojie Wang
- Department of Pharmacology, Basic Medicine School of Shandong University, Jinan, 250012, Shandong, China
| | - Danyang Li
- Department of Rehabilitation, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Chuan Wang
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Xinguo Hou
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Xiangzhi Li
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, Life Science School of Shandong University, Qingdao, 266237, Shandong, China
| | - Kai Liang
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China; Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, 250012, Shandong, China; Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, 250012, Shandong, China; Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan, 250012, Shandong, China
| | - Fei Yan
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China; Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, 250012, Shandong, China; Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, 250012, Shandong, China; Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan, 250012, Shandong, China.
| | - Li Chen
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China; Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, 250012, Shandong, China; Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, 250012, Shandong, China; Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan, 250012, Shandong, China.
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Rezazadeh H, Sharifi MR, Sharifi M, Soltani N. Magnesium sulfate improves insulin resistance in high fat diet induced diabetic parents and their offspring. Eur J Pharmacol 2021; 909:174418. [PMID: 34411605 DOI: 10.1016/j.ejphar.2021.174418] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 07/31/2021] [Accepted: 08/11/2021] [Indexed: 01/01/2023]
Abstract
In the present study, first, the role of high-fat diet (HFD) in insulin resistance (IR) in offspring with diabetic and non-diabetic parents, and then the effect of magnesium sulfate (Mg) administration on improved IR in HFD diabetic parents, and their offspring were investigated. Induction of diabetes was carried out by eating HFD and a low dose of streptozotocin (STZ). Diabetic rats were divided into three groups: diabetic control (DC), insulin, and Mg-treated (Mg). The non-diabetic control (NDC) group received a normal diet. Their offspring were fed on a regular diet for four months. Blood glucose and body weight of all animals were measured weekly, and IPGTT, urine volume, and water intake were measured monthly. In both parents and their offspring, the hyperinsulinemic euglycemic clamp was conducted, and blood samples were obtained. In all groups, the expression of IRS1, Akt and GLUT4 genes in muscle was measured. The HFD-fed rats exhibited a significant increase in blood glucose, body weight and IPGTT. In diabetic parents and their offspring, Mg or insulin therapy lowered blood glucose, IPGTT, and HbA1c relative to the DC group. They also increased GIR in parents and their offspring. Compared to the DC group, the expression of IRS1, Akt and GLUT4 genes was increased in both parents. Mg had positive effects on the expression of IRS1, Akt and GLUT4 genes in Mg treated offspring and reduced IR in them. As a result, magnesium may have beneficial effects on IR by increasing the expression of IRS1, Akt and GLUT4 genes.
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Affiliation(s)
- Hossein Rezazadeh
- Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohammad Reza Sharifi
- Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohmmadreza Sharifi
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Nepton Soltani
- Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
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Roles and action mechanisms of WNT4 in cell differentiation and human diseases: a review. Cell Death Discov 2021; 7:287. [PMID: 34642299 PMCID: PMC8511224 DOI: 10.1038/s41420-021-00668-w] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 08/24/2021] [Accepted: 09/20/2021] [Indexed: 02/07/2023] Open
Abstract
WNT family member 4 (WNT4), which belongs to the conserved WNT protein family, plays an important role in the development and differentiation of many cell types during the embryonic development and adult homeostasis. Increasing evidence has shown that WNT4 is a special ligand that not only activates the β-catenin independent pathway but also acts on β-catenin signaling based on different cellular processes. This article is a summary of the current knowledge about the expression, regulation, and function of WNT4 ligands and their signal pathways in cell differentiation and human disease processes. WNT4 is a promoter in osteogenic differentiation in bone marrow stromal cells (BMSCs) by participating in bone homeostasis regulation in osteoporotic diseases. Non-canonical WNT4 signaling is necessary for metabolic maturation of pancreatic β-cell. WNT4 is also necessary for decidual cell differentiation and decidualization, which plays an important role in preeclampsia. WNT4 promotes neuronal differentiation of neural stem cell and dendritic cell (DC) into conventional type 1 DC (cDC1). Besides, WNT4 mediates myofibroblast differentiation in the skin, kidney, lung, and liver during scarring or fibrosis. On the negative side, WNT4 is highly expressed in cancer tissues, playing a pro-carcinogenic role in many cancer types. This review provides an overview of the progress in elucidating the role of WNT4 signaling pathway components in cell differentiation in adults, which may provide useful clues for the diagnosis, prevention, and therapy of human diseases.
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Khamis T, Abdelalim AF, Saeed AA, Edress NM, Nafea A, Ebian HF, Algendy R, Hendawy DM, Arisha AH, Abdallah SH. Breast milk MSCs upregulated β-cells PDX1, Ngn3, and PCNA expression via remodeling ER stress /inflammatory /apoptotic signaling pathways in type 1 diabetic rats. Eur J Pharmacol 2021; 905:174188. [PMID: 34004210 DOI: 10.1016/j.ejphar.2021.174188] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 04/30/2021] [Accepted: 05/12/2021] [Indexed: 01/01/2023]
Abstract
Type 1 diabetes mellitus (T1DM) is one of the autoimmune diseases characterized by beta-cell dysfunction with serious health complications. Br-MSCs represent a novel valid candidate in regenerative medicine disciplines. Yet, the full potential of Br-MSCs in managing type 1 diabetes remains elusive. Indeed, this study was designed to explore a novel approach investigating the possible regenerative capacity of Br-MSCs in type1 diabetic islet on the level of the cellular mRNA expression of different molecular pathways involved in pancreatic beta-cell dysfunction. Sixty adult male Sprague-Dawley rats were randomly assigned into 3 groups (20 rats each); the control group, type1 diabetic group, and the type 1 diabetic Br-MSCs treated group. And, for the first time, our results revealed that intraperitoneally transplanted Br-MSCs homed to the diabetic islet and improved fasting blood glucose, serum insulin level, pancreatic oxidative stress, upregulated pancreatic mRNA expression for: regenerative markers (Pdx1, Ngn3, PCNA), INS, beta-cell receptors (IRS1, IRβ, PPARγ), pancreatic growth factors (IGF-1, VEGFβ1, FGFβ), anti-inflammatory cytokine (IL10) and anti-apoptotic marker (BCL2) too, Br-MSCs downregulated pancreatic mRNA expression for: inflammatory markers (NFKβ, TNFα, IL1β, IL6, IL8, MCP1), apoptotic markers for both intrinsic and extrinsic pathways (FAS, FAS-L, P53, P38, BAX, Caspase3), ER stress markers (ATF6, ATF3, ATF4, BIP, CHOP, JNK, XBP1) and autophagy inhibitor (mTOR). In conclusion, Br-MSCs could be considered as a new insight in beta cell regenerative therapy improving the deteriorated diabetic islet microenvironment via modulating; ER stress, inflammatory, and apoptotic signaling pathways besides, switching on the cellular quality control system (autophagy) thus enhancing beta-cell function.
