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Urbanczyk M, Abuhelou A, Köninger M, Jeyagaran A, Carvajal-Berrio D, Kim E, Marzi J, Loskill P, Layland SL, Schenke-Layland K. Heterogeneity of Endothelial Cells Impacts the Functionality of Human Pancreatic In Vitro Models. Tissue Eng Part A 2024. [PMID: 39453887 DOI: 10.1089/ten.tea.2024.0176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2024] Open
Abstract
Endothelial cells (ECs) play a crucial role in maintaining tissue homeostasis and functionality. Depending on their tissue of origin, ECs can be highly heterogeneous regarding their morphology, gene and protein expression, functionality, and signaling pathways. Understanding the interaction between organ-specific ECs and their surrounding tissue is therefore critical when investigating tissue homeostasis, disease development, and progression. In vitro models often lack organ-specific ECs, potentially limiting the translatability and validity of the obtained results. The goal of this study was to assess the differences between commonly used EC sources in tissue engineering applications, including human umbilical vein ECs (HUVECs), human dermal microvascular ECs (hdmvECs), and human foreskin microvascular ECs (hfmvECs), and organ-specific human pancreatic microvascular ECs (hpmvECs), and test their impact on functionality within an in vitro pancreas test system used for diabetes research. Utilizing high-resolution Raman microspectroscopy and Raman imaging in combination with established protein and gene expression analyses and exposure to defined physical signals within microfluidic cultures, we identified that ECs exhibit significant differences in their biochemical composition, relevant protein expression, angiogenic potential, and response to the application of mechanical shear stress. Proof-of-concept results showed that the coculture of isolated human islets of Langerhans with hpmvECs significantly increased the functionality when compared with control islets and islets cocultured with HUVECs. Our study demonstrates that the choice of EC type significantly impacts the experimental results, which needs to be considered when implementing ECs into in vitro models.
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Affiliation(s)
- Max Urbanczyk
- Institute of Biomedical Engineering, Department for Medical Technologies and Regenerative Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Athar Abuhelou
- Institute of Biomedical Engineering, Department for Medical Technologies and Regenerative Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Marie Köninger
- Institute of Biomedical Engineering, Department for Medical Technologies and Regenerative Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Abiramy Jeyagaran
- Institute of Biomedical Engineering, Department for Medical Technologies and Regenerative Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Daniel Carvajal-Berrio
- Institute of Biomedical Engineering, Department for Medical Technologies and Regenerative Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Ellie Kim
- Institute of Biomedical Engineering, Department for Medical Technologies and Regenerative Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Julia Marzi
- Institute of Biomedical Engineering, Department for Medical Technologies and Regenerative Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
- NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany, Reutlingen, Germany
| | - Peter Loskill
- NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany, Reutlingen, Germany
- Institute of Biomedical Engineering, Department for Microphysiological Systems, Faculty of Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
- 3R Center Tübingen for In Vitro Models and Alternatives to Animal Testing, Tübingen, Germany
| | - Shannon L Layland
- Institute of Biomedical Engineering, Department for Medical Technologies and Regenerative Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
- Department of Women's Health Tübingen, University of Tübingen, Tübingen, Germany
| | - Katja Schenke-Layland
- Institute of Biomedical Engineering, Department for Medical Technologies and Regenerative Medicine, Eberhard Karls University Tübingen, Tübingen, Germany
- NMI Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany, Reutlingen, Germany
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Wang L, Wan J, Xu Y, Huang Y, Wang D, Zhu D, Chen Q, Lu Y, Guo Q. Endothelial Cells Promote Pseudo-islet Function Through BTC-EGFR-JAK/STAT Signaling Pathways. Ann Biomed Eng 2024; 52:2610-2626. [PMID: 38829457 DOI: 10.1007/s10439-024-03548-3] [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: 09/20/2023] [Accepted: 05/20/2024] [Indexed: 06/05/2024]
Abstract
Interactions between cells are of fundamental importance in affecting cell function. In vivo, endothelial cells and islet cells are close to each other, which makes endothelial cells essential for islet cell development and maintenance of islet cell function. We used endothelial cells to construct 3D pseudo-islets, which demonstrated better glucose regulation and greater insulin secretion compared to conventional pseudo-islets in both in vivo and in vitro trials. However, the underlying mechanism of how endothelial cells promote beta cell function localized within islets is still unknown. We performed transcriptomic sequencing, differential gene analysis, and enrichment analysis on two types of pseudo-islets to show that endothelial cells can promote the function of internal beta cells in pseudo-islets through the BTC-EGFR-JAK/STAT signaling pathway. Min6 cells secreted additional BTC after co-culture of endothelial cells with MIN6 cells outside the body. After BTC knockout in vitro, we found that beta cells functioned differently: insulin secretion levels decreased significantly, while the expression of key proteins in the EGFR-mediated JAK/STAT signaling pathway simultaneously decreased, further confirming our results. Through our experiments, we elucidate the molecular mechanisms by which endothelial cells maintain islet function in vitro, which provides a theoretical basis for the construction of pseudo-islets and islet cell transplants for the treatment of diabetes mellitus.
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Affiliation(s)
- Lin Wang
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China
| | - Jian Wan
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China
| | - Yang Xu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China
| | - Yan Huang
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China
| | - Dongzhi Wang
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China
| | - Donghui Zhu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China
| | - Qiyang Chen
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China
| | - Yuhua Lu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China.
- Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China.
| | - Qingsong Guo
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China.
- Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China.
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Fagundes RR, Zaldumbide A, Taylor CT. Role of hypoxia-inducible factor 1 in type 1 diabetes. Trends Pharmacol Sci 2024; 45:798-810. [PMID: 39127527 DOI: 10.1016/j.tips.2024.07.001] [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: 06/05/2024] [Revised: 07/08/2024] [Accepted: 07/11/2024] [Indexed: 08/12/2024]
Abstract
Type 1 diabetes (T1D) is a common autoimmune disease in which dysregulated glucose metabolism is a key feature. T1D is both poorly understood and in need of improved therapeutics. Hypoxia is frequently encountered in multiple tissues in T1D patients including the pancreas and sites of diabetic complications. Hypoxia-inducible factor (HIF)-1, a ubiquitous master regulator of the adaptive response to hypoxia, promotes glucose metabolism through transcriptional and non-transcriptional mechanisms and alters disease progression in multiple preclinical T1D models. However, how HIF-1 activation in β-cells of the pancreas and immune cells (two key cell types in T1D) ultimately affects disease progression remains controversial. We discuss recent advances in our understanding of the role of hypoxia/HIF-1-induced glycolysis in T1D and explore the possible use of drugs targeting this pathway as potential new therapeutics.
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Affiliation(s)
- Raphael R Fagundes
- Department of Cell and Chemical Biology, Leiden University Medical Center, Albinusdreef 2, Leiden, The Netherlands
| | - Arnaud Zaldumbide
- Department of Cell and Chemical Biology, Leiden University Medical Center, Albinusdreef 2, Leiden, The Netherlands
| | - Cormac T Taylor
- School of Medicine and Conway Institute of Biomolecular and Biomedical Research and Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland.
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Edri S, Rosenthal V, Ginsburg O, Newman Frisch A, Pierreux CE, Sharon N, Levenberg S. 3D model of mouse embryonic pancreas and endocrine compartment using stem cell-derived mesoderm and pancreatic progenitors. iScience 2024; 27:109959. [PMID: 38832019 PMCID: PMC11144751 DOI: 10.1016/j.isci.2024.109959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 03/21/2024] [Accepted: 05/08/2024] [Indexed: 06/05/2024] Open
Abstract
The developing mouse pancreas is surrounded by mesoderm compartments providing signals that induce pancreas formation. Most pancreatic organoid protocols lack this mesoderm niche and only partially capture the pancreatic cell repertoire. This work aims to generate pancreatic aggregates by differentiating mouse embryonic stem cells (mESCs) into mesoderm progenitors (MPs) and pancreas progenitors (PPs), without using Matrigel. First, mESCs were differentiated into epiblast stem cells (EpiSCs) to enhance the PP differentiation rate. Next, PPs and MPs aggregated together giving rise to various pancreatic cell types, including endocrine, acinar, and ductal cells, and to endothelial cells. Single-cell RNA sequencing analysis revealed a larger endocrine population within the PP + MP aggregates, as compared to PPs alone or PPs in Matrigel aggregates. The PP + MP aggregate gene expression signatures and its endocrine population percentage closely resembled those of the endocrine population found in the mouse embryonic pancreas, which holds promise for studying pancreas development.
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Affiliation(s)
- Shlomit Edri
- Faculty of Biomedical Engineering, Technion – Israel Institute of Technology, Haifa 3200003, Israel
| | - Vardit Rosenthal
- Faculty of Biomedical Engineering, Technion – Israel Institute of Technology, Haifa 3200003, Israel
| | - Or Ginsburg
- Faculty of Biomedical Engineering, Technion – Israel Institute of Technology, Haifa 3200003, Israel
| | - Abigail Newman Frisch
- Faculty of Biomedical Engineering, Technion – Israel Institute of Technology, Haifa 3200003, Israel
| | | | - Nadav Sharon
- Faculty of Biology, Technion – Israel Institute of Technology, Haifa 3200003, Israel
| | - Shulamit Levenberg
- Faculty of Biomedical Engineering, Technion – Israel Institute of Technology, Haifa 3200003, Israel
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Eberhard D, Balkenhol S, Köster A, Follert P, Upschulte E, Ostermann P, Kirschner P, Uhlemeyer C, Charnay I, Preuss C, Trenkamp S, Belgardt BF, Dickscheid T, Esposito I, Roden M, Lammert E. Semaphorin-3A regulates liver sinusoidal endothelial cell porosity and promotes hepatic steatosis. NATURE CARDIOVASCULAR RESEARCH 2024; 3:734-753. [PMID: 39196233 PMCID: PMC11358038 DOI: 10.1038/s44161-024-00487-z] [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] [Received: 02/22/2023] [Accepted: 05/07/2024] [Indexed: 08/29/2024]
Abstract
Prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease, increases worldwide and associates with type 2 diabetes and other cardiometabolic diseases. Here we demonstrate that Sema3a is elevated in liver sinusoidal endothelial cells of animal models for obesity, type 2 diabetes and MASLD. In primary human liver sinusoidal endothelial cells, saturated fatty acids induce expression of SEMA3A, and loss of a single allele is sufficient to reduce hepatic fat content in diet-induced obese mice. We show that semaphorin-3A regulates the number of fenestrae through a signaling cascade that involves neuropilin-1 and phosphorylation of cofilin-1 by LIM domain kinase 1. Finally, inducible vascular deletion of Sema3a in adult diet-induced obese mice reduces hepatic fat content and elevates very low-density lipoprotein secretion. Thus, we identified a molecular pathway linking hyperlipidemia to microvascular defenestration and early development of MASLD.
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Affiliation(s)
- Daniel Eberhard
- Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, Düsseldorf, Germany
| | - Sydney Balkenhol
- Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, Düsseldorf, Germany
- Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Andrea Köster
- Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, Düsseldorf, Germany
| | - Paula Follert
- Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, Düsseldorf, Germany
| | - Eric Upschulte
- Cécile & Oskar Vogt Institute of Brain Research, Medical Faculty and University Hospital Düsseldorf, Düsseldorf, Germany
- Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, Jülich, Germany
- Helmholtz AI, Research Center Jülich, Jülich, Germany
| | - Philipp Ostermann
- Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, Düsseldorf, Germany
| | - Philip Kirschner
- Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, Düsseldorf, Germany
| | - Celina Uhlemeyer
- Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Iannis Charnay
- Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, Düsseldorf, Germany
| | - Christina Preuss
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
| | - Sandra Trenkamp
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
| | - Bengt-Frederik Belgardt
- Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Timo Dickscheid
- Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, Jülich, Germany
- Helmholtz AI, Research Center Jülich, Jülich, Germany
- Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Computer Science, Düsseldorf, Germany
| | - Irene Esposito
- Institute of Pathology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
| | - Michael Roden
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
- Division of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
| | - Eckhard Lammert
- Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural Sciences, Institute of Metabolic Physiology, Düsseldorf, Germany.
- Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany.
- German Center for Diabetes Research (DZD), Neuherberg, Germany.
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Slak Rupnik M, Hara M. Local Dialogues Between the Endocrine and Exocrine Cells in the Pancreas. Diabetes 2024; 73:533-541. [PMID: 38215069 PMCID: PMC10958587 DOI: 10.2337/db23-0760] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 01/03/2024] [Indexed: 01/14/2024]
Abstract
For many years, it has been taught in medical textbooks that the endocrine and exocrine parts of the pancreas have separate blood supplies that do not mix. Therefore, they have been studied by different scientific communities, and patients with pancreatic disorders are treated by physicians in different medical disciplines, where endocrine and exocrine function are the focus of endocrinologists and gastroenterologists, respectively. The conventional model that every islet in each pancreatic lobule receives a dedicated arterial blood supply was first proposed in 1932, and it has been inherited to date. Recently, in vivo intravital recording of red blood cell flow in mouse islets as well as in situ structural analysis of 3D pancreatic vasculature from hundreds of islets provided evidence for preferentially integrated pancreatic blood flow in six mammalian species. The majority of islets have no association with the arteriole, and there is bidirectional blood exchange between the two segments. Such vascularization may allow an entire downstream region of islets and acinar cells to be simultaneously exposed to a topologically and temporally specific plasma content, which could underlie an adaptive sensory function as well as common pathogeneses of both portions of the organ in pancreatic diseases, including diabetes. ARTICLE HIGHLIGHTS
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Affiliation(s)
- Marjan Slak Rupnik
- Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Manami Hara
- Department of Medicine, The University of Chicago, Chicago, IL
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Lu Y, Tian H, Peng H, Wang Q, Bunnell BA, Bazan NG, Hong S. Novel lipid mediator 7 S,14 R-docosahexaenoic acid: biogenesis and harnessing mesenchymal stem cells to ameliorate diabetic mellitus and retinal pericyte loss. Front Cell Dev Biol 2024; 12:1380059. [PMID: 38533089 PMCID: PMC10963555 DOI: 10.3389/fcell.2024.1380059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 02/29/2024] [Indexed: 03/28/2024] Open
Abstract
Introduction: Stem cells can be used to treat diabetic mellitus and complications. ω3-docosahexaenoic acid (DHA) derived lipid mediators are inflammation-resolving and protective. This study found novel DHA-derived 7S,14R-dihydroxy-4Z,8E,10Z,12E,16Z,19Z-docosahexaenoic acid (7S,14R-diHDHA), a maresin-1 stereoisomer biosynthesized by leukocytes and related enzymes. Moreover, 7S,14R-diHDHA can enhance mesenchymal stem cell (MSC) functions in the amelioration of diabetic mellitus and retinal pericyte loss in diabetic db/db mice. Methods: MSCs treated with 7S,14R-diHDHA were delivered into db/db mice i.v. every 5 days for 35 days. Results: Blood glucose levels in diabetic mice were lowered by 7S,14R-diHDHA-treated MSCs compared to control and untreated MSC groups, accompanied by improved glucose tolerance and higher blood insulin levels. 7S,14R-diHDHA-treated MSCs increased insulin+ β-cell ratio and decreased glucogan+ α-cell ratio in islets, as well as reduced macrophages in pancreas. 7S,14R-diHDHA induced MSC functions in promoting MIN6 β-cell viability and insulin secretion. 7S,14R-diHDHA induced MSC paracrine functions by increasing the generation of hepatocyte growth factor and vascular endothelial growth factor. Furthermore, 7S,14R-diHDHA enhanced MSC functions to ameliorate diabetes-caused pericyte loss in diabetic retinopathy by increasing their density in retina in db/db mice. Discussion: Our findings provide a novel strategy for improving therapy for diabetes and diabetic retinopathy using 7S,14R-diHDHA-primed MSCs.
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Affiliation(s)
- Yan Lu
- Neuroscience Center of Excellence, School of Medicine, L.S.U. Health, New Orleans, LA, United States
| | - Haibin Tian
- Neuroscience Center of Excellence, School of Medicine, L.S.U. Health, New Orleans, LA, United States
- Tongji University, Shanghai, China
| | - Hongying Peng
- Biostatistics, Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Quansheng Wang
- Neuroscience Center of Excellence, School of Medicine, L.S.U. Health, New Orleans, LA, United States
- Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Bruce A. Bunnell
- Tulane University School of Medicine, Center for Stem Cell Research and Regenerative Medicine, New Orleans, LA, United States
| | - Nicolas G. Bazan
- Neuroscience Center of Excellence, School of Medicine, L.S.U. Health, New Orleans, LA, United States
- Department of Ophthalmology, School of Medicine, L.S.U. Health, New Orleans, LA, United States
| | - Song Hong
- Neuroscience Center of Excellence, School of Medicine, L.S.U. Health, New Orleans, LA, United States
- Department of Ophthalmology, School of Medicine, L.S.U. Health, New Orleans, LA, United States
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Andriolo LG, Cammisotto V, Spagnoli A, Alunni Fegatelli D, Chicone M, Di Rienzo G, Dell’Anna V, Lobreglio G, Serio G, Pignatelli P. Overview of angiogenesis and oxidative stress in cancer. World J Meta-Anal 2023; 11:253-265. [DOI: 10.13105/wjma.v11.i6.253] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 03/07/2023] [Accepted: 07/10/2023] [Indexed: 09/13/2023] Open
Abstract
Neoplasms can be considered as a group of aberrant cells that need more vascular supply to fulfill all their functions. Therefore, they promote angiogenesis through the same neovascularization pathway used physiologically. Angiogenesis is a process characterized by a heterogeneous distribution of oxygen caused by the tumor and oxidative stress; the latter being one of the most powerful stimuli of angiogenesis. As a result of altered tumor metabolism due to hypoxia, acidosis occurs. The angiogenic process and oxidative stress can be detected by measuring serum and tissue biomarkers. The study of the mechanisms underlying angiogenesis and oxidative stress could lead to the identification of new biomarkers, ameliorating the selection of patients with neoplasms and the prediction of their response to possible anti-tumor therapies. In particular, in the treatment of patients with similar clinical tumor phenotypes but different prognoses, the new biomarkers could be useful. Moreover, they may lead to a better understanding of the mechanisms underlying drug resistance. Experimental studies show that blocking the vascular supply results in antiproliferative activity in vivo in neuroendocrine tumor cells, which require a high vascular supply.
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Affiliation(s)
- Luigi Gaetano Andriolo
- Department of General and Specialistic Surgery Paride Stefanini, Policlinico Umberto I, University of Rome Sapienza, Rome 06100, Italy
- Unità Operativa Complessa Chirurgia Toracica, Ospedale Vito Fazzi, Lecce 73100, Italy
| | - Vittoria Cammisotto
- Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences, University of Rome Sapienza, Rome 06100, Italy
| | - Alessandra Spagnoli
- Department of Public Health and Infectious Diseases, University of Rome Sapienza, Rome 06100, Italy
| | - Danilo Alunni Fegatelli
- Department of Public Health and Infectious Diseases, University of Rome Sapienza, Rome 06100, Italy
| | - Michele Chicone
- Department of Clinical Pathology and Microbiology, Ospedale Vito Fazzi, Lecce 73100, Italy
| | - Gaetano Di Rienzo
- Unità Operativa Complessa Chirurgia Toracica, Ospedale Vito Fazzi, Lecce 73100, Italy
| | | | - Giambattista Lobreglio
- Department of Clinical Pathology and Microbiology, Ospedale Vito Fazzi, Lecce 73100, Italy
| | - Giovanni Serio
- Pathological Anatomy Unit, Ospedale Vito Fazzi, Lecce 73100, Italy
| | - Pasquale Pignatelli
- Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences, University of Rome Sapienza, Rome 06100, Italy
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9
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Aldous N, Moin ASM, Abdelalim EM. Pancreatic β-cell heterogeneity in adult human islets and stem cell-derived islets. Cell Mol Life Sci 2023; 80:176. [PMID: 37270452 DOI: 10.1007/s00018-023-04815-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 04/27/2023] [Accepted: 05/19/2023] [Indexed: 06/05/2023]
Abstract
Recent studies reported that pancreatic β-cells are heterogeneous in terms of their transcriptional profiles and their abilities for insulin secretion. Sub-populations of pancreatic β-cells have been identified based on the functionality and expression of specific surface markers. Under diabetes condition, β-cell identity is altered leading to different β-cell sub-populations. Furthermore, cell-cell contact between β-cells and other endocrine cells within the islet play an important role in regulating insulin secretion. This highlights the significance of generating a cell product derived from stem cells containing β-cells along with other major islet cells for treating patients with diabetes, instead of transplanting a purified population of β-cells. Another key question is how close in terms of heterogeneity are the islet cells derived from stem cells? In this review, we summarize the heterogeneity in islet cells of the adult pancreas and those generated from stem cells. In addition, we highlight the significance of this heterogeneity in health and disease conditions and how this can be used to design a stem cell-derived product for diabetes cell therapy.
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Affiliation(s)
- Noura Aldous
- College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Education City, Doha, Qatar
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Education City, PO Box 34110, Doha, Qatar
| | - Abu Saleh Md Moin
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Education City, PO Box 34110, Doha, Qatar
- Research Department, Royal College of Surgeons in Ireland Bahrain, Adliya, Kingdom of Bahrain
| | - Essam M Abdelalim
- College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Education City, Doha, Qatar.
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Education City, PO Box 34110, Doha, Qatar.
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10
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Sabet Sarvestani F, Tamaddon AM, Yaghoobi R, Geramizadeh B, Abolmaali SS, Kaviani M, Keshtkar S, Pakbaz S, Azarpira N. Indirect co-culture of islet cells in 3D biocompatible collagen/laminin scaffold with angiomiRs transfected mesenchymal stem cells. Cell Biochem Funct 2023; 41:296-308. [PMID: 36815688 DOI: 10.1002/cbf.3781] [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: 12/20/2022] [Revised: 02/05/2023] [Accepted: 02/06/2023] [Indexed: 02/24/2023]
Abstract
Diabetes is an autoimmune disease in which the pancreatic islets produce insufficient insulin. One of the treatment strategies is islet isolation, which may damage these cells as they lack vasculature. Biocompatible scaffolds are one of the efficient techniques for dealing with this issue. The current study is aimed to determine the effect of transfected BM-MSCS with angiomiR-126 and -210 on the survival and functionality of islets loaded into a 3D scaffold via laminin (LMN). AngiomiRs/Poly Ethylenimine polyplexes were transfected into bone marrow-mesenchymal stem cells (BM-MSCs), followed by 3-day indirect co-culturing with islets laden in collagen (Col)-based hydrogel scaffolds containing LMN. Islet proliferation and viability were significantly increased in LMN-containing scaffolds, particularly in the miRNA-126 treated group. Insulin gene expression was superior in Col scaffolds, especially, in the BM-MSCs/miRNA-126 treated group. VEGF was upregulated in the LMN-containing scaffolds in both miRNA-treated groups, specifically in the miRNA-210, leading to VEGF secretion. MiRNAs' target genes showed no downregulation in LMN-free scaffolds; while a drastic downregulation was seen in the LMN-containing scaffolds. The highest insulin secretion was recorded in the Oxidized dextran (Odex)/ColLMN+ group with miRNA-126. LMN-containing biocompatible scaffolds, once combined with angiomiRs and their downstream effectors, promote islets survival and restore function, leading to enhanced angiogenesis and glycemic status.
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Affiliation(s)
| | - Ali-Mohammad Tamaddon
- Department of Pharmaceutical Nanotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Islamic Republic of Iran, Shiraz, Iran.,Center for Nanotechnology in Drug Delivery, Shiraz University of Medical Sciences, Shiraz, Islamic Republic of Iran, Shiraz, Iran
| | - Ramin Yaghoobi
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Bita Geramizadeh
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Samira Sadat Abolmaali
- Department of Pharmaceutical Nanotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Islamic Republic of Iran, Shiraz, Iran
| | - Maryam Kaviani
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Somayeh Keshtkar
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Molecular Dermatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sara Pakbaz
- Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.,Department of Laboratory Medicine & Pathobiology, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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11
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Urbanczyk M, Zbinden A, Schenke-Layland K. Organ-specific endothelial cell heterogenicity and its impact on regenerative medicine and biomedical engineering applications. Adv Drug Deliv Rev 2022; 186:114323. [PMID: 35568103 DOI: 10.1016/j.addr.2022.114323] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 04/23/2022] [Accepted: 05/05/2022] [Indexed: 02/08/2023]
Abstract
Endothelial cells (ECs) are a key cellular component of the vascular system as they form the inner lining of the blood vessels. Recent findings highlight that ECs express extensive phenotypic heterogenicity when following the vascular tree from the major vasculature down to the organ capillaries. However, in vitro models, used for drug development and testing, or to study the role of ECs in health and disease, rarely acknowledge this EC heterogenicity. In this review, we highlight the main differences between different EC types, briefly summarize their different characteristics and focus on the use of ECs in in vitro models. We introduce different approaches on how ECs can be utilized in co-culture test systems in the field of brain, pancreas, and liver research to study the role of the endothelium in health and disease. Finally, we discuss potential improvements to current state-of-the-art in vitro models and future directions.
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12
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Miceli V, Fornasier M, Bulati M, Amico G, Conaldi PG, Casu A, Murgia S. In Vitro Evaluation of Nanoerythrosome Cytotoxicity and Uptake in Pancreatic Endothelial Cells: Implications for β-Cell Imaging Applications. LANGMUIR : THE ACS JOURNAL OF SURFACES AND COLLOIDS 2022; 38:3403-3411. [PMID: 35262354 DOI: 10.1021/acs.langmuir.1c03153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Biomolecule-targeted imaging represents one of the most difficult challenges in medicine. Nanoerythrosomes (NERs) are nanovesicles obtained after lysis of red blood cells, and they are promising tools for drug delivery and imaging. In this work, a formulation based on NERs functionalized with 7-amino-3-methylcoumarin via cross-linking was tested on rat INS-1E and mouse MIN6 β-cells and endothelial MSI cell lines. First, the morphology, size, ζ-potentials, and spectroscopic properties of the aggregates were investigated, highlighting that the functionalization did not significantly affect the nanoparticles' physicochemical features. In vitro, the nanoparticles did not significantly affect the proliferation and function of INS-1E and MIN6 β-cells at different concentrations. Only at the highest concentration tested on the MSI cell line, the formulation inhibited proliferation. Furthermore, NER aggregates were not internalized in both INS-1E and MIN6 cell lines, while a diffuse fluorescence was noticed in the cytosol of the MSI cell line at the highest concentrations. These findings proved that NER formulations might represent a new nanotool for β-cell imaging as a part of a strategy aimed to prevent any intracellular accumulation, thus reducing/avoiding side effects.
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Affiliation(s)
- Vitale Miceli
- Research Department, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90127 Palermo, Italy
| | - Marco Fornasier
- Department of Chemical and Geological Sciences, University of Cagliari, s.s. bivio Sestu, 09042-I Monserrato, Italy
- CSGI, Consorzio Interuniversitario per lo Sviluppo dei Sistemi a Grande Interfase, via della Lastruccia 3, Sesto Fiorentino, 50019 Florence, Italy
| | - Matteo Bulati
- Research Department, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90127 Palermo, Italy
| | - Giandomenico Amico
- Research Department, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90127 Palermo, Italy
- Ri.MED Foundation, via Bandiera 11, I-90133 Palermo, Italy
| | - Pier Giulio Conaldi
- Research Department, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90127 Palermo, Italy
| | - Anna Casu
- Translational Research Institute─AdventHealth, Orlando, Florida 32804, United States
- Department of Diagnostic and Therapeutic Services, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), via E. Tricomi 5, I-90127 Palermo, Italy
| | - Sergio Murgia
- CSGI, Consorzio Interuniversitario per lo Sviluppo dei Sistemi a Grande Interfase, via della Lastruccia 3, Sesto Fiorentino, 50019 Florence, Italy
- Department of Life and Environmental Sciences, University of Cagliari and CSGI, via Ospedale 72, I-09124 Cagliari, Italy
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13
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Wang HL, Wang L, Zhao CY, Lan HY. Role of TGF-Beta Signaling in Beta Cell Proliferation and Function in Diabetes. Biomolecules 2022; 12:373. [PMID: 35327565 PMCID: PMC8945211 DOI: 10.3390/biom12030373] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 02/21/2022] [Accepted: 02/24/2022] [Indexed: 12/27/2022] Open
Abstract
Beta (β) cell dysfunction or loss is the common pathological feature in all types of diabetes mellitus (diabetes). Resolving the underlying mechanism may facilitate the treatment of diabetes by preserving the β cell population and function. It is known that TGF-β signaling plays diverse roles in β cell development, function, proliferation, apoptosis, and dedifferentiation. Inhibition of TGF-β signaling expands β cell lineage in the development. However, deletion of Tgfbr1 has no influence on insulin demand-induced but abolishes inflammation-induced β cell proliferation. Among canonical TGF-β signaling, Smad3 but not Smad2 is the predominant repressor of β cell proliferation in response to systemic insulin demand. Deletion of Smad3 simultaneously improves β cell function, apoptosis, and systemic insulin resistance with the consequence of eliminated overt diabetes in diabetic mouse models, revealing Smad3 as a key mediator and ideal therapeutic target for type-2 diabetes. However, Smad7 shows controversial effects on β cell proliferation and glucose homeostasis in animal studies. On the other hand, overexpression of Tgfb1 prevents β cells from autoimmune destruction without influence on β cell function. All these findings reveal the diverse regulatory roles of TGF-β signaling in β cell biology.
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Affiliation(s)
- Hong-Lian Wang
- Research Center for Integrative Medicine, The Affiliated Traditional Medicine Hospital of Southwest Medical University, Luzhou 646000, China; (H.-L.W.); (L.W.)
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Li Wang
- Research Center for Integrative Medicine, The Affiliated Traditional Medicine Hospital of Southwest Medical University, Luzhou 646000, China; (H.-L.W.); (L.W.)
| | - Chang-Ying Zhao
- Department of Endocrinology, The Affiliated Traditional Medicine Hospital of Southwest Medical University, Luzhou 646000, China;
| | - Hui-Yao Lan
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China
- Guangdong Academy of Sciences, Guangdong Provincial People’s Hospital Joint Research Laboratory on Immunological and Genetic Kidney Diseases, The Chinese University of Hong Kong, Hong Kong 999077, China
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14
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Yao J, Yu Y, Nyberg SL. Induced Pluripotent Stem Cells for the Treatment of Liver Diseases: Novel Concepts. Cells Tissues Organs 2022; 211:368-384. [PMID: 32615573 PMCID: PMC7775900 DOI: 10.1159/000508182] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 04/24/2020] [Indexed: 01/03/2023] Open
Abstract
Millions of people worldwide with incurable liver disease die because of inadequate treatment options and limited availability of donor organs for liver transplantation. Regenerative medicine as an innovative approach to repairing and replacing cells, tissues, and organs is undergoing a major revolution due to the unprecedented need for organs for patients around the world. Induced pluripotent stem cells (iPSCs) have been widely studied in the field of liver regeneration and are considered to be the most promising candidate therapies. This review will conclude the current state of efforts to derive human iPSCs for potential use in the modeling and treatment of liver disease.
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Affiliation(s)
- Jia Yao
- William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN, USA.,Clinical Research and Project Management Office, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Yue Yu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation; Nanjing, China
| | - Scott L. Nyberg
- William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN, USA.,Corresponding Author: Scott L. Nyberg, William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN 55905, USA, Tel: Rochester, MN 55905, USA, Fax: (507) 284-2511,
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15
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Du H, Yin Z, Zhao Y, Li H, Dai B, Fan J, He M, Nie X, Wang CY, Wang DW, Chen C. miR-320a induces pancreatic β cells dysfunction in diabetes by inhibiting MafF. MOLECULAR THERAPY-NUCLEIC ACIDS 2021; 26:444-457. [PMID: 34631276 PMCID: PMC8479292 DOI: 10.1016/j.omtn.2021.08.027] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Accepted: 08/19/2021] [Indexed: 11/01/2022]
Abstract
A variety of studies indicate that microRNAs (miRNAs) are involved in diabetes. However, the direct role of miR-320a in the pathophysiology of pancreatic β cells under diabetes mellitus remains unclear. In the current study, islet transplantation and hyperglycemic clamp assays were performed in miR-320a transgenic mice to explore the effects of miR-320a on pancreatic β cells in vivo. Meanwhile, β cell-specific overexpression or inhibition of miR-320a was delivered by adeno-associated virus (AAV8). In vitro, overexpression or downregulation of miR-320a was introduced in cultured rat islet tumor cells (INS1). RNA immunoprecipitation sequencing (RIP-Seq), luciferase reporter assay, and western blotting were performed to identify the target genes. Results showed that miR-320a was increased in the pancreatic β cells from high-fat-diet (HFD)-treated mice. Overexpression of miR-320a could not only deteriorate the HFD-induced pancreatic islet dysfunction, but also initiate pancreatic islet dysfunction spontaneously in vivo. Meanwhile, miR-320a increased the ROS level, inhibited proliferation, and induced apoptosis of cultured β cells in vitro. Finally, we identified that MafF was the target of miR-320a that responsible for the dysfunction of pancreatic β cells. Our data suggested that miR-320a could damage the pancreatic β cells directly and might be a potential therapeutic target of diabetes.
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Affiliation(s)
- Hengzhi Du
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China.,Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan 430030, China
| | - Zhongwei Yin
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China.,Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan 430030, China
| | - Yanru Zhao
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China.,Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan 430030, China
| | - Huaping Li
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China.,Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan 430030, China
| | - Beibei Dai
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China.,Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan 430030, China
| | - Jiahui Fan
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China.,Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan 430030, China
| | - Mengying He
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China.,Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan 430030, China
| | - Xiang Nie
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China.,Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan 430030, China
| | - Cong-Yi Wang
- The Center for Biomedical Research, Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Sciences and Technology, 1095 Jiefang Ave., Wuhan 430030, China
| | - Dao Wen Wang
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China.,Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan 430030, China
| | - Chen Chen
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095# Jiefang Ave., Wuhan 430030, China.,Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan 430030, China
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16
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Strategies for Vascularizing Pancreatic Islets and Stem Cell–Derived Islet Organoids. CURRENT TRANSPLANTATION REPORTS 2021. [DOI: 10.1007/s40472-021-00334-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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17
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Tsai PS, Chiu CY, Sheu ML, Yang CY, Lan KC, Liu SH. Advanced glycation end products activated endothelial-to-mesenchymal transition in pancreatic islet endothelial cells and triggered islet fibrosis in diabetic mice. Chem Biol Interact 2021; 345:109562. [PMID: 34153226 DOI: 10.1016/j.cbi.2021.109562] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 06/07/2021] [Accepted: 06/15/2021] [Indexed: 12/26/2022]
Abstract
Advanced glycation end products (AGEs) are associated with the pathogenesis of diabetic vascular complications. Induction of the endothelial-to-mesenchymal transition (EndMT) is associated with the pathogenesis of fibrotic diseases. The roles of AGEs in islet EndMT induction and diabetes-related islet microvasculopathy and fibrosis remain unclear. This study investigated the pathological roles of AGEs in islet EