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Wang LK, Kong CC, Yu TY, Sun HS, Yang L, Sun Y, Li MY, Wang W. Endoplasmic reticulum stress and forkhead box protein O1 inhibition mediate palmitic acid and high glucose-induced β-cell dedifferentiation. World J Diabetes 2025; 16:95431. [DOI: 10.4239/wjd.v16.i5.95431] [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: 04/10/2024] [Revised: 01/13/2025] [Accepted: 03/24/2025] [Indexed: 04/25/2025] Open
Abstract
BACKGROUND Type 2 diabetes mellitus is characterized by pancreatic β-cell dysfunction and insulin resistance. Studies have suggested that β-cell dedifferentiation is one of the pathogeneses of β-cell dysfunction, but the detailed mechanism is still unclear. Most studies of β-cell dedifferentiation rely on rodent models and human pathological specimens. The development of in vitro systems can facilitate the exploration of β-cell dedifferentiation.
AIM To investigate the molecular mechanism of β-cell dedifferentiation. Hence, an in vitro model of β-cell dedifferentiation induced by palmitic acid and high glucose was established using the INS-1 832/13 cell line.
METHODS The study was further analyzed using RNA-sequencing, transmission electron microscopy, quantitative real-time polymerase chain reaction and Western blot.
RESULTS Results showed that the treatment of palmitic acid and high glucose significantly up-regulated β-cell forbidden genes and endocrine precursor cell marker genes, and down-regulated the expression of β-cell specific markers. Data showed that dedifferentiated INS-1 cells up-regulated the expression of endoplasmic reticulum (ER) stress-related genes. Moreover, the results also showed that forkhead box O1 (Foxo1) inhibition potentiated genetic changes in β-cell dedifferentiation induced by palmitic acid and high glucose.
CONCLUSION ER stress is sufficient to trigger β-cell dedifferentiation and is necessary for palmitic acid and high glucose-induced β-cell dedifferentiation. Foxo1 inhibition can further enhance these phenomena.
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Affiliation(s)
- Li-Kun Wang
- Department of Endocrinology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, Fujian Province, China
| | - Chu-Chu Kong
- Department of Endocrinology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, Fujian Province, China
| | - Ting-Yan Yu
- Department of Endocrinology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, Fujian Province, China
| | - Hui-Song Sun
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, Fujian Province, China
| | - Lu Yang
- Department of Endocrinology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, Fujian Province, China
| | - Ying Sun
- Department of Equipment and Materials, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China
| | - Ming-Yu Li
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, Fujian Province, China
| | - Wei Wang
- Department of Endocrinology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China
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Niu F, Liu W, Ren Y, Tian Y, Shi W, Li M, Li Y, Xiong Y, Qian L. β-cell neogenesis: A rising star to rescue diabetes mellitus. J Adv Res 2024; 62:71-89. [PMID: 37839502 PMCID: PMC11331176 DOI: 10.1016/j.jare.2023.10.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 10/08/2023] [Accepted: 10/08/2023] [Indexed: 10/17/2023] Open
Abstract
BACKGROUND Diabetes Mellitus (DM), a chronic metabolic disease characterized by elevated blood glucose, is caused by various degrees of insulin resistance and dysfunctional insulin secretion, resulting in hyperglycemia. The loss and failure of functional β-cells are key mechanisms resulting in type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). AIM OF REVIEW Elucidating the underlying mechanisms of β-cell failure, and exploring approaches for β-cell neogenesis to reverse β-cell dysfunction may provide novel strategies for DM therapy. KEY SCIENTIFIC CONCEPTS OF REVIEW Emerging studies reveal that genetic susceptibility, endoplasmic reticulum (ER) stress, oxidative stress, islet inflammation, and protein modification linked to multiple signaling pathways contribute to DM pathogenesis. Over the past few years, replenishing functional β-cell by β-cell neogenesis to restore the number and function of pancreatic β-cells has remarkably exhibited a promising therapeutic approach for DM therapy. In this review, we provide a comprehensive overview of the underlying mechanisms of β-cell failure in DM, highlight the effective approaches for β-cell neogenesis, as well as discuss the current clinical and preclinical agents research advances of β-cell neogenesis. Insights into the challenges of translating β-cell neogenesis into clinical application for DM treatment are also offered.
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Affiliation(s)
- Fanglin Niu
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, the Affiliated Hospital of Northwest University, Xi'an No.3 Hospital, Xi'an, Shaanxi, PR China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China
| | - Wenxuan Liu
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, the Affiliated Hospital of Northwest University, Xi'an No.3 Hospital, Xi'an, Shaanxi, PR China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China
| | - Yuanyuan Ren
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, the Affiliated Hospital of Northwest University, Xi'an No.3 Hospital, Xi'an, Shaanxi, PR China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China
| | - Ye Tian
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, the Affiliated Hospital of Northwest University, Xi'an No.3 Hospital, Xi'an, Shaanxi, PR China; Department of Neurology, Affiliated Hospital of Northwest University, Xi'an No.3 Hospital, Xi'an, Shaanxi, China
| | - Wenzhen Shi
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, the Affiliated Hospital of Northwest University, Xi'an No.3 Hospital, Xi'an, Shaanxi, PR China; Medical Research Center, the affiliated Hospital of Northwest University, Xi'an No.3 Hospital, Xi'an, Shaanxi, China
| | - Man Li
- Department of Endocrinology, the Affiliated Hospital of Northwest University, Xi'an No.3 Hospital, Xi'an, Shaanxi, China
| | - Yujia Li
- Department of Endocrinology, the Affiliated Hospital of Northwest University, Xi'an No.3 Hospital, Xi'an, Shaanxi, China
| | - Yuyan Xiong
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, the Affiliated Hospital of Northwest University, Xi'an No.3 Hospital, Xi'an, Shaanxi, PR China; Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China
| | - Lu Qian
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, the Affiliated Hospital of Northwest University, Xi'an No.3 Hospital, Xi'an, Shaanxi, PR China; Department of Endocrinology, the Affiliated Hospital of Northwest University, Xi'an No.3 Hospital, Xi'an, Shaanxi, China
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Son J, Accili D. Reversing pancreatic β-cell dedifferentiation in the treatment of type 2 diabetes. Exp Mol Med 2023; 55:1652-1658. [PMID: 37524865 PMCID: PMC10474037 DOI: 10.1038/s12276-023-01043-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 03/29/2023] [Accepted: 04/24/2023] [Indexed: 08/02/2023] Open
Abstract
The maintenance of glucose homeostasis is fundamental for survival and health. Diabetes develops when glucose homeostasis fails. Type 2 diabetes (T2D) is characterized by insulin resistance and pancreatic β-cell failure. The failure of β-cells to compensate for insulin resistance results in hyperglycemia, which in turn drives altered lipid metabolism and β-cell failure. Thus, insulin secretion by pancreatic β-cells is a primary component of glucose homeostasis. Impaired β-cell function and reduced β-cell mass are found in diabetes. Both features stem from a failure to maintain β-cell identity, which causes β-cells to dedifferentiate into nonfunctional endocrine progenitor-like cells or to trans-differentiate into other endocrine cell types. In this regard, one of the key issues in achieving disease modification is how to reestablish β-cell identity. In this review, we focus on the causes and implications of β-cell failure, as well as its potential reversibility as a T2D treatment.
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Affiliation(s)
- Jinsook Son
- Department of Medicine and Naomi Berrie Diabetes Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA.
| | - Domenico Accili
- Department of Medicine and Naomi Berrie Diabetes Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA
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Cell Replacement Therapy for Type 1 Diabetes Patients: Potential Mechanisms Leading to Stem-Cell-Derived Pancreatic β-Cell Loss upon Transplant. Cells 2023; 12:cells12050698. [PMID: 36899834 PMCID: PMC10000642 DOI: 10.3390/cells12050698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 02/09/2023] [Accepted: 02/20/2023] [Indexed: 02/25/2023] Open
Abstract
Cell replacement therapy using stem-cell-derived insulin-producing β-like cells (sBCs) has been proposed as a practical cure for patients with type one diabetes (T1D). sBCs can correct diabetes in preclinical animal models, demonstrating the promise of this stem cell-based approach. However, in vivo studies have demonstrated that most sBCs, similarly to cadaveric human islets, are lost upon transplantation due to ischemia and other unknown mechanisms. Hence, there is a critical knowledge gap in the current field concerning the fate of sBCs upon engraftment. Here we review, discuss effects, and propose additional potential mechanisms that could contribute toward β-cell loss in vivo. We summarize and highlight some of the literature on phenotypic loss in β-cells under both steady, stressed, and diseased diabetic conditions. Specifically, we focus on β-cell death, dedifferentiation into progenitors, trans-differentiation into other hormone-expressing cells, and/or interconversion into less functional β-cell subtypes as potential mechanisms. While current cell replacement therapy efforts employing sBCs carry great promise as an abundant cell source, addressing the somewhat neglected aspect of β-cell loss in vivo will further accelerate sBC transplantation as a promising therapeutic modality that could significantly enhance the life quality of T1D patients.
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Accili D, Du W, Kitamoto T, Kuo T, McKimpson W, Miyachi Y, Mukhanova M, Son J, Wang L, Watanabe H. Reflections on the state of diabetes research and prospects for treatment. Diabetol Int 2023; 14:21-31. [PMID: 36636157 PMCID: PMC9829952 DOI: 10.1007/s13340-022-00600-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 08/02/2022] [Indexed: 01/16/2023]
Abstract
Research on the etiology and treatment of diabetes has made substantial progress. As a result, several new classes of anti-diabetic drugs have been introduced in clinical practice. Nonetheless, the number of patients achieving glycemic control targets has not increased for the past 20 years. Two areas of unmet medical need are the restoration of insulin sensitivity and the reversal of pancreatic beta cell failure. In this review, we integrate research advances in transcriptional regulation of insulin action and pathophysiology of beta cell dedifferentiation with their potential impact on prospects of a durable "cure" for patients suffering from type 2 diabetes.
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Affiliation(s)
- Domenico Accili
- Department of Medicine and Berrie Diabetes Center, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY 10032 USA
| | - Wen Du
- Department of Medicine and Berrie Diabetes Center, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY 10032 USA
| | - Takumi Kitamoto
- Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, Chiba, Chiba 260-8670 Japan
| | - Taiyi Kuo
- Department of Neurobiology, Physiology, and Behavior, University of California at Davis, Davis, CA 95616 USA
| | - Wendy McKimpson
- Department of Medicine and Berrie Diabetes Center, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY 10032 USA
| | - Yasutaka Miyachi
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka Japan
| | - Maria Mukhanova
- Department of Medicine and Berrie Diabetes Center, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY 10032 USA
| | - Jinsook Son
- Department of Medicine and Berrie Diabetes Center, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY 10032 USA
| | - Liheng Wang
- Department of Medicine and Berrie Diabetes Center, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY 10032 USA
| | - Hitoshi Watanabe
- Department of Medicine and Berrie Diabetes Center, Vagelos College of Physicians and Surgeons of Columbia University, New York, NY 10032 USA
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Role of the Transcription Factor MAFA in the Maintenance of Pancreatic β-Cells. Int J Mol Sci 2022; 23:ijms23094478. [PMID: 35562869 PMCID: PMC9101179 DOI: 10.3390/ijms23094478] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 04/16/2022] [Accepted: 04/17/2022] [Indexed: 02/04/2023] Open
Abstract
Pancreatic β-cells are specialized to properly regulate blood glucose. Maintenance of the mature β-cell phenotype is critical for glucose metabolism, and β-cell failure results in diabetes mellitus. Recent studies provide strong evidence that the mature phenotype of β-cells is maintained by several transcription factors. These factors are also required for β-cell differentiation from endocrine precursors or maturation from immature β-cells during pancreatic development. Because the reduction or loss of these factors leads to β-cell failure and diabetes, inducing the upregulation or inhibiting downregulation of these transcription factors would be beneficial for studies in both diabetes and stem cell biology. Here, we discuss one such factor, i.e., the transcription factor MAFA. MAFA is a basic leucine zipper family transcription factor that can activate the expression of insulin in β-cells with PDX1 and NEUROD1. MAFA is indeed indispensable for the maintenance of not only insulin expression but also function of adult β-cells. With loss of MAFA in type 2 diabetes, β-cells cannot maintain their mature phenotype and are dedifferentiated. In this review, we first briefly summarize the functional roles of MAFA in β-cells and then mainly focus on the molecular mechanism of cell fate conversion regulated by MAFA.
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Transcriptional control of pancreatic β-cell identity and plasticity during the pathogenesis of type 2 diabetes. J Genet Genomics 2022; 49:316-328. [DOI: 10.1016/j.jgg.2022.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 02/23/2022] [Accepted: 03/06/2022] [Indexed: 11/21/2022]
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Desentis-Desentis MF. Regenerative approaches to preserve pancreatic β-cell mass and function in diabetes pathogenesis. Endocrine 2022; 75:338-350. [PMID: 34825343 DOI: 10.1007/s12020-021-02941-5] [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: 03/31/2021] [Accepted: 11/07/2021] [Indexed: 01/21/2023]
Abstract
In both type 1 diabetes (T1D) and type 2 diabetes (T2D), there is a substantial β-cell mass loss. Residual β-cell mass is susceptible to cellular damage because of specific pancreatic β-cell characteristics. β cells have a low proliferation rate, being in human adults almost zero and a low antioxidant system that makes β cells susceptible to oxidative stress and increases their vulnerability to cell destruction. Different strategies have been addressed to preserve pancreatic β-cell residual mass and function in patients with diabetes. However, the effect of many compounds proposed in rodent models to trigger β-cell replication has different results in human β cells. In this review, scientific evidence of β-cell of two major regenerative approaches has been gathered. Regeneration proceedings for pancreatic β cells are promising and could improve β-cell proliferation capacity and contribute to the conservation of mature β-cell phenotypic characteristics. This evidence supports the notion that regenerative medicine could be a helpful strategy to yield amelioration of T1D and T2D pathogenesis.
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Affiliation(s)
- Maria Fernanda Desentis-Desentis
- Department of Molecular Biology and Genomics, University Center for Health Sciences, University of Guadalajara, Jalisco, Mexico.
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Cai Z, Liu F, Yang Y, Li D, Hu S, Song L, Yu S, Li T, Liu B, Luo H, Zhang W, Zhou Z, Zhang J. GRB10 regulates β cell mass by inhibiting β cell proliferation and stimulating β cell dedifferentiation. J Genet Genomics 2021; 49:208-216. [PMID: 34861413 DOI: 10.1016/j.jgg.2021.11.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 11/07/2021] [Accepted: 11/15/2021] [Indexed: 12/14/2022]
Abstract
Decreased functional β-cell mass is the hallmark of diabetes, but the cause of this metabolic defect remains elusive. Here, we show that the expression levels of the growth factor receptor-bound protein 10 (GRB10), a negative regulator of insulin and mTORC1 signaling, are markedly induced in islets of diabetic mice and high glucose-treated insulinoma cell line INS-1cells. β-cell-specific knockout of Grb10 in mice increased β-cell mass and improved β-cell function. Grb10-deficient β-cells exhibit enhanced mTORC1 signaling and reduced β-cell dedifferentiation, which could be blocked by rapamycin. On the contrary, Grb10 overexpression induced β-cell dedifferentiation in MIN6 cells. Our study identifies GRB10 as a critical regulator of β-cell dedifferentiation and β-cell mass, which exerts its effect by inhibiting mTORC1 signaling.
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Affiliation(s)
- Zixin Cai
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Fen Liu
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Yan Yang
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Dandan Li
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Shanbiao Hu
- Department of Urological Organ Transplantation, the Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Lei Song
- Department of Urological Organ Transplantation, the Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Shaojie Yu
- Department of Urological Organ Transplantation, the Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Ting Li
- Department of Liver Organ Transplantation, the Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Bilian Liu
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Hairong Luo
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Weiping Zhang
- Department of Pathophysiology, Naval Medical University, Shanghai 200433, China
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Jingjing Zhang
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China.
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Title AC, Silva PN, Godbersen S, Hasenöhrl L, Stoffel M. The miR-200-Zeb1 axis regulates key aspects of β-cell function and survival in vivo. Mol Metab 2021; 53:101267. [PMID: 34116231 PMCID: PMC8258987 DOI: 10.1016/j.molmet.2021.101267] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/24/2021] [Accepted: 06/03/2021] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVE The miR-200-Zeb1 axis regulates the epithelial-to-mesenchymal transition (EMT), differentiation, and resistance to apoptosis. A better understanding of these processes in diabetes is highly relevant, as β-cell dedifferentiation and apoptosis contribute to the loss of functional β-cell mass and diabetes progression. Furthermore, EMT promotes the loss of β-cell identity in the in vitro expansion of human islets. Though the miR-200 family has previously been identified as a regulator of β-cell apoptosis in vivo, studies focusing on Zeb1 are lacking. The aim of this study was thus to investigate the role of Zeb1 in β-cell function and survival in vivo. METHODS miR-200 and Zeb1 are involved in a double-negative feedback loop. We characterized a mouse model in which miR-200 binding sites in the Zeb1 3'UTR are mutated (Zeb1200), leading to a physiologically relevant upregulation of Zeb1 mRNA expression. The role of Zeb1 was investigated in this model via metabolic tests and analysis of isolated islets. Further insights into the distinct contributions of the miR-200 and Zeb1 branches of the feedback loop were obtained by crossing the Zeb1200 allele into a background of miR-141-200c overexpression. RESULTS Mild Zeb1 derepression in vivo led to broad transcriptional changes in islets affecting β-cell identity, EMT, insulin secretion, cell-cell junctions, the unfolded protein response (UPR), and the response to ER stress. The aggregation and insulin secretion of dissociated islets of mice homozygous for the Zeb1200 mutation (Zeb1200M) were impaired, and Zeb1200M islets were resistant to thapsigargin-induced ER stress ex vivo. Zeb1200M mice had increased circulating proinsulin levels but no overt metabolic phenotype, reflecting the strong compensatory ability of islets to maintain glucose homeostasis. CONCLUSIONS This study signifies the importance of the miR-200-Zeb1 axis in regulating key aspects of β-cell function and survival. A better understanding of this axis is highly relevant in developing therapeutic strategies for inducing β-cell redifferentiation and maintaining β-cell identity in in vitro islet expansion.
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Affiliation(s)
- Alexandra C Title
- Institute of Molecular Health Sciences (IMHS), ETH Zürich, Otto-Stern-Weg 7, 8093, Zürich, Switzerland; Competence Center Personalized Medicine, ETH Zürich, Voltastrasse 24, 8044, Zürich, Switzerland
| | - Pamuditha N Silva
- Institute of Molecular Health Sciences (IMHS), ETH Zürich, Otto-Stern-Weg 7, 8093, Zürich, Switzerland
| | - Svenja Godbersen
- Institute of Molecular Health Sciences (IMHS), ETH Zürich, Otto-Stern-Weg 7, 8093, Zürich, Switzerland
| | - Lynn Hasenöhrl
- Institute of Molecular Health Sciences (IMHS), ETH Zürich, Otto-Stern-Weg 7, 8093, Zürich, Switzerland
| | - Markus Stoffel
- Institute of Molecular Health Sciences (IMHS), ETH Zürich, Otto-Stern-Weg 7, 8093, Zürich, Switzerland; Competence Center Personalized Medicine, ETH Zürich, Voltastrasse 24, 8044, Zürich, Switzerland; Medical Faculty, University of Zürich, 8091, Zürich, Switzerland.
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11
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Li B, Cheng Y, Yin Y, Xue J, Yu S, Gao J, Liu J, Zang L, Mu Y. Reversion of early- and late-stage β-cell dedifferentiation by human umbilical cord-derived mesenchymal stem cells in type 2 diabetic mice. Cytotherapy 2021; 23:510-520. [PMID: 33736932 DOI: 10.1016/j.jcyt.2021.01.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 01/11/2021] [Accepted: 01/20/2021] [Indexed: 01/08/2023]
Abstract
BACKGROUND AIMS The authors aimed to observe β-cell dedifferentiation in type 2 diabetes mellitus (T2DM) and investigate the reversal effect of umbilical cord-derived mesenchymal stem cells (UC-MSCs) on early- and late-stage β-cell dedifferentiation. METHODS In high-fat diet (HFD)/streptozotocin (STZ)-induced T2DM mice, the authors examined the predominant role of β-cell dedifferentiation over apoptosis in the development of T2DM and observed the reversion of β-cell dedifferentiation by UC-MSCs. Next, the authors used db/db mice to observe the progress of β-cell dedifferentiation from early to late stage, after which UC-MSC infusions of the same amount were performed in the early and late stages of dedifferentiation. Improvement in metabolic indices and restoration of β-cell dedifferentiation markers were examined. RESULTS In HFD/STZ-induced T2DM mice, the proportion of β-cell dedifferentiation was much greater than that of apoptosis, demonstrating that β-cell dedifferentiation was the predominant contributor to T2DM. UC-MSC infusions significantly improved glucose homeostasis and reversed β-cell dedifferentiation. In db/db mice, UC-MSC infusions in the early stage significantly improved glucose homeostasis and reversed β-cell dedifferentiation. In the late stage, UC-MSC infusions mildly improved glucose homeostasis and partially reversed β-cell dedifferentiation. Combining with other studies, the authors found that the reversal effect of UC-MSCs on β-cell dedifferentiation relied on the simultaneous relief of glucose and lipid metabolic disorders. CONCLUSIONS UC-MSC therapy is a promising strategy for reversing β-cell dedifferentiation in T2DM, and the reversal effect is greater in the early stage than in the late stage of β-cell dedifferentiation.
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Affiliation(s)
- Bing Li
- Department of Endocrinology, First Medical Center of People's Liberation Army General Hospital, Beijing, China
| | - Yu Cheng
- Department of Endocrinology, First Medical Center of People's Liberation Army General Hospital, Beijing, China
| | - Yaqi Yin
- Department of Endocrinology, First Medical Center of People's Liberation Army General Hospital, Beijing, China
| | - Jing Xue
- Department of Endocrinology, First Medical Center of People's Liberation Army General Hospital, Beijing, China
| | - Songyan Yu
- Department of Endocrinology, First Medical Center of People's Liberation Army General Hospital, Beijing, China
| | - Jieqing Gao
- Department of Endocrinology, Beijing Rehabilitation Hospital of Capital Medical University, Beijing, China
| | - Jiejie Liu
- Department of Molecular Biology, Institute of Basic Medicine, School of Life Science, People's Liberation Army General Hospital, Beijing, China
| | - Li Zang
- Department of Endocrinology, First Medical Center of People's Liberation Army General Hospital, Beijing, China.
| | - Yiming Mu
- Department of Endocrinology, First Medical Center of People's Liberation Army General Hospital, Beijing, China.
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12
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Zhang J, Liu F. The De-, Re-, and trans-differentiation of β-cells: Regulation and function. Semin Cell Dev Biol 2020; 103:68-75. [DOI: 10.1016/j.semcdb.2020.01.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2019] [Revised: 12/09/2019] [Accepted: 01/03/2020] [Indexed: 12/11/2022]
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13
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Elsharkawi I, Parambath D, Saber-Ayad M, Khan AA, El-Serafi AT. Exploring the effect of epigenetic modifiers on developing insulin-secreting cells. Hum Cell 2019; 33:1-9. [PMID: 31755075 DOI: 10.1007/s13577-019-00292-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Accepted: 10/11/2019] [Indexed: 12/24/2022]
Abstract
Diabetes is a worldwide health problem with increasing incidence. The current management modalities did not succeed to decrease comorbidities. This study aimed at enhancing the regenerative solution for diabetes by improving the differentiation of mesenchymal stromal cells (MSC) into glucose-sensitive, insulin-secreting cells through an epigenetic modification approach. A 3-day treatment protocol with the epigenetic modifiers, either decitabine (5-aza-2'-deoxycytidine; Aza); a DNA methylation inhibitor or Vorinostat (suberoylanilide hydroxamic acid; SAHA); a histone deacetylase inhibitor was added to two different human stem cell lines. The cells followed a multi-step differentiation protocol that provided the critical triggers in a temporal approach. Aza-pretreated group showed higher intracellular expression of insulin and the transcription factor 'PDX-1'. The cells responded to the high glucose challenge by secreting insulin in the media, as shown by ELISA. Gene expression showed induction of the genes for insulin, the glucose transporter 2, glucokinase, as well as the transcription factors MafA and NKX6.1. Although SAHA showed upregulation of insulin secretion, in comparison to control, the cells could not respond to the high glucose challenge. Interestingly, Aza-treated cells showed a significant decrease in the global DNA methylation level at the end of the culture. In conclusion, this additional step with Aza could enhance the response of MSC to the classical differentiation protocol for insulin-secreting cells and may help in establishing a regenerative solution for patients with diabetes.
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Affiliation(s)
| | | | - Maha Saber-Ayad
- College of Medicine, University of Sharjah, Sharjah, UAE.,Sharjah Institute for Medical Research, University of Sharjah, Sharjah, UAE.,College of Medicine, Cairo University, Cairo, Egypt
| | - Amir Ali Khan
- Department of Applied Biology, College of Science, University of Sharjah, Sharjah, UAE
| | - Ahmed T El-Serafi
- College of Medicine, University of Sharjah, Sharjah, UAE. .,Faculty of Medicine, Suez Canal University, Ismailia, Egypt. .,Department of Hand Surgery and Plastic Surgery and Burns, 401A, Building 462, Floor 11, Linköping University Hospital, P. O. Box: 581 85, Linköping, Sweden.
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14
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Efrat S. Beta-Cell Dedifferentiation in Type 2 Diabetes: Concise Review. Stem Cells 2019; 37:1267-1272. [PMID: 31298804 DOI: 10.1002/stem.3059] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2019] [Accepted: 06/18/2019] [Indexed: 02/06/2023]
Abstract
Type 2 diabetes (T2D) is caused by an inherited predisposition to pancreatic islet β-cell failure, which is manifested under cellular stress induced by metabolic overload. The decrease in the functional β-cell mass associated with T2D has been attributed primarily to β-cell death; however, studies in recent years suggested that β-cell dedifferentiation may contribute to this decline. The mechanisms linking genetic factors and cellular stress to β-cell dedifferentiation remain largely unknown. This study evaluated the evidence for β-cell dedifferentiation in T2D, and T2D and examined experimental systems in which its mechanisms may be studied. Understanding these mechanisms may allow prevention of β-cell dedifferentiation or induction of cell redifferentiation for restoration of the functional β-cell mass. Stem Cells 2019;37:1267-1272.
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Affiliation(s)
- Shimon Efrat
- Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
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15
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Kuo T, Damle M, González BJ, Egli D, Lazar MA, Accili D. Induction of α cell-restricted Gc in dedifferentiating β cells contributes to stress-induced β-cell dysfunction. JCI Insight 2019; 5:128351. [PMID: 31120862 DOI: 10.1172/jci.insight.128351] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Diabetic β cell failure is associated with β cell dedifferentiation. To identify effector genes of dedifferentiation, we integrated analyses of histone methylation as a surrogate of gene activation status and RNA expression in β cells sorted from mice with multiparity-induced diabetes. Interestingly, only a narrow subset of genes demonstrated concordant changes to histone methylation and RNA levels in dedifferentiating β cells. Notable among them was the α cell signature gene Gc, encoding a vitamin D-binding protein. While diabetes was associated with Gc induction, Gc-deficient islets did not induce β cell dedifferentiation markers and maintained normal ex vivo insulin secretion in the face of metabolic challenge. Moreover, Gc-deficient mice exhibited a more robust insulin secretory response than normal controls during hyperglycemic clamps. The data are consistent with a functional role of Gc activation in β cell dysfunction, and indicate that multiparity-induced diabetes is associated with altered β cell fate.
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Affiliation(s)
- Taiyi Kuo
- Department of Medicine and Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, New York, USA
| | - Manashree Damle
- The Institute for Diabetes, Obesity, and Metabolism, and Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Bryan J González
- Department of Medicine and Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, New York, USA.,Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, New York, USA
| | - Dieter Egli
- Department of Medicine and Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, New York, USA.,Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, New York, USA
| | - Mitchell A Lazar
- The Institute for Diabetes, Obesity, and Metabolism, and Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Domenico Accili
- Department of Medicine and Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, New York, USA
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16
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Li Y, Deng S, Peng J, Wang X, Essandoh K, Mu X, Peng T, Meng ZX, Fan GC. MicroRNA-223 is essential for maintaining functional β-cell mass during diabetes through inhibiting both FOXO1 and SOX6 pathways. J Biol Chem 2019; 294:10438-10448. [PMID: 31118273 DOI: 10.1074/jbc.ra119.007755] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 05/16/2019] [Indexed: 01/26/2023] Open
Abstract
The initiation and development of diabetes are mainly ascribed to the loss of functional β-cells. Therapies designed to regenerate β-cells provide great potential for controlling glucose levels and thereby preventing the devastating complications associated with diabetes. This requires detailed knowledge of the molecular events and underlying mechanisms in this disorder. Here, we report that expression of microRNA-223 (miR-223) is up-regulated in islets from diabetic mice and humans, as well as in murine Min6 β-cells exposed to tumor necrosis factor α (TNFα) or high glucose. Interestingly, miR-223 knockout (KO) mice exhibit impaired glucose tolerance and insulin resistance. Further analysis reveals that miR-223 deficiency dramatically suppresses β-cell proliferation and insulin secretion. Mechanistically, using luciferase reporter gene assays, histological analysis, and immunoblotting, we demonstrate that miR-223 inhibits both forkhead box O1 (FOXO1) and SRY-box 6 (SOX6) signaling, a unique bipartite mechanism that modulates expression of several β-cell markers (pancreatic and duodenal homeobox 1 (PDX1), NK6 homeobox 1 (NKX6.1), and urocortin 3 (UCN3)) and cell cycle-related genes (cyclin D1, cyclin E1, and cyclin-dependent kinase inhibitor P27 (P27)). Importantly, miR-223 overexpression in β-cells could promote β-cell proliferation and improve β-cell function. Taken together, our results suggest that miR-223 is a critical factor for maintaining functional β-cell mass and adaptation during metabolic stress.
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Affiliation(s)
- Yutian Li
- From the Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267
| | - Shan Deng
- From the Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267.,Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China 430074
| | - Jiangtong Peng
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China 430074
| | - Xiaohong Wang
- From the Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267
| | - Kobina Essandoh
- From the Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267
| | - Xingjiang Mu
- From the Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267
| | - Tianqing Peng
- Critical Illness Research, Lawson Health Research Institute, Ontario, Canada N6C 2R5, and
| | - Zhuo-Xian Meng
- Department of Pathology and Pathophysiology, Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China 310058
| | - Guo-Chang Fan
- From the Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267,
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17
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Maschio DA, Matheus VA, Collares‐Buzato CB. Islet cells are the source of Wnts that can induce beta‐cell proliferation in vitro. J Cell Physiol 2019; 234:19852-19865. [DOI: 10.1002/jcp.28584] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 03/06/2019] [Accepted: 03/14/2019] [Indexed: 12/21/2022]
Affiliation(s)
- Daniela A. Maschio
- Department of Biochemistry and Tissue Biology Institute of Biology, University of Campinas (UNICAMP) Campinas São Paulo Brazil
| | - Valquíria A. Matheus
- Department of Biochemistry and Tissue Biology Institute of Biology, University of Campinas (UNICAMP) Campinas São Paulo Brazil
| | - Carla B. Collares‐Buzato
- Department of Biochemistry and Tissue Biology Institute of Biology, University of Campinas (UNICAMP) Campinas São Paulo Brazil
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18
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Baeyens L, Lemper M, Staels W, De Groef S, De Leu N, Heremans Y, German MS, Heimberg H. (Re)generating Human Beta Cells: Status, Pitfalls, and Perspectives. Physiol Rev 2018; 98:1143-1167. [PMID: 29717931 DOI: 10.1152/physrev.00034.2016] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Diabetes mellitus results from disturbed glucose homeostasis due to an absolute (type 1) or relative (type 2) deficiency of insulin, a peptide hormone almost exclusively produced by the beta cells of the endocrine pancreas in a tightly regulated manner. Current therapy only delays disease progression through insulin injection and/or oral medications that increase insulin secretion or sensitivity, decrease hepatic glucose production, or promote glucosuria. These drugs have turned diabetes into a chronic disease as they do not solve the underlying beta cell defects or entirely prevent the long-term complications of hyperglycemia. Beta cell replacement through islet transplantation is a more physiological therapeutic alternative but is severely hampered by donor shortage and immune rejection. A curative strategy should combine newer approaches to immunomodulation with beta cell replacement. Success of this approach depends on the development of practical methods for generating beta cells, either in vitro or in situ through beta cell replication or beta cell differentiation. This review provides an overview of human beta cell generation.
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Affiliation(s)
- Luc Baeyens
- Beta Cell Neogenesis (BENE), Vrije Universiteit Brussel, Brussels , Belgium ; Diabetes Center, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, and Department of Medicine, University of California San Francisco , San Francisco, California ; Genentech Safety Assessment, South San Francisco, California ; Investigative Toxicology, UCB BioPharma, Braine-l'Alleud, Belgium ; Department of Pediatrics, Division of Pediatric Endocrinology, Ghent University, Hospital and Department of Pediatrics and Genetics , Ghent , Belgium ; Department of Endocrinology, Universitair Ziekenhuis Brussel, Brussels , Belgium ; and Department of Endocrinology, Algemeen Stedelijk Ziekenhuis Aalst, Aalst, Belgium
| | - Marie Lemper
- Beta Cell Neogenesis (BENE), Vrije Universiteit Brussel, Brussels , Belgium ; Diabetes Center, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, and Department of Medicine, University of California San Francisco , San Francisco, California ; Genentech Safety Assessment, South San Francisco, California ; Investigative Toxicology, UCB BioPharma, Braine-l'Alleud, Belgium ; Department of Pediatrics, Division of Pediatric Endocrinology, Ghent University, Hospital and Department of Pediatrics and Genetics , Ghent , Belgium ; Department of Endocrinology, Universitair Ziekenhuis Brussel, Brussels , Belgium ; and Department of Endocrinology, Algemeen Stedelijk Ziekenhuis Aalst, Aalst, Belgium
| | - Willem Staels
- Beta Cell Neogenesis (BENE), Vrije Universiteit Brussel, Brussels , Belgium ; Diabetes Center, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, and Department of Medicine, University of California San Francisco , San Francisco, California ; Genentech Safety Assessment, South San Francisco, California ; Investigative Toxicology, UCB BioPharma, Braine-l'Alleud, Belgium ; Department of Pediatrics, Division of Pediatric Endocrinology, Ghent University, Hospital and Department of Pediatrics and Genetics , Ghent , Belgium ; Department of Endocrinology, Universitair Ziekenhuis Brussel, Brussels , Belgium ; and Department of Endocrinology, Algemeen Stedelijk Ziekenhuis Aalst, Aalst, Belgium
| | - Sofie De Groef
- Beta Cell Neogenesis (BENE), Vrije Universiteit Brussel, Brussels , Belgium ; Diabetes Center, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, and Department of Medicine, University of California San Francisco , San Francisco, California ; Genentech Safety Assessment, South San Francisco, California ; Investigative Toxicology, UCB BioPharma, Braine-l'Alleud, Belgium ; Department of Pediatrics, Division of Pediatric Endocrinology, Ghent University, Hospital and Department of Pediatrics and Genetics , Ghent , Belgium ; Department of Endocrinology, Universitair Ziekenhuis Brussel, Brussels , Belgium ; and Department of Endocrinology, Algemeen Stedelijk Ziekenhuis Aalst, Aalst, Belgium
| | - Nico De Leu
- Beta Cell Neogenesis (BENE), Vrije Universiteit Brussel, Brussels , Belgium ; Diabetes Center, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, and Department of Medicine, University of California San Francisco , San Francisco, California ; Genentech Safety Assessment, South San Francisco, California ; Investigative Toxicology, UCB BioPharma, Braine-l'Alleud, Belgium ; Department of Pediatrics, Division of Pediatric Endocrinology, Ghent University, Hospital and Department of Pediatrics and Genetics , Ghent , Belgium ; Department of Endocrinology, Universitair Ziekenhuis Brussel, Brussels , Belgium ; and Department of Endocrinology, Algemeen Stedelijk Ziekenhuis Aalst, Aalst, Belgium
| | - Yves Heremans
- Beta Cell Neogenesis (BENE), Vrije Universiteit Brussel, Brussels , Belgium ; Diabetes Center, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, and Department of Medicine, University of California San Francisco , San Francisco, California ; Genentech Safety Assessment, South San Francisco, California ; Investigative Toxicology, UCB BioPharma, Braine-l'Alleud, Belgium ; Department of Pediatrics, Division of Pediatric Endocrinology, Ghent University, Hospital and Department of Pediatrics and Genetics , Ghent , Belgium ; Department of Endocrinology, Universitair Ziekenhuis Brussel, Brussels , Belgium ; and Department of Endocrinology, Algemeen Stedelijk Ziekenhuis Aalst, Aalst, Belgium
| | - Michael S German
- Beta Cell Neogenesis (BENE), Vrije Universiteit Brussel, Brussels , Belgium ; Diabetes Center, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, and Department of Medicine, University of California San Francisco , San Francisco, California ; Genentech Safety Assessment, South San Francisco, California ; Investigative Toxicology, UCB BioPharma, Braine-l'Alleud, Belgium ; Department of Pediatrics, Division of Pediatric Endocrinology, Ghent University, Hospital and Department of Pediatrics and Genetics , Ghent , Belgium ; Department of Endocrinology, Universitair Ziekenhuis Brussel, Brussels , Belgium ; and Department of Endocrinology, Algemeen Stedelijk Ziekenhuis Aalst, Aalst, Belgium
| | - Harry Heimberg
- Beta Cell Neogenesis (BENE), Vrije Universiteit Brussel, Brussels , Belgium ; Diabetes Center, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, and Department of Medicine, University of California San Francisco , San Francisco, California ; Genentech Safety Assessment, South San Francisco, California ; Investigative Toxicology, UCB BioPharma, Braine-l'Alleud, Belgium ; Department of Pediatrics, Division of Pediatric Endocrinology, Ghent University, Hospital and Department of Pediatrics and Genetics , Ghent , Belgium ; Department of Endocrinology, Universitair Ziekenhuis Brussel, Brussels , Belgium ; and Department of Endocrinology, Algemeen Stedelijk Ziekenhuis Aalst, Aalst, Belgium
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19
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MicroRNA Expression Analysis of In Vitro Dedifferentiated Human Pancreatic Islet Cells Reveals the Activation of the Pluripotency-Related MicroRNA Cluster miR-302s. Int J Mol Sci 2018; 19:ijms19041170. [PMID: 29649109 PMCID: PMC5979342 DOI: 10.3390/ijms19041170] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Revised: 04/06/2018] [Accepted: 04/09/2018] [Indexed: 12/12/2022] Open
Abstract
β-cell dedifferentiation has been recently suggested as an additional mechanism contributing to type-1 and to type-2 diabetes pathogenesis. Moreover, several studies demonstrated that in vitro culture of native human pancreatic islets derived from non-diabetic donors resulted in the generation of an undifferentiated cell population. Additional evidence from in vitro human β-cell lineage tracing experiments, demonstrated that dedifferentiated cells derive from β-cells, thus representing a potential in vitro model of β-cell dedifferentiation. Here, we report the microRNA expression profiles analysis of in vitro dedifferentiated islet cells in comparison to mature human native pancreatic islets. We identified 13 microRNAs upregulated and 110 downregulated in islet cells upon in vitro dedifferentiation. Interestingly, among upregulated microRNAs, we observed the activation of microRNA miR-302s cluster, previously defined as pluripotency-associated. Bioinformatic analysis indicated that miR-302s are predicted to target several genes involved in the control of β-cell/epithelial phenotype maintenance; accordingly, such genes were downregulated upon human islet in vitro dedifferentiation. Moreover, we uncovered that cell–cell contacts are needed to maintain low/null expression levels of miR-302. In conclusion, we showed that miR-302 microRNA cluster genes are involved in in vitro dedifferentiation of human pancreatic islet cells and inhibits the expression of multiple genes involved in the maintenance of β-cell mature phenotype.
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20
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Ma Z, Xin Z, Hu W, Jiang S, Yang Z, Yan X, Li X, Yang Y, Chen F. Forkhead box O proteins: Crucial regulators of cancer EMT. Semin Cancer Biol 2018; 50:21-31. [PMID: 29427645 DOI: 10.1016/j.semcancer.2018.02.004] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Revised: 12/02/2017] [Accepted: 02/05/2018] [Indexed: 12/12/2022]
Abstract
The epithelial-mesenchymal transition (EMT) is an acknowledged cellular transition process in which epithelial cells acquire mesenchymal-like properties that endow cancer cells with increased migratory and invasive behavior. Forkhead box O (FOXO) proteins have been shown to orchestrate multiple EMT-associated pathways and EMT-related transcription factors (EMT-TFs), thereby modulating the EMT process. The focus of the current review is to evaluate the latest research progress regarding the roles of FOXO proteins in cancer EMT. First, a brief overview of the EMT process in cancer and a general background on the FOXO family are provided. Next, we present the interactions between FOXO proteins and multiple EMT-associated pathways during malignancy development. Finally, we propose several novel potential directions for future research. Collectively, the information compiled herein should serve as a comprehensive repository of information on this topic and should aid in the design of additional studies and the future development of FOXO proteins as therapeutic targets.
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Affiliation(s)
- Zhiqiang Ma
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an 710069 China; Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, 1 Xinsi Road, Xi'an 710038, China
| | - Zhenlong Xin
- Department of Occupational and Environmental Health and The Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
| | - Wei Hu
- Department of Immunology, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
| | - Shuai Jiang
- Department of Aerospace Medicine, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
| | - Zhi Yang
- Department of Biomedical Engineering, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
| | - Xiaolong Yan
- Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, 1 Xinsi Road, Xi'an 710038, China
| | - Xiaofei Li
- Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, 1 Xinsi Road, Xi'an 710038, China
| | - Yang Yang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an 710069 China; Department of Biomedical Engineering, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China.
| | - Fulin Chen
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an 710069 China.
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21
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Wang W, Liu C, Jimenez-Gonzalez M, Song WJ, Hussain MA. The undoing and redoing of the diabetic β-cell. J Diabetes Complications 2017; 31:912-917. [PMID: 28242267 DOI: 10.1016/j.jdiacomp.2017.01.028] [cited] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Revised: 12/23/2016] [Accepted: 01/31/2017] [Indexed: 01/26/2025]
Abstract
A hallmark of type 2 diabetes (T2DM) is the reduction in functional β-cell mass, which is considered at least in part to result from an imbalance of β-cell renewal and apoptosis, with the latter being accelerated during metabolic stress. More recent studies, however, suggest that the loss of functional β-cell mass is not as much due to β-cell death but rather to de-differentiation of β-cells when these cells are exposed to metabolic stressors, opening the possibility to re-differentiate and restore functional β-cell mass by therapeutic intervention. In parallel, clinical observations suggest that temporary intensive insulin therapy in early diagnosed humans with T2DM, so as to "rest" endogenous β-cells, allows these patients to regain adequate insulin secretion and to maintain euglycemia for prolonged periods free of continued pharmacotherapy. Whether observations made in (mostly rodent) models of diabetes mellitus and in clinical trials are revealing identical mechanisms and therapeutic opportunities remains a tantalizing possibility. Our intention is for this review to serve as an overview of the field and commentary of this particularly exciting field of research.
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Affiliation(s)
- Wei Wang
- Metabolism Division, Departments of Pediatrics, Medicine and Biological Chemistry, Johns Hopkins University School of Medicine, 600 N Wolfe Street, CMSC 10-113, Baltimore, MD 21287
| | - Chune Liu
- Metabolism Division, Departments of Pediatrics, Medicine and Biological Chemistry, Johns Hopkins University School of Medicine, 600 N Wolfe Street, CMSC 10-113, Baltimore, MD 21287
| | - Maria Jimenez-Gonzalez
- Metabolism Division, Departments of Pediatrics, Medicine and Biological Chemistry, Johns Hopkins University School of Medicine, 600 N Wolfe Street, CMSC 10-113, Baltimore, MD 21287
| | - Woo-Jin Song
- Metabolism Division, Departments of Pediatrics, Medicine and Biological Chemistry, Johns Hopkins University School of Medicine, 600 N Wolfe Street, CMSC 10-113, Baltimore, MD 21287
| | - Mehboob A Hussain
- Metabolism Division, Departments of Pediatrics, Medicine and Biological Chemistry, Johns Hopkins University School of Medicine, 600 N Wolfe Street, CMSC 10-113, Baltimore, MD 21287.
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22
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Wang W, Liu C, Jimenez-Gonzalez M, Song WJ, Hussain MA. The undoing and redoing of the diabetic β-cell. J Diabetes Complications 2017; 31:912-917. [PMID: 28242267 PMCID: PMC5450161 DOI: 10.1016/j.jdiacomp.2017.01.028] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Revised: 12/23/2016] [Accepted: 01/31/2017] [Indexed: 02/08/2023]
Abstract
A hallmark of type 2 diabetes (T2DM) is the reduction in functional β-cell mass, which is considered at least in part to result from an imbalance of β-cell renewal and apoptosis, with the latter being accelerated during metabolic stress. More recent studies, however, suggest that the loss of functional β-cell mass is not as much due to β-cell death but rather to de-differentiation of β-cells when these cells are exposed to metabolic stressors, opening the possibility to re-differentiate and restore functional β-cell mass by therapeutic intervention. In parallel, clinical observations suggest that temporary intensive insulin therapy in early diagnosed humans with T2DM, so as to "rest" endogenous β-cells, allows these patients to regain adequate insulin secretion and to maintain euglycemia for prolonged periods free of continued pharmacotherapy. Whether observations made in (mostly rodent) models of diabetes mellitus and in clinical trials are revealing identical mechanisms and therapeutic opportunities remains a tantalizing possibility. Our intention is for this review to serve as an overview of the field and commentary of this particularly exciting field of research.
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Affiliation(s)
- Wei Wang
- Metabolism Division, Departments of Pediatrics, Medicine and Biological Chemistry, Johns Hopkins University School of Medicine, 600 N Wolfe Street, CMSC 10-113, Baltimore, MD 21287
| | - Chune Liu
- Metabolism Division, Departments of Pediatrics, Medicine and Biological Chemistry, Johns Hopkins University School of Medicine, 600 N Wolfe Street, CMSC 10-113, Baltimore, MD 21287
| | - Maria Jimenez-Gonzalez
- Metabolism Division, Departments of Pediatrics, Medicine and Biological Chemistry, Johns Hopkins University School of Medicine, 600 N Wolfe Street, CMSC 10-113, Baltimore, MD 21287
| | - Woo-Jin Song
- Metabolism Division, Departments of Pediatrics, Medicine and Biological Chemistry, Johns Hopkins University School of Medicine, 600 N Wolfe Street, CMSC 10-113, Baltimore, MD 21287
| | - Mehboob A Hussain
- Metabolism Division, Departments of Pediatrics, Medicine and Biological Chemistry, Johns Hopkins University School of Medicine, 600 N Wolfe Street, CMSC 10-113, Baltimore, MD 21287.
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23
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Martinez-Sanchez A, Rutter GA, Latreille M. MiRNAs in β-Cell Development, Identity, and Disease. Front Genet 2017; 7:226. [PMID: 28123396 PMCID: PMC5225124 DOI: 10.3389/fgene.2016.00226] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Accepted: 12/21/2016] [Indexed: 12/22/2022] Open
Abstract
Pancreatic β-cells regulate glucose metabolism by secreting insulin, which in turn stimulates the utilization or storage of the sugar by peripheral tissues. Insulin insufficiency and a prolonged period of insulin resistance are usually the core components of type 2 diabetes (T2D). Although, decreased insulin levels in T2D have long been attributed to a decrease in β-cell function and/or mass, this model has recently been refined with the recognition that a loss of β-cell “identity” and dedifferentiation also contribute to the decline in insulin production. MicroRNAs (miRNAs) are key regulatory molecules that display tissue-specific expression patterns and maintain the differentiated state of somatic cells. During the past few years, great strides have been made in understanding how miRNA circuits impact β-cell identity. Here, we review current knowledge on the role of miRNAs in regulating the acquisition of the β-cell fate during development and in maintaining mature β-cell identity and function during stress situations such as obesity, pregnancy, aging, or diabetes. We also discuss how miRNA function could be harnessed to improve our ability to generate β-cells for replacement therapy for T2D.
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Affiliation(s)
- Aida Martinez-Sanchez
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London London, UK
| | - Guy A Rutter
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London London, UK
| | - Mathieu Latreille
- Cellular Identity and Metabolism Group, MRC London Institute of Medical SciencesLondon, UK; Institute of Clinical Sciences, Faculty of Medicine, Imperial College LondonLondon, UK
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24
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Efrat S. Mechanisms of adult human β-cell in vitro dedifferentiation and redifferentiation. Diabetes Obes Metab 2016; 18 Suppl 1:97-101. [PMID: 27615137 DOI: 10.1111/dom.12724] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Accepted: 04/20/2016] [Indexed: 12/13/2022]
Abstract
Recent studies in animal models and human pathological specimens suggest the involvement of β-cell dedifferentiation in β-cell dysfunction associated with type 2 diabetes. Dedifferentiated β-cells may be exploited for endogenous renewal of the β-cell mass. However, studying human β-cell dedifferentiation in diabetes presents major difficulties. We have analysed mechanisms involved in human β-cell dedifferentiation in vitro, under conditions that allow cell proliferation. Although there are important differences between the two cellular environments, β-cell dedifferentiation in the two conditions is likely to share a number of common pathways. Insights from the in vitro studies may lead to development of approaches for redifferentiation of endogenous dedifferentiated β-cells.
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Affiliation(s)
- S Efrat
- Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv, Israel.
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25
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Sionov RV, Finesilver G, Sapozhnikov L, Soroker A, Zlotkin-Rivkin E, Saad Y, Kahana M, Bodaker M, Alpert E, Mitrani E. Beta Cells Secrete Significant and Regulated Levels of Insulin for Long Periods when Seeded onto Acellular Micro-Scaffolds. Tissue Eng Part A 2016; 21:2691-702. [PMID: 26416226 DOI: 10.1089/ten.tea.2014.0711] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
The aim of this work is to obtain significant and regulated insulin secretion from human beta cells ex vivo. Long-term culture of human pancreatic islets and attempts at expanding human islet cells normally result in loss of beta-cell phenotype. We propose that to obtain proper ex vivo beta cell function, there is a need to develop three-dimensional structures that mimic the natural islet tissue microenvironment. We here describe the preparation of endocrine micro-pancreata (EMPs) that are made up of acellular organ-derived micro-scaffolds seeded with human intact or enzymatically dissociated islets. We show that EMPs constructed by seeding whole islets, freshly enzymatically-dissociated islets or even dissociated islets grown first in standard monolayer cultures express high levels of key beta-cell specific genes and secrete quantities of insulin per cell similar to freshly isolated human islets in a glucose-regulated manner for more than 3 months in vitro.
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Affiliation(s)
- Ronit Vogt Sionov
- Department of Cell and Developmental Biology, The Hebrew University of Jerusalem , The Alexander Silberman Institute of Life Sciences, Jerusalem, Israel
| | - Gershon Finesilver
- Department of Cell and Developmental Biology, The Hebrew University of Jerusalem , The Alexander Silberman Institute of Life Sciences, Jerusalem, Israel
| | - Lena Sapozhnikov
- Department of Cell and Developmental Biology, The Hebrew University of Jerusalem , The Alexander Silberman Institute of Life Sciences, Jerusalem, Israel
| | - Avigail Soroker
- Department of Cell and Developmental Biology, The Hebrew University of Jerusalem , The Alexander Silberman Institute of Life Sciences, Jerusalem, Israel
| | - Efrat Zlotkin-Rivkin
- Department of Cell and Developmental Biology, The Hebrew University of Jerusalem , The Alexander Silberman Institute of Life Sciences, Jerusalem, Israel
| | - Yocheved Saad
- Department of Cell and Developmental Biology, The Hebrew University of Jerusalem , The Alexander Silberman Institute of Life Sciences, Jerusalem, Israel
| | - Meygal Kahana
- Department of Cell and Developmental Biology, The Hebrew University of Jerusalem , The Alexander Silberman Institute of Life Sciences, Jerusalem, Israel
| | - Matan Bodaker
- Department of Cell and Developmental Biology, The Hebrew University of Jerusalem , The Alexander Silberman Institute of Life Sciences, Jerusalem, Israel
| | - Evgenia Alpert
- Department of Cell and Developmental Biology, The Hebrew University of Jerusalem , The Alexander Silberman Institute of Life Sciences, Jerusalem, Israel
| | - Eduardo Mitrani
- Department of Cell and Developmental Biology, The Hebrew University of Jerusalem , The Alexander Silberman Institute of Life Sciences, Jerusalem, Israel
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26
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Abstract
Since insulin discovery, islet transplantation was the first protocol to show the possibility to cure patients with type 1 diabetes using low-risk procedures. The scarcity of pancreas donors triggered a burst of studies focused on the production of new β cells in vitro. These were rapidly dominated by pluripotent stem cells (PSCs) demonstrating diabetes-reversal potential in diabetic mice. Subsequent enthusiasm fostered a clinical trial with immunoisolated embryonic-derived pancreatic progenitors. Yet safety is the Achilles' heel of PSCs, and a whole branch of β cell engineering medicine focuses on transdifferentiation of adult pancreatic cells. New data showed the possibility to chemically stimulate acinar or α cells to undergo β cell neogenesis and provide opportunities to intervene in situ without the need for a transplant, at least after weighing benefits against systemic adverse effects. The current studies suggested the pancreas as a reservoir of facultative progenitors (e.g., in the duct lining) could be exploited ex vivo for expansion and β cell differentiation in timely fashion and without the hurdles of PSC use. Diabetes cell therapy is thus a growing field not only with great potential but also with many pitfalls to overcome for becoming fully envisioned as a competitor to the current treatment standards.
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Affiliation(s)
- Philippe A Lysy
- Institut de Recherche Expérimentale et Clinique, Pediatric Research Laboratory, Université Catholique de Louvain, Brussels, Belgium.
- Pediatric Endocrinology Unit, Cliniques Universitaires Saint Luc, Université Catholique de Louvain, Brussels, Belgium.
| | - Elisa Corritore
- Institut de Recherche Expérimentale et Clinique, Pediatric Research Laboratory, Université Catholique de Louvain, Brussels, Belgium
| | - Etienne M Sokal
- Institut de Recherche Expérimentale et Clinique, Pediatric Research Laboratory, Université Catholique de Louvain, Brussels, Belgium
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27
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Toren-Haritan G, Efrat S. TGFβ Pathway Inhibition Redifferentiates Human Pancreatic Islet β Cells Expanded In Vitro. PLoS One 2015; 10:e0139168. [PMID: 26418361 PMCID: PMC4587799 DOI: 10.1371/journal.pone.0139168] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Accepted: 09/08/2015] [Indexed: 11/18/2022] Open
Abstract
In-vitro expansion of insulin-producing cells from adult human pancreatic islets could provide an abundant cell source for diabetes therapy. However, proliferation of β-cell-derived (BCD) cells is associated with loss of phenotype and epithelial-mesenchymal transition (EMT). Nevertheless, BCD cells maintain open chromatin structure at β-cell genes, suggesting that they could be readily redifferentiated. The transforming growth factor β (TGFβ) pathway has been implicated in EMT in a range of cell types. Here we show that human islet cell expansion in vitro involves upregulation of the TGFβ pathway. Blocking TGFβ pathway activation using short hairpin RNA (shRNA) against TGFβ Receptor 1 (TGFBR1, ALK5) transcripts inhibits BCD cell proliferation and dedifferentiation. Treatment of expanded BCD cells with ALK5 shRNA results in their redifferentiation, as judged by expression of β-cell genes and decreased cell proliferation. These effects, which are reproducible in cells from multiple human donors, are mediated, at least in part, by AKT-FOXO1 signaling. ALK5 inhibition synergizes with a soluble factor cocktail to promote BCD cell redifferentiation. The combined treatment may offer a therapeutically applicable way for generating an abundant source of functional insulin-producing cells following ex-vivo expansion.
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Affiliation(s)
- Ginat Toren-Haritan
- Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Shimon Efrat
- Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
- * E-mail:
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28
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Sintov E, Nathan G, Knoller S, Pasmanik-Chor M, Russ HA, Efrat S. Inhibition of ZEB1 expression induces redifferentiation of adult human β cells expanded in vitro. Sci Rep 2015; 5:13024. [PMID: 26264186 PMCID: PMC4532995 DOI: 10.1038/srep13024] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Accepted: 07/15/2015] [Indexed: 01/20/2023] Open
Abstract
In-vitro expansion of functional adult human β-cells is an attractive approach for generating insulin-producing cells for transplantation. However, human islet cell expansion in culture results in loss of β-cell phenotype and epithelial-mesenchymal transition (EMT). This process activates expression of ZEB1 and ZEB2, two members of the zinc-finger homeobox family of E-cadherin repressors, which play key roles in EMT. Downregulation of ZEB1 using shRNA in expanded β-cell-derived (BCD) cells induced mesenchymal-epithelial transition (MET), β-cell gene expression, and proliferation attenuation. In addition, inhibition of ZEB1 expression potentiated redifferentiation induced by a combination of soluble factors, as judged by an improved response to glucose stimulation and a 3-fold increase in the fraction of C-peptide-positive cells to 60% of BCD cells. Furthermore, ZEB1 shRNA led to increased insulin secretion in cells transplanted in vivo. Our findings suggest that the effects of ZEB1 inhibition are mediated by attenuation of the miR-200c target genes SOX6 and SOX2. These findings, which were reproducible in cells derived from multiple human donors, emphasize the key role of ZEB1 in EMT in cultured BCD cells and support the value of ZEB1 inhibition for BCD cell redifferentiation and generation of functional human β-like cells for cell therapy of diabetes.
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Affiliation(s)
- Elad Sintov
- Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Gili Nathan
- Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Sarah Knoller
- Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Metsada Pasmanik-Chor
- Bioinformatics Unit, George Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Holger A Russ
- Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Shimon Efrat
- Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
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29
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Cheng Y, Kang H, Shen J, Hao H, Liu J, Guo Y, Mu Y, Han W. Beta-cell regeneration from vimentin+/MafB+ cells after STZ-induced extreme beta-cell ablation. Sci Rep 2015; 5:11703. [PMID: 26129776 PMCID: PMC4486952 DOI: 10.1038/srep11703] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2014] [Accepted: 06/02/2015] [Indexed: 12/16/2022] Open
Abstract
Loss of functional beta-cells is fundamental in both type 1 and type 2 diabetes. In situ beta-cell regeneration therefore has garnered great interest as an approach to diabetes therapy. Here, after elimination of pre-existing beta cells by a single high-dose of streptozotocin (STZ), we demonstrated that a considerable amount of beta-like-cells was generated within 48 hrs. But the newly formed insulin producing cells failed to respond to glucose challenge at this time and diminished afterwards. Insulin treatment to normalize the glucose level protected the neogenic beta-like cells and the islet function was also gradually matured. Strikingly, intermediate cells lacking epithelial marker E-cadherin but expressing mesenchymal cell-specific marker vimentin appeared within 16 hrs following STZ exposure, which served as the major source of insulin-producing cells observed at 24 hrs. Moreover, these intermediate cells strongly expressed alpha-cell-specific marker MafB. In summary, the data presented here identified a novel intermediate cell type as beta-cell progenitors, showing mesenchymal cell feature as well as alpha-cell marker MafB. Our results might have important implications for efforts to stimulate beta-cell regeneration.
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Affiliation(s)
- Yu Cheng
- Department of Endocrinology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853, China
- Department of Molecular Biology, Institute of Basic Medicine, School of Life Science, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853, China
| | - Hongjun Kang
- Department of Critical Care Medicine, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853, China
| | - Jing Shen
- Department of Endocrinology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853, China
- Department of Molecular Biology, Institute of Basic Medicine, School of Life Science, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853, China
- Department of Endocrinology, Chinese PLA 309 Hospital, 17 Heishanhu Road, Beijing 100091, China
| | - Haojie Hao
- Department of Molecular Biology, Institute of Basic Medicine, School of Life Science, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853, China
| | - Jiejie Liu
- Department of Molecular Biology, Institute of Basic Medicine, School of Life Science, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853, China
| | - Yelei Guo
- Department of Molecular Biology, Institute of Basic Medicine, School of Life Science, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853, China
| | - Yiming Mu
- Department of Endocrinology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853, China
| | - Weidong Han
- Department of Molecular Biology, Institute of Basic Medicine, School of Life Science, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853, China
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30
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Tanabe S. Origin of cells and network information. World J Stem Cells 2015; 7:535-540. [PMID: 25914760 PMCID: PMC4404388 DOI: 10.4252/wjsc.v7.i3.535] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Revised: 01/20/2015] [Accepted: 02/09/2015] [Indexed: 02/06/2023] Open
Abstract
All cells are derived from one cell, and the origin of different cell types is a subject of curiosity. Cells construct life through appropriately timed networks at each stage of development. Communication among cells and intracellular signaling are essential for cell differentiation and for life processes. Cellular molecular networks establish cell diversity and life. The investigation of the regulation of each gene in the genome within the cellular network is therefore of interest. Stem cells produce various cells that are suitable for specific purposes. The dynamics of the information in the cellular network changes as the status of cells is altered. The components of each cell are subject to investigation.
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Affiliation(s)
- Shihori Tanabe
- Shihori Tanabe, National Institute of Health Sciences, Tokyo 158-8501, Japan
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