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Affiliation(s)
- Tarek Khamis
- Department of Pharmacology, Faculty of Veterinary Medicine, Zagazig University, 44519, Zagazig, Egypt; Laboratory of Biotechnology, Faculty of Veterinary Medicine, Zagazig University, 44519, Zagazig, Egypt.
| | - Abdelalim F Abdelalim
- Department of Pharmacology, Faculty of Veterinary Medicine, Zagazig University, 44519, Zagazig, Egypt
| | - Ahmed A Saeed
- Department of Pharmacology, Faculty of Veterinary Medicine, Zagazig University, 44519, Zagazig, Egypt
| | - Nagah M Edress
- Department of Pharmacology, Faculty of Veterinary Medicine, Zagazig University, 44519, Zagazig, Egypt
| | - Alaa Nafea
- Department of Pediatrics, Faculty of Medicine, Zagazig University, 44519, Zagazig, Egypt
| | - Huda F Ebian
- Department of Clinical Pathology, Faculty of Medicine, Zagazig University, 44519, Zagazig, Egypt
| | - Reem Algendy
- Department of Milk Hygiene, Food Control Department, Faculty of Veterinary Medicine, Zagazig University, 44519, Zagazig, Egypt
| | - Doaa M Hendawy
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Zagazig University, 44511, Zagazig, Egypt
| | - Ahmed Hamed Arisha
- Department of Animal Physiology and Biochemistry, Faculty of Veterinary Medicine, Badr University in Cairo (BUC), Badr City, Cairo, Egypt; Department of Physiology, Faculty of Veterinary Medicine, Zagazig University, 44519, Zagazig, Egypt; Laboratory of Biotechnology, Faculty of Veterinary Medicine, Zagazig University, 44519, Zagazig, Egypt.
| | - Somia Hassan Abdallah
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Zagazig University, 44511, Zagazig, Egypt
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He Q, Song J, Cui C, Wang J, Hu H, Guo X, Yang M, Wang L, Yan F, Liang K, Liu Z, Liu F, Sun Z, Dong M, Hou X, Chen L. Mesenchymal stem cell-derived exosomal miR-146a reverses diabetic β-cell dedifferentiation. Stem Cell Res Ther 2021; 12:449. [PMID: 34380570 PMCID: PMC8356465 DOI: 10.1186/s13287-021-02371-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 05/05/2021] [Indexed: 01/06/2023] Open
Abstract
Background Mesenchymal stem cells (MSCs) show promising therapeutic potential in treating type 2 diabetes mellitus (T2DM) in clinical studies. Accumulating evidence has suggested that the therapeutic effects of MSCs are not due to their direct differentiation into functional β-cells but are instead mediated by their paracrine functions. Among them, exosomes, nano-sized extracellular vesicles, are important substances that exert paracrine functions. However, the underlying mechanisms of exosomes in ameliorating T2DM remain largely unknown. Methods Bone marrow mesenchymal stem cell (bmMSC)-derived exosomes (bmMDEs) were administrated to T2DM rats and high-glucose-treated primary islets in order to detect their effects on β-cell dedifferentiation. Differential miRNAs were then screened via miRNA sequencing, and miR-146a was isolated after functional verification. TargetScan, reporter gene detection, insulin secretion assays, and qPCR validation were used to predict downstream target genes and involved signaling pathways of miR-146a. Results Our results showed that bmMDEs reversed diabetic β-cell dedifferentiation and improved β-cell insulin secretion both in vitro and in vivo. Results of miRNA sequencing in bmMDEs and subsequent functional screening demonstrated that miR-146a, a highly conserved miRNA, improved β-cell function. We further found that miR-146a directly targeted Numb, a membrane-bound protein involved in cell fate determination, leading to activation of β-catenin signaling in β-cells. Exosomes derived from miR-146a-knockdown bmMSCs lost the ability to improve β-cell function. Conclusions These findings demonstrate that bmMSC-derived exosomal miR-146a protects against diabetic β-cell dysfunction by acting on the NUMB/β-catenin signaling pathway, which may represent a novel therapeutic strategy for T2DM. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02371-0.
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Affiliation(s)
- Qin He
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, No. 107 Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Jia Song
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, No. 107 Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Chen Cui
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, No. 107 Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Jinbang Wang
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, No. 107 Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Huiqing Hu
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, No. 107 Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Xinghong Guo
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, No. 107 Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Mengmeng Yang
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, No. 107 Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Lingshu Wang
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, No. 107 Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Fei Yan
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, No. 107 Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Kai Liang
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, No. 107 Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Zhaojian Liu
- Department of Cell Biology, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China
| | - Fuqiang Liu
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, No. 107 Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Zheng Sun
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, No. 107 Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Ming Dong
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, No. 107 Wenhua Xi Road, Jinan, 250012, Shandong, China.,Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, 250012, China.,Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, 250012, China
| | - Xinguo Hou
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, No. 107 Wenhua Xi Road, Jinan, 250012, Shandong, China.,Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, 250012, China.,Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, 250012, China
| | - Li Chen
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, No. 107 Wenhua Xi Road, Jinan, 250012, Shandong, China. .,Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, 250012, China. .,Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, 250012, China. .,Jinan Clinical Research Center for Endocrine and Metabolic Diseases, Jinan, 250012, China.
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El-Derany MO, Noureldein MH. Bone marrow mesenchymal stem cells and their derived exosomes resolve doxorubicin-induced chemobrain: critical role of their miRNA cargo. Stem Cell Res Ther 2021; 12:322. [PMID: 34090498 PMCID: PMC8180158 DOI: 10.1186/s13287-021-02384-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 05/13/2021] [Indexed: 02/06/2023] Open
Abstract
Background Doxorubicin (DOX), a widely used chemotherapeutic agent, can cause neurodegeneration in the brain, which leads to a condition known as chemobrain. In fact, chemobrain is a deteriorating condition which adversely affects the lives of cancer survivors. This study aimed to examine the potential therapeutic effects of bone marrow mesenchymal stem cells (BMSCs) and their derived exosomes (BMSCs-Exo) in DOX-induced chemobrain in rat models. Methods Chemobrain was induced by exposing rats to DOX (2 mg/kg, i.p) once weekly for 4 consecutive weeks. After 48 h of the last DOX dose, a subset of rats was supplied with either an intravenous injection of BMSCs (1 × 106) or a single dose of 150 μg of BMSCs-Exo. Behavioral tests were conducted 7 days post injection. Rats were sacrificed after 14 days from BMSCs or BMSCs-Exo injection. Results BMSCs and BMSCs-Exo successfully restored DOX-induced cognitive and behavioral distortion. These actions were mediated via decreasing hippocampal neurodegeneration and neural demyelination through upregulating neural myelination factors (myelin%, Olig2, Opalin expression), neurotropic growth factors (BDNF, FGF-2), synaptic factors (synaptophysin), and fractalkine receptor expression (Cx3cr1). Halting neurodegeneration in DOX-induced chemobrain was achieved through epigenetic induction of key factors in Wnt/β-catenin and hedgehog signaling pathways mediated primarily by the most abundant secreted exosomal miRNAs (miR-21-5p, miR-125b-5p, miR-199a-3p, miR-24-3p, let-7a-5p). Moreover, BMSCs and BMSCs-Exo significantly abrogate the inflammatory state (IL-6, TNF-α), apoptotic state (BAX/Bcl2), astrocyte, and microglia activation (GFAP, IBA-1) in DOX-induced chemobrain with a significant increase in the antioxidant mediators (GSH, GPx, SOD activity). Conclusions BMSCs and their derived exosomes offer neuroprotection against DOX-induced chemobrain via genetic and epigenetic abrogation of hippocampal neurodegeneration through modulating Wnt/β-catenin and hedgehog signaling pathways and through reducing inflammatory, apoptotic, and oxidative stress state. Graphical abstract Proposed mechanisms of the protective effects of bone marrow stem cells (BMSCs) and their exosomes (BMSCs-Exo) in doxorubicin (DOX)-induced chemobrain. Blue arrows: induce. Red arrows: inhibit.
![]() Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02384-9.
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Affiliation(s)
- Marwa O El-Derany
- Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Cairo, 11566, Egypt.
| | - Mohamed H Noureldein
- Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Cairo, 11566, Egypt.,Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.,American University of Beirut Diabetes Program, Beirut, Lebanon
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Choi MY, Lim SJ, Kim MJ, Wee YM, Kwon H, Jung CH, Kim YH, Han DJ, Shin S. Islet isograft transplantation improves insulin sensitivity in a murine model of type 2 diabetes. Endocrine 2021; 72:660-671. [PMID: 33713015 DOI: 10.1007/s12020-021-02655-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Accepted: 01/29/2021] [Indexed: 12/25/2022]
Abstract
PURPOSE Type 2 diabetes develops in the presence of chronic overnutrition and genetic susceptibility, and causes insulin resistance and relative insulin deficiency. We hypothesized that islet transplantation can improve insulin sensitivity by modifying the mediators of insulin sensitivity in the pancreas, liver, muscle, and adipose tissues. METHODS Eight-week-old male mice were used as both recipients and donors in this study. To induce type 2 diabetes with partial β-cell failure, the mice were fed a high-fat diet for 4 weeks and then injected with low-dose streptozotocin. Approximately 400 islet cells from a donor mouse were injected into the renal capsule of a recipient mouse for islet transplantation. After 6 weeks following transplantation, the mediators of insulin sensitivity in the pancreas, liver, muscle, and adipose tissues were quantitatively compared between islet-transplanted and non-transplanted groups. RESULTS Intravenous glucose tolerance test showed that whereas the non-transplanted mice failed to show notable reductions in the glucose level, the islet-transplanted mice showed significant reductions in the serum glucose level to ~200 mg/dL at 6 weeks after islet transplantation. The islet-transplanted mice showed significantly higher Matsuda index and significantly lower HOMA-IR than did the non-transplanted mice, thus signifying improved insulin sensitivity. CONCLUSIONS Islet transplantation resulted in improvements in multiple indices of insulin sensitivity in a murine model of type 2 diabetes. Islet transplantation may be utilized to improve insulin sensitivity in patients with type 2 diabetes.
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Affiliation(s)
- Monica Young Choi
- Division of Kidney and Pancreas Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Seong Jun Lim
- Division of Kidney and Pancreas Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Mi Joung Kim
- Division of Kidney and Pancreas Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Yu-Mee Wee
- Division of Kidney and Pancreas Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Hyunwook Kwon
- Division of Kidney and Pancreas Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Chang Hee Jung
- Asan Diabetes Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Young Hoon Kim
- Division of Kidney and Pancreas Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Duck Jong Han
- Division of Kidney and Pancreas Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Sung Shin
- Division of Kidney and Pancreas Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
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Nie X, Wei X, Ma H, Fan L, Chen WD. The complex role of Wnt ligands in type 2 diabetes mellitus and related complications. J Cell Mol Med 2021; 25:6479-6495. [PMID: 34042263 PMCID: PMC8278111 DOI: 10.1111/jcmm.16663] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 05/02/2021] [Accepted: 05/10/2021] [Indexed: 12/15/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is one of the major chronic diseases, whose prevalence is increasing dramatically worldwide and can lead to a range of serious complications. Wnt ligands (Wnts) and their activating Wnt signalling pathways are closely involved in the regulation of various processes that are important for the occurrence and progression of T2DM and related complications. However, our understanding of their roles in these diseases is quite rudimentary due to the numerous family members of Wnts and conflicting effects via activating the canonical and/or non-canonical Wnt signalling pathways. In this review, we summarize the current findings on the expression pattern and exact role of each human Wnt in T2DM and related complications, including Wnt1, Wnt2, Wnt2b, Wnt3, Wnt3a, Wnt4, Wnt5a, Wnt5b, Wnt6, Wnt7a, Wnt7b, Wnt8a, Wnt8b, Wnt9a, Wnt9b, Wnt10a, Wnt10b, Wnt11 and Wnt16. Moreover, the role of main antagonists (sFRPs and WIF-1) and coreceptor (LRP6) of Wnts in T2DM and related complications and main challenges in designing Wnt-based therapeutic approaches for these diseases are discussed. We hope a deep understanding of the mechanistic links between Wnt signalling pathways and diabetic-related diseases will ultimately result in a better management of these diseases.
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Affiliation(s)
- Xiaobo Nie
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, People's Hospital of Hebi, Henan University, Kaifeng, China
| | - Xiaoyun Wei
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, People's Hospital of Hebi, Henan University, Kaifeng, China
| | - Han Ma
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, People's Hospital of Hebi, Henan University, Kaifeng, China
| | - Lili Fan
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, People's Hospital of Hebi, Henan University, Kaifeng, China
| | - Wei-Dong Chen
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, People's Hospital of Hebi, Henan University, Kaifeng, China.,Key Laboratory of Molecular Pathology, School of Basic Medical Science, Inner Mongolia Medical University, Hohhot, China
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30
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Harman RM, Marx C, Van de Walle GR. Translational Animal Models Provide Insight Into Mesenchymal Stromal Cell (MSC) Secretome Therapy. Front Cell Dev Biol 2021; 9:654885. [PMID: 33869217 PMCID: PMC8044970 DOI: 10.3389/fcell.2021.654885] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 03/01/2021] [Indexed: 12/13/2022] Open
Abstract
The therapeutic potential of the mesenchymal stromal cell (MSC) secretome, consisting of all molecules secreted by MSCs, is intensively studied. MSCs can be readily isolated, expanded, and manipulated in culture, and few people argue with the ethics of their collection. Despite promising pre-clinical studies, most MSC secretome-based therapies have not been implemented in human medicine, in part because the complexity of bioactive factors secreted by MSCs is not completely understood. In addition, the MSC secretome is variable, influenced by individual donor, tissue source of origin, culture conditions, and passage. An increased understanding of the factors that make up the secretome and the ability to manipulate MSCs to consistently secrete factors of biologic importance will improve MSC therapy. To aid in this goal, we can draw from the wealth of information available on secreted factors from MSC isolated from veterinary species. These translational animal models will inspire efforts to move human MSC secretome therapy from bench to bedside.
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Affiliation(s)
| | | | - Gerlinde R. Van de Walle
- Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY, United States
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31
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Hu W, Wang R, Sun B. Meteorin-Like Ameliorates β Cell Function by Inhibiting β Cell Apoptosis of and Promoting β Cell Proliferation via Activating the WNT/β-Catenin Pathway. Front Pharmacol 2021; 12:627147. [PMID: 33815109 PMCID: PMC8010136 DOI: 10.3389/fphar.2021.627147] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Accepted: 02/03/2021] [Indexed: 11/29/2022] Open
Abstract
Meteorin-like (Metrnl) is a newly discovered myokine. Plasma Metrnl is decreased in subjects with newly diagnosed type 2 diabetes (T2D) and correlated with insulin resistance. This study aims to determine the effects of Metrnl on the apoptosis and proliferation of β cell. Mouse insulinoma MIN6 cells were divided into six groups: normal control, low glucose, high glucose, Vehicle, Metrnl, and Dickkopf 1 (DKK1) groups. MIN6 cells in Metrnl group were transfected with recombinant pCDH-Metrnl vector. WNT/β-catenin pathway was inhibited using DKK1. Then the apoptosis of MIN6 cells was detected using flow cytometry and TUNEL labeling. Immunofluorescence of Ki67 or Edu-594 was used to determine the β cell proliferation. db/db mice were confirmed as T2D group. Lentivirus-Metrnl was injected from the caudal vein of db/db mice once every two weeks for two times. High glucose induced the apoptosis of MIN6 cells and elevated expression of caspase 3. In addition, high glucose resulted in reduced β cell proliferation, cell viability, insulin secretion as well as decreased expression of β-catenin and TCF4. Metrnl ameliorated the above effects of high glucose. And the protecting role of Metrnl was inhibited by DKK1. T2D mice showed higher body weight and blood glucose compared with the controls. The β cell apoptosis was increased while the β cell proliferation and WNT/β-catenin pathway were inhibited in T2D mice. Metrnl treatment partly reversed the above changes in T2D mice. Metrnl ameliorates β cell function by inhibiting β cell apoptosis of and promoting β cell proliferation via activating the WNT/β-catenin pathway.
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Affiliation(s)
- Wenchao Hu
- Department of Endocrinology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, China
| | - Rui Wang
- Department of Blood Transfusion, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, China
| | - Bei Sun
- NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin, China
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32
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Rezazadeh H, Sharifi MR, Sharifi M, Soltani N. Gamma-aminobutyric acid attenuates insulin resistance in type 2 diabetic patients and reduces the risk of insulin resistance in their offspring. Biomed Pharmacother 2021; 138:111440. [PMID: 33667789 DOI: 10.1016/j.biopha.2021.111440] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 02/21/2021] [Accepted: 02/23/2021] [Indexed: 12/13/2022] Open
Abstract
The role of gamma-aminobutyric acid (GABA) in attenuates insulin resistance (IR) in type 2 diabetic (T2D) patients and the reduction of the risk of IR in their offspring, and the function of GLUT4, IRS1 and Akt2 genes expression were investigated. T2D was induced by high fat diet and 35 mg/kg of streptozotocin. The male and female diabetic rats were then divided into three groups: CD, GABA, and insulin. NDC group received a normal diet. All the animals were studied for a six-month. Their offspring were just fed with normal diet for four months. Blood glucose was measured weekly in patients and their offspring. Intraperitoneal glucose tolerance test (IPGTT), urine volume, and water consumption in both patients and their offspring were performed monthly. The hyperinsulinemic euglycemic clamp in both patients and their offspring was done and blood sample collected to measure Hemoglobin A1c (HbA1c). IRS1, Akt and GLUT4 gene expressions in muscle were evaluated in all the groups. GABA or insulin therapy decreased blood glucose, IPGTT, and HbA1c in patients and their offspring compared to DC group. They also increased GIR in patients and their offspring. IRS1, Akt and GLUT4 gene expressions improved in both patients in comparison with DC group. GABA exerts beneficial effects on IRS1 and Akt gene expressions in GABA treated offspring. GABA therapy improved insulin resistance in diabetic patients by increasing the expression of GLUT4. It is also indirectly able to reduce insulin resistance in their offspring possibly through the increased gene expressions of IRS1 and Akt.
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Affiliation(s)
- Hossein Rezazadeh
- Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohammad Reza Sharifi
- Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohmmadreza Sharifi
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Nepton Soltani
- Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
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Sun J, Huang X, Niu C, Wang X, Li W, Liu M, Wang Y, Huang S, Chen X, Li X, Wang Y, Jin L, Xiao J, Cong W. aFGF alleviates diabetic endothelial dysfunction by decreasing oxidative stress via Wnt/β-catenin-mediated upregulation of HXK2. Redox Biol 2020; 39:101811. [PMID: 33360774 PMCID: PMC7772795 DOI: 10.1016/j.redox.2020.101811] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 11/16/2020] [Accepted: 11/20/2020] [Indexed: 12/13/2022] Open
Abstract
Vascular complications of diabetes are a serious challenge in clinical practice, and effective treatments are an unmet clinical need. Acidic fibroblast growth factor (aFGF) has potent anti-oxidative properties and therefore has become a research focus for the treatment of diabetic vascular complications. However, the specific mechanisms by which aFGF regulates these processes remain unclear. The purpose of this study was to investigate whether aFGF alleviates diabetic endothelial dysfunction by suppressing mitochondrial oxidative stress. We found that aFGF markedly decreased mitochondrial superoxide generation in both db/db mice and endothelial cells incubated with high glucose (30 mM) plus palmitic acid (PA, 0.1 mM), and restored diabetes-impaired Wnt/β-catenin signaling. Pretreatment with the Wnt/β-catenin signaling inhibitors IWR-1-endo (IWR) and ICG-001 abolished aFGF-mediated attenuation of mitochondrial superoxide generation and endothelial protection. Furthermore, the effects of aFGF on endothelial protection under diabetic conditions were suppressed by c-Myc knockdown. Mechanistically, c-Myc knockdown triggered mitochondrial superoxide generation, which was related to decreased expression and subsequent impaired mitochondrial localization of hexokinase 2 (HXK2). The role of HXK2 in aFGF-mediated attenuation of mitochondrial superoxide levels and EC protection was further confirmed by si-Hxk2 and a cell-permeable form of hexokinase II VDAC binding domain (HXK2VBD) peptide, which inhibits mitochondrial localization of HXK2. Taken together, these findings suggest that the endothelial protective effect of aFGF under diabetic conditions could be partly attributed to its role in suppressing mitochondrial superoxide generation via HXK2, which is mediated by the Wnt/β-catenin/c-Myc axis.
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Affiliation(s)
- Jia Sun
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China
| | - Xiaozhong Huang
- Department of Pediatric Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, PR China
| | - Chao Niu
- Pediatric Research Institute, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, PR China
| | - Xuejiao Wang
- Department of Histology and Embryology, Institute of Neuroscience, Wenzhou Medical University, Wenzhou, 325000, China
| | - Wanqian Li
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China
| | - Mengxue Liu
- Department of Histology and Embryology, Institute of Neuroscience, Wenzhou Medical University, Wenzhou, 325000, China
| | - Ying Wang
- Department of Pharmacy, Jinhua Women & Children Health Hospital, Jinhua, PR China
| | - Shuai Huang
- Zhejiang Provincial Key Laboratory of Interventional Pulmonology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, PR China
| | - Xixi Chen
- Department of Pharmacy, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, PR China
| | - Xiaokun Li
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China
| | - Yang Wang
- Department of Histology and Embryology, Institute of Neuroscience, Wenzhou Medical University, Wenzhou, 325000, China.
| | - Litai Jin
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China.
| | - Jian Xiao
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China.
| | - Weitao Cong
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China.
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Sávio-Silva C, Beyerstedt S, Soinski-Sousa PE, Casaro EB, Balby-Rocha MTA, Simplício-Filho A, Alves-Silva J, Rangel ÉB. Mesenchymal Stem Cell Therapy for Diabetic Kidney Disease: A Review of the Studies Using Syngeneic, Autologous, Allogeneic, and Xenogeneic Cells. Stem Cells Int 2020; 2020:8833725. [PMID: 33505469 PMCID: PMC7812547 DOI: 10.1155/2020/8833725] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 10/31/2020] [Accepted: 11/03/2020] [Indexed: 12/18/2022] Open
Abstract
Diabetic kidney disease (DKD) is a microvascular complication of diabetes mellitus (DM) and comprises multifactorial pathophysiologic mechanisms. Despite current treatment, around 30-40% of individuals with type 1 and type 2 DM (DM1 and DM2) have progressive DKD, which is the most common cause of end-stage chronic kidney disease worldwide. Mesenchymal stem cell- (MSC-) based therapy has important biological and therapeutic implications for curtailing DKD progression. As a chronic disease, DM may impair MSC microenvironment, but there is compelling evidence that MSC derived from DM1 individuals maintain their cardinal properties, such as potency, secretion of trophic factors, and modulation of immune cells, so that both autologous and allogeneic MSCs are safe and effective. Conversely, MSCs derived from DM2 individuals are usually dysfunctional, exhibiting higher rates of senescence and apoptosis and a decrease in clonogenicity, proliferation, and angiogenesis potential. Therefore, more studies in humans are needed to reach a conclusion if autologous MSCs from DM2 individuals are effective for treatment of DM-related complications. Importantly, the bench to bedside pathway has been constructed in the last decade for assessing the therapeutic potential of MSCs in the DM setting. Laboratory research set the basis for establishing further translation research including preclinical development and proof of concept in model systems. Phase I clinical trials have evaluated the safety profile of MSC-based therapy in humans, and phase II clinical trials (proof of concept in trial participants) still need to answer important questions for treating DKD, yet metabolic control has already been documented. Therefore, randomized and controlled trials considering the source, optimal cell number, and route of delivery in DM patients are further required to advance MSC-based therapy. Future directions include strategies to reduce MSC heterogeneity, standardized protocols for isolation and expansion of those cells, and the development of well-designed large-scale trials to show significant efficacy during a long follow-up, mainly in individuals with DKD.
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Affiliation(s)
- Christian Sávio-Silva
- Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
| | - Stephany Beyerstedt
- Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
| | - Poliana E. Soinski-Sousa
- Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
| | - Expedito B. Casaro
- Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
| | | | - Antônio Simplício-Filho
- Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
| | - Jamille Alves-Silva
- Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
| | - Érika B. Rangel
- Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
- Nephrology Division, Federal University of São Paulo, São Paulo, SP, Brazil
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Guo X, Li D, Song J, Yang Q, Wang M, Yang Y, Wang L, Hou X, Chen L, Li X. Mof regulates glucose level via altering different α-cell subset mass and intra-islet glucagon-like peptide-1, glucagon secretion. Metabolism 2020; 109:154290. [PMID: 32522488 DOI: 10.1016/j.metabol.2020.154290] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 06/02/2020] [Accepted: 06/05/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Males absent on the first (Mof) is implicated in gene control of diverse biological processes, such as cell growth, differentiation, apoptosis and autophagy. However, the relationship between glucose regulation and Mof-mediated transcription events remains unexplored. We aimed to unravel the role of Mof in glucose regulation by using global and pancreatic α-cell-specific Mof-deficient mice in vivo and α-TC1-6 cell line in vitro. METHODS We used tamoxifen-induced temporal Mof-deficient mice first to show Mof regulate glucose homeostasis, islet cell proportions and hormone secretion. Then we used α-cell-specific Mof-deficient mice to clarify how α-cell subsets and β-cell mass were regulated and corresponding hormone level alterations. Ultimately, we used small interfering RNA (siRNA) to knockdown Mof in α-TC1-6 and unravel the mechanism regulating α-cell mass and glucagon secretion. RESULTS Mof was mainly expressed in α-cells. Global Mof deficiency led to lower glucose levels, attributed by decreased α/β-cell ratio and glucagon secretion. α-cell-specific Mof-deficient mice exhibited similar alterations, with more reduced prohormone convertase 2 (PC2)-positive α-cell mass, responsible for less glucagon, and enhanced prohormone convertase 1 (PC1/3)-positive α-cell mass, leading to more glucagon-like peptide-1 (GLP-1) secretion, thus increased β-cell mass and insulin secretion. In vitro, increased DNA damage, dysregulated autophagy, enhanced apoptosis and altered cell fate factors expressions upon Mof knockdown were observed. Genes and pathways linked to impaired glucagon secretion were uncovered through transcriptome sequencing. CONCLUSION Mof is a potential interventional target for glucose regulation, from the aspects of both α-cell subset mass and glucagon, intra-islet GLP-1 secretion. Upon Mof deficiency, Up-regulated PC1/3 but down-regulated PC2-positive α-cell mass, leads to more GLP-1 and insulin but less glucagon secretion, and contributed to lower glucose level.
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Affiliation(s)
- Xinghong Guo
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Qingdao 266237, Shandong, China; Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, China
| | - Danyang Li
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Qingdao 266237, Shandong, China; Department of Rehabilitation, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, China
| | - Jia Song
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, China
| | - Qibing Yang
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Qingdao 266237, Shandong, China
| | - Meng Wang
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Qingdao 266237, Shandong, China
| | - Yang Yang
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Qingdao 266237, Shandong, China
| | - Lingshu Wang
- Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan 250012, Shandong, China; Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan 250012, Shandong, China
| | - Xinguo Hou
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, China
| | - Li Chen
- Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, China; Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan 250012, Shandong, China; Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan 250012, Shandong, China.
| | - Xiangzhi Li
- Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Sciences, Shandong University, Qingdao 266237, Shandong, China.
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miR-132-3p priming enhances the effects of mesenchymal stromal cell-derived exosomes on ameliorating brain ischemic injury. Stem Cell Res Ther 2020; 11:260. [PMID: 32600449 PMCID: PMC7322840 DOI: 10.1186/s13287-020-01761-0] [Citation(s) in RCA: 89] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2019] [Revised: 05/28/2020] [Accepted: 06/08/2020] [Indexed: 02/07/2023] Open
Abstract
Backgrounds/aims Mesenchymal stromal cell-derived exosomes (MSC-EXs) could exert protective effects on recipient cells by transferring the contained microRNAs (miRs), and miR-132-3p is one of angiogenic miRs. However, whether the combination of MSC-EXs and miR-132-3p has better effects in ischemic cerebrovascular disease remains unknown. Methods Mouse MSCs transfected with scrambler control or miR-132-3p mimics were used to generate MSC-EXs and miR-132-3p-overexpressed MSC-EXs (MSC-EXsmiR-132-3p). The effects of EXs on hypoxia/reoxygenation (H/R)-injured ECs in ROS generation, apoptosis, and barrier function were analyzed. The levels of RASA1, Ras, phosphorylations of PI3K, Akt and endothelial nitric oxide synthesis (eNOS), and tight junction proteins (Claudin-5 and ZO-1) were measured. Ras and PI3K inhibitors were used for pathway analysis. In transient middle cerebral artery occlusion (tMCAO) mouse model, the effects of MSC-EXs on the cerebral vascular ROS production and apoptosis, cerebral vascular density (cMVD), Evans blue extravasation, brain water content, neurological deficit score (NDS), and infarct volume were determined. Results MSC-EXs could deliver their carried miR-132-3p into target ECs, which functionally downregulated the target protein RASA1, while upregulated the expression of Ras and the downstream PI3K phosphorylation. Compared to MSC-EXs, MSC-EXsmiR-132-3p were more effective in decreasing ROS production, apoptosis, and tight junction disruption in H/R-injured ECs. These effects were associated with increased levels of phosphorylated Akt and eNOS, which could be abolished by PI3K inhibitor (LY294002) or Ras inhibitor (NSC 23766). In the tMCAO mouse model, the infusion of MSC-EXsmiR-132-3p was more effective than MSC-EXs in reducing cerebral vascular ROS production, BBB dysfunction, and brain injury. Conclusion Our results suggest that miR-132-3p promotes the beneficial effects of MSC-EXs on brain ischemic injury through protecting cerebral EC functions.
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He Q, Wang L, Zhao R, Yan F, Sha S, Cui C, Song J, Hu H, Guo X, Yang M, Cui Y, Sun Y, Sun Z, Liu F, Dong M, Hou X, Chen L. Mesenchymal stem cell-derived exosomes exert ameliorative effects in type 2 diabetes by improving hepatic glucose and lipid metabolism via enhancing autophagy. Stem Cell Res Ther 2020; 11:223. [PMID: 32513303 PMCID: PMC7278170 DOI: 10.1186/s13287-020-01731-6] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 04/05/2020] [Accepted: 05/14/2020] [Indexed: 12/13/2022] Open
Abstract
Background Mesenchymal stem cell (MSC)-based therapy is currently considered to be an effective treatment strategy for diabetes and hepatic disorders, such as liver cirrhosis and non-alcoholic fatty liver disease. Exosomes are important mediators of cellular connections, and increasing evidence has suggested that exosomes derived from MSCs may be used as direct therapeutic agents; their mechanisms of action, however, remain largely unclear. Here, we evaluated the efficacy and molecular mechanisms of human umbilical cord MSC-derived exosomes (HucMDEs) on hepatic glucose and lipid metabolism in type 2 diabetes mellitus (T2DM). Methods HucMDEs were used to treat T2DM rats, as well as palmitic acid (PA)-treated L-O2 cells, in order to determine the effects of HucMDEs on hepatic glucose and lipid metabolism. To evaluate the changes in autophagy and potential signaling pathways, autophagy-related proteins (BECN1, microtubule-associated protein 1 light chain 3 beta [MAP 1LC3B]), autophagy-related genes (ATGs, ATG5, and ATG7), AMP-activated protein kinase (AMPK), and phosphorylated AMPK (p-AMPK) were assessed by Western blotting. Results HucMDEs promoted hepatic glycolysis, glycogen storage, and lipolysis, and reduced gluconeogenesis. Additionally, autophagy potentially contributed to the effects of HucMDE treatment. Transmission electron microscopy revealed an increased formation of autophagosomes in HucMDE-treated groups, and the autophagy marker proteins, BECN1 and MAP 1LC3B, were also increased. Moreover, autophagy inhibitor 3-methyladenine significantly reduced the effects of HucMDEs on glucose and lipid metabolism in T2DM rats. Based on its phosphorylation status, we found that the AMPK signaling pathway was activated and induced autophagy in T2DM rats and PA-treated L-O2 cells. Meanwhile, the transfection of AMPK siRNA or application of the AMPK inhibitor, Comp C, weakened the therapeutic effects of HucMDEs on glucose and lipid metabolism. Conclusions These findings demonstrate that HucMDEs improved hepatic glucose and lipid metabolism in T2DM rats by activating autophagy via the AMPK pathway, which provides novel evidence suggesting the potential for HucMDEs in clinically treating T2DM patients.
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Affiliation(s)
- Qin He
- Department of Endocrinology, Qilu Hospital of Shandong University, No. 107 Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Lingshu Wang
- Department of Endocrinology, Qilu Hospital of Shandong University, No. 107 Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Ruxing Zhao
- Department of Endocrinology, Qilu Hospital of Shandong University, No. 107 Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Fei Yan
- Department of Endocrinology, Qilu Hospital of Shandong University, No. 107 Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Sha Sha
- Department of Endocrinology, Qilu Hospital of Shandong University, No. 107 Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Chen Cui
- Department of Endocrinology, Qilu Hospital of Shandong University, No. 107 Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Jia Song
- Department of Endocrinology, Qilu Hospital of Shandong University, No. 107 Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Huiqing Hu
- Department of Endocrinology, Qilu Hospital of Shandong University, No. 107 Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Xinghong Guo
- Department of Endocrinology, Qilu Hospital of Shandong University, No. 107 Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Mengmeng Yang
- Department of Endocrinology, Qilu Hospital of Shandong University, No. 107 Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Yixin Cui
- Department of Endocrinology, Qilu Hospital of Shandong University, No. 107 Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Yujing Sun
- Department of Endocrinology, Qilu Hospital of Shandong University, No. 107 Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Zheng Sun
- Department of Endocrinology, Qilu Hospital of Shandong University, No. 107 Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Fuqiang Liu
- Department of Endocrinology, Qilu Hospital of Shandong University, No. 107 Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Ming Dong
- Department of Endocrinology, Qilu Hospital of Shandong University, No. 107 Wenhua Xi Road, Jinan, 250012, Shandong, China.,Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, 250012, Shandong, China.,Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, 250012, Shandong, China
| | - Xinguo Hou
- Department of Endocrinology, Qilu Hospital of Shandong University, No. 107 Wenhua Xi Road, Jinan, 250012, Shandong, China. .,Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, 250012, Shandong, China. .,Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, 250012, Shandong, China.
| | - Li Chen
- Department of Endocrinology, Qilu Hospital of Shandong University, No. 107 Wenhua Xi Road, Jinan, 250012, Shandong, China. .,Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, 250012, Shandong, China. .,Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, 250012, Shandong, China.
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Lin Y, Zhu W, Chen X. The involving progress of MSCs based therapy in atherosclerosis. Stem Cell Res Ther 2020; 11:216. [PMID: 32503682 PMCID: PMC7275513 DOI: 10.1186/s13287-020-01728-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 04/25/2020] [Accepted: 05/13/2020] [Indexed: 02/07/2023] Open
Abstract
Atherosclerosis is a chronic progressive vascular inflammation characterized by lipid deposition and plaque formation, for which vascular cell dysfunction and impaired immune responses are involved. Up to now, lipid-lowering drugs remain the main therapy for treating atherosclerosis; however, the surgical or interventional therapy is often applied, and yet, morbidity and mortality of such cardiovascular disease remain high worldwide. Over the past decades, an anti-inflammatory approach has become an important therapeutic target for dealing with atherosclerosis, as altered immune responses have been regarded as an essential player in the pathological process of vascular abnormality induced by hyperlipidemia. Interestingly, mesenchymal stem cells, one type of stem cells with the capabilities of self-renewal and multi-potential, have demonstrated their unique immunomodulatory function in the various pathological process, especially in atherosclerosis. While some controversies remain regarding their therapeutic efficacy and working mechanisms, our present review aims to summarize the current research progress on stem cell-based therapy, focusing on its immunomodulatory effects on the pathogenesis of atherosclerosis and how endothelial cells, smooth muscle cells, and other immune cells are regulated by MSC-based therapy.
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Affiliation(s)
- Ying Lin
- School of Medicine, Ningbo University, Ningbo, Zhejiang, China.,Department of Cardiology, Ningbo First hospital, Ningbo, Zhejiang, China.,Department of Cardiology and Key Lab of Cardiovascular Disease, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Wei Zhu
- Department of Cardiology and Key Lab of Cardiovascular Disease, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
| | - Xiaomin Chen
- School of Medicine, Ningbo University, Ningbo, Zhejiang, China. .,Department of Cardiology, Ningbo First hospital, Ningbo, Zhejiang, China.
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Angeloni C, Gatti M, Prata C, Hrelia S, Maraldi T. Role of Mesenchymal Stem Cells in Counteracting Oxidative Stress-Related Neurodegeneration. Int J Mol Sci 2020; 21:ijms21093299. [PMID: 32392722 PMCID: PMC7246730 DOI: 10.3390/ijms21093299] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 04/30/2020] [Accepted: 05/04/2020] [Indexed: 02/07/2023] Open
Abstract
Neurodegenerative diseases include a variety of pathologies such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and so forth, which share many common characteristics such as oxidative stress, glycation, abnormal protein deposition, inflammation, and progressive neuronal loss. The last century has witnessed significant research to identify mechanisms and risk factors contributing to the complex etiopathogenesis of neurodegenerative diseases, such as genetic, vascular/metabolic, and lifestyle-related factors, which often co-occur and interact with each other. Apart from several environmental or genetic factors, in recent years, much evidence hints that impairment in redox homeostasis is a common mechanism in different neurological diseases. However, from a pharmacological perspective, oxidative stress is a difficult target, and antioxidants, the only strategy used so far, have been ineffective or even provoked side effects. In this review, we report an analysis of the recent literature on the role of oxidative stress in Alzheimer’s and Parkinson’s diseases as well as in amyotrophic lateral sclerosis, retinal ganglion cells, and ataxia. Moreover, the contribution of stem cells has been widely explored, looking at their potential in neuronal differentiation and reporting findings on their application in fighting oxidative stress in different neurodegenerative diseases. In particular, the exposure to mesenchymal stem cells or their secretome can be considered as a promising therapeutic strategy to enhance antioxidant capacity and neurotrophin expression while inhibiting pro-inflammatory cytokine secretion, which are common aspects of neurodegenerative pathologies. Further studies are needed to identify a tailored approach for each neurodegenerative disease in order to design more effective stem cell therapeutic strategies to prevent a broad range of neurodegenerative disorders.
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Affiliation(s)
- Cristina Angeloni
- School of Pharmacy, University of Camerino, Via Gentile III da Varano, 62032 Camerino, Italy;
| | - Martina Gatti
- Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, Via del Pozzo 71, 41124 Modena, Italy; (M.G.); (T.M.)
| | - Cecilia Prata
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum—University of Bologna, Via Irnerio 48, 40126 Bologna, Italy
- Correspondence:
| | - Silvana Hrelia
- Department for Life Quality Studies, Alma Mater Studiorum—University of Bologna, Corso d’Augusto 237, 47921 Rimini, Italy;
| | - Tullia Maraldi
- Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, Via del Pozzo 71, 41124 Modena, Italy; (M.G.); (T.M.)
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Zhang W, Yu L, Han X, Pan J, Deng J, Zhu L, Lu Y, Huang W, Liu S, Li Q, Liu Y. The secretome of human dental pulp stem cells protects myoblasts from hypoxia‑induced injury via the Wnt/β‑catenin pathway. Int J Mol Med 2020; 45:1501-1513. [PMID: 32323739 PMCID: PMC7138287 DOI: 10.3892/ijmm.2020.4525] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2019] [Accepted: 01/29/2020] [Indexed: 12/21/2022] Open
Abstract
Human dental pulp stem cells (hDPSCs) present several advantages, including their ability to be non-invasively harvested without ethical concern. The secretome of hDPSCs can promote the functional recovery of various tissue injuries. However, the protective effects on hypoxia-induced skeletal muscle injury remain to be explored. The present study demonstrated that C2C12 myoblast coculture with hDPSCs attenuated CoCl2-induced hypoxic injury compared with C2C12 alone. The hDPSC secretome increased cell viability and differentiation and decreased G2/M cell cycle arrest under hypoxic conditions. These results were further verified using hDPSC-conditioned medium (hDPSC-CM). The present data revealed that the protective effects of hDPSC-CM depend on the concentration ratio of the CM. In terms of the underlying molecular mechanism, hDPSC-CM activated the Wnt/β-catenin pathway, which increased the protein levels of Wnt1, phosphorylated-glycogen synthase kinase-3β and β-catenin and the mRNA levels of Wnt target genes. By contrast, an inhibitor (XAV939) of Wnt/β-catenin diminished the protective effects of hDPSC-CM. Taken together, the findings of the present study demonstrated that the hDPSC secretome alleviated the hypoxia-induced myoblast injury potentially through regulating the Wnt/β-catenin pathway. These findings may provide new insight into a therapeutic alternative using the hDPSC secretome in skeletal muscle hypoxia-related diseases.
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Affiliation(s)
- Weihua Zhang
- Department of Orthodontics, Shanghai Stomatological Hospital, Fudan University, Shanghai 200001, P.R. China
| | - Liming Yu
- Department of Orthodontics, Shanghai Stomatological Hospital, Fudan University, Shanghai 200001, P.R. China
| | - Xinxin Han
- Department of Orthodontics, Shanghai Stomatological Hospital, Fudan University, Shanghai 200001, P.R. China
| | - Jie Pan
- Department of Orthodontics, Shanghai Stomatological Hospital, Fudan University, Shanghai 200001, P.R. China
| | - Jiajia Deng
- Department of Orthodontics, Shanghai Stomatological Hospital, Fudan University, Shanghai 200001, P.R. China
| | - Luying Zhu
- Oral Biomedical Engineering Laboratory, Shanghai Stomatological Hospital, Fudan University, Shanghai 200001, P.R. China
| | - Yun Lu
- Department of Orthodontics, Shanghai Stomatological Hospital, Fudan University, Shanghai 200001, P.R. China
| | - Wei Huang
- Department of Orthodontics, Shanghai Stomatological Hospital, Fudan University, Shanghai 200001, P.R. China
| | - Shangfeng Liu
- Department of Orthodontics, Shanghai Stomatological Hospital, Fudan University, Shanghai 200001, P.R. China
| | - Qiang Li
- Department of Orthodontics, Shanghai Stomatological Hospital, Fudan University, Shanghai 200001, P.R. China
| | - Yuehua Liu
- Department of Orthodontics, Shanghai Stomatological Hospital, Fudan University, Shanghai 200001, P.R. China
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Li X, Lang H, Li B, Zhang C, Sun N, Lin J, Zhang J. Change in Viability and Function of Pancreatic Islets after Coculture with Mesenchymal Stromal Cells: A Systemic Review and Meta-Analysis. J Diabetes Res 2020; 2020:5860417. [PMID: 32309447 PMCID: PMC7132593 DOI: 10.1155/2020/5860417] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2019] [Accepted: 03/16/2020] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND There is no clear consensus on the effect of coculture of islets with mesenchymal stem cells (MSCs) on islet function and viability. METHODS We conducted a meta-analysis of relevant studies to evaluate the effect of coculture of islets with MSCs on the function and viability of islets, both in vitro and in vivo. We searched PubMed, Embase, and Web of Science databases for all relevant studies that compared the effect of coculture of islets with MSCs on the function and viability of islets (language of publication: English; reference period: January 2000-May 2019). Data pertaining to islet function and viability, concentrations of some cytokines, and in vivo experimental outcomes were extracted and compared. RESULTS Twenty-four articles were included in the meta-analysis. In comparison to islets cultured alone, coculture of islets with MSCs was associated with a significantly higher islet viability [weighted mean difference (WMD), -15.59; -22.34 to -8.83; P < 0.00001], insulin level (WMD, -5.74; -9.29 to -2.19; P = 0.002), insulin secretion index (WMD, -2.45; -3.70 to -1.21; P = 0.0001), and higher concentrations of interleukin-6 (WMD, -1225.66; -2044.47 to -406.86; P = 0.003) and vascular endothelial growth factor (WMD, -1.19; -2.25 to -0.14; P = 0.03). Direct coculture of islets and MSCs significantly increased islet viability (WMD, -19.82; -26.56 to -13.07; P < 0.00001). In the in vivo experiments, coculture of islets with MSCs induced lower fasting blood glucose level (on postoperative days 21 and 28, WMD, 102.60; 27.14 to 178.05; P = 0.008 and WMD, 121.19; 49.56 to 192.82; P = 0.0009) and better glucose tolerance (blood glucose at 30 minutes after intraperitoneal injection of glucose, WMD, 85.92; 5.33 to 166.51; P = 0.04). CONCLUSION Coculture of islets with MSCs improves insulin secretory function of islets and enhances islet viability. Direct coculture of two cells significantly increased islet viability. MSC-based strategy may be beneficial for clinical islet transplantation for type 1 diabetes in the future.
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Affiliation(s)
- Xiaohang Li
- Department of Hepatobiliary Surgery and Organ Transplant, First Affiliated Hospital, China Medical University, No. 155, Nanjing North Street, Shenyang, 110001 Liaoning Province, China
| | - Hongxin Lang
- Department of Stem Cells and Regenerative Medicine, Shenyang Key Laboratory for Stem Cells and Regenerative Medicine, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, No. 77 Puhe Street, Shenbei New District, Shenyang, 110122 Liaoning Province, China
| | - Baifeng Li
- Department of Hepatobiliary Surgery and Organ Transplant, First Affiliated Hospital, China Medical University, No. 155, Nanjing North Street, Shenyang, 110001 Liaoning Province, China
| | - Chengshuo Zhang
- Department of Hepatobiliary Surgery and Organ Transplant, First Affiliated Hospital, China Medical University, No. 155, Nanjing North Street, Shenyang, 110001 Liaoning Province, China
| | - Ning Sun
- Department of Hepatobiliary Surgery and Organ Transplant, First Affiliated Hospital, China Medical University, No. 155, Nanjing North Street, Shenyang, 110001 Liaoning Province, China
| | - Jianzhen Lin
- Department of Hepatobiliary Surgery and Organ Transplant, First Affiliated Hospital, China Medical University, No. 155, Nanjing North Street, Shenyang, 110001 Liaoning Province, China
| | - Jialin Zhang
- Department of Hepatobiliary Surgery and Organ Transplant, First Affiliated Hospital, China Medical University, No. 155, Nanjing North Street, Shenyang, 110001 Liaoning Province, China
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Li X, Li Z, Wang J, Li Z, Cui H, Dai G, Chen S, Zhang M, Zheng Z, Zhan Z, Liu H. Wnt4 signaling mediates protective effects of melatonin on new bone formation in an inflammatory environment. FASEB J 2019; 33:10126-10139. [PMID: 31216173 DOI: 10.1096/fj.201900093rr] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Growing evidence shows that the inhibitory effect of inflammatory cytokines on new bone formation by osteogenic precursor cells is a critical cause of net bone-density reduction. Melatonin has been proven to be a potential therapeutic candidate for osteoporosis. However, whether it is capable of antagonizing the suppressing effect of inflammatory cytokines on osteogenic precursor cells is so far elusive. In this study, using the cell culture system of human bone marrow stromal cells and MC3T3-E1 preosteoblasts, we recorded the following vital observations that provided insights of melatonin-induced bone formation: 1) melatonin induced bone formation in both normal and inflammatory conditions; 2) Wnt4 was essential for melatonin-induced bone formation in inflammatory stimulation; 3) melatonin- and Wnt4-induced bone formation occurred via activation of β-catenin and p38-JNK MAPK pathways by interaction with a distinct frizzled LDL receptor-related protein complex; 4) melatonin suppressed the inhibitory effect of NF-κB on osteogenesis in a Wnt4-dependent manner; and 5) melatonin induced Wnt4 expression through the ERK1/2-Pax2-Egr1 pathway. In summary, we showed a novel mechanism of melatonin-induced bone formation in an inflammatory environment. Melatonin-induced Wnt4 expression is essential for its osteoinductive effect and the inhibitory effect of NF-κB on bone formation. Our novel findings may provide useful information for its potential translational application.-Li, X., Li, Z., Wang, J., Li, Z., Cui, H., Dai, G., Chen, S., Zhang, M., Zheng, Z., Zhan, Z., Liu, H. Wnt4 signaling mediates protective effects of melatonin on new bone formation in an inflammatory environment.
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Affiliation(s)
- Xiang Li
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zihao Li
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jianru Wang
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, Guangzhou, China
| | - Zemin Li
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, Guangzhou, China
| | - Haowen Cui
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Guo Dai
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Siwen Chen
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Mingliang Zhang
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhaomin Zheng
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, Guangzhou, China
| | - Zhongping Zhan
- Department of Rheumatology and Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Hui Liu
- Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, Guangzhou, China
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Si J, Zhou R, Zhao B, Xie Y, Gan L, Zhang J, Wang Y, Zhou X, Ren X, Zhang H. Effects of ionizing radiation and HLY78 on the zebrafish embryonic developmental toxicity. Toxicology 2019; 411:143-153. [DOI: 10.1016/j.tox.2018.10.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Revised: 09/18/2018] [Accepted: 10/11/2018] [Indexed: 01/02/2023]
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Rackham CL, Jones PM. Potential of mesenchymal stromal cells for improving islet transplantation outcomes. Curr Opin Pharmacol 2018; 43:34-39. [PMID: 30103073 DOI: 10.1016/j.coph.2018.07.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Revised: 07/25/2018] [Accepted: 07/27/2018] [Indexed: 12/16/2022]
Abstract
Allogeneic islet transplantation as a therapy for Type 1 Diabetes (T1D) is restricted by the limited availability of donor islets, loss of functional islets during pre-transplantation culture in vitro and further extensive loss during the immediate post-transplantation period when islet function and survival is compromised by the hypoxic, inflammatory host environment. In the longer term pathogenic T cell responses drive autoimmunity and chronic allograft rejection. Experimental studies have demonstrated that mesenchymal stromal cells (MSCs) have significant potential to improve the outcomes of clinical islet transplantation. This review explores the potential for MSCs and their 'secretome' to influence donor islet cell function and survival, as well as the host niche. We discuss the possibility of harnessing the therapeutic benefits of MSCs in a cell-free strategy to offer a well-defined, cell-free approach to improve the outcomes of clinical islet transplantation.
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Affiliation(s)
- Chloe L Rackham
- Department of Diabetes, School of Life Course Sciences, King's College London, Guy's Campus, London SE1 1UL, UK.
| | - Peter M Jones
- Department of Diabetes, School of Life Course Sciences, King's College London, Guy's Campus, London SE1 1UL, UK
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Zhu W, Yuan Y, Liao G, Li L, Liu J, Chen Y, Zhang J, Cheng J, Lu Y. Mesenchymal stem cells ameliorate hyperglycemia-induced endothelial injury through modulation of mitophagy. Cell Death Dis 2018; 9:837. [PMID: 30082798 PMCID: PMC6078996 DOI: 10.1038/s41419-018-0861-x] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2018] [Revised: 06/24/2018] [Accepted: 07/05/2018] [Indexed: 02/05/2023]
Abstract
Mitochondrial dysfunction and excessive mitochondrial reactive oxygen species (ROS) are fundamental contributors to endothelial injury in diabetic states. Mesenchymal stem cells (MSCs) have exhibited an extraordinary cytoprotective effect that extends to the modulation of mitochondrial homeostasis. However, the underlying mechanisms have not been clearly defined. Emerging evidence has suggested that mitophagy could counteract mitochondrial-derived oxidative stress through the selective elimination of impaired or dysfunctional mitochondria. Therefore, we investigated whether MSCs could ameliorate high-glucose-induced endothelial injury through the modulation of mitophagy. We observed that exposure of human umbilical vein endothelial cells (HUVECs) to high glucose triggers mitochondrial impairment with excessive mitochondrial fragmentation and ROS generation, loss of membrane potential and reduced ATP production. Furthermore, mitophagy was blunted upon high glucose insult, which accelerated dysfunctional mitochondrial accumulation, initiating the mitochondrial apoptotic pathway and, eventually, endothelial dysfunction. MSCs treatment notably attenuated these perturbations accompanied by an enhancement of Pink1 and Parkin expression, whereas these beneficial effects of MSCs were abolished when either Pink1 or Parkin was knocked down. In aortas of diabetic rats, defective mitophagy was observed, which coincided with marked mitochondrial dysfunction. Ultrastructurally, RAECs from diabetic rats revealed a significant reduction in autophagic vacuoles and a marked increase in fragmented mitochondria. Importantly, the infusion of MSCs restored Pink1/Parkin-mediated mitophagy, ameliorated mitochondrial dysfunction and attenuated apoptosis in endothelial cells in diabetic rats. These results suggest that MSCs may protect endothelial cells from hyperglycemia-induced injury by ameliorating mitochondrial dysfunction via Pink1/Parkin –mediated mitophagy
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Affiliation(s)
- Wuzheng Zhu
- Key Laboratory of Transplant Engineering and Immunology, NHFPC; Regenerative Medicine Research Centre, West China Hospital, SichuanUniversity, Chengdu, People's Republic of China
| | - Yujia Yuan
- Key Laboratory of Transplant Engineering and Immunology, NHFPC; Regenerative Medicine Research Centre, West China Hospital, SichuanUniversity, Chengdu, People's Republic of China
| | - Guangneng Liao
- Key Laboratory of Transplant Engineering and Immunology, NHFPC; Regenerative Medicine Research Centre, West China Hospital, SichuanUniversity, Chengdu, People's Republic of China
| | - Lan Li
- Key Laboratory of Transplant Engineering and Immunology, NHFPC; Regenerative Medicine Research Centre, West China Hospital, SichuanUniversity, Chengdu, People's Republic of China
| | - Jingping Liu
- Key Laboratory of Transplant Engineering and Immunology, NHFPC; Regenerative Medicine Research Centre, West China Hospital, SichuanUniversity, Chengdu, People's Republic of China
| | - Younan Chen
- Key Laboratory of Transplant Engineering and Immunology, NHFPC; Regenerative Medicine Research Centre, West China Hospital, SichuanUniversity, Chengdu, People's Republic of China
| | - Jie Zhang
- Key Laboratory of Transplant Engineering and Immunology, NHFPC; Regenerative Medicine Research Centre, West China Hospital, SichuanUniversity, Chengdu, People's Republic of China
| | - Jingqiu Cheng
- Key Laboratory of Transplant Engineering and Immunology, NHFPC; Regenerative Medicine Research Centre, West China Hospital, SichuanUniversity, Chengdu, People's Republic of China.
| | - Yanrong Lu
- Key Laboratory of Transplant Engineering and Immunology, NHFPC; Regenerative Medicine Research Centre, West China Hospital, SichuanUniversity, Chengdu, People's Republic of China.
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Sohrabipour S, Sharifi MR, Talebi A, Sharifi M, Soltani N. GABA dramatically improves glucose tolerance in streptozotocin-induced diabetic rats fed with high-fat diet. Eur J Pharmacol 2018; 826:75-84. [DOI: 10.1016/j.ejphar.2018.01.047] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Revised: 01/22/2018] [Accepted: 01/26/2018] [Indexed: 12/16/2022]
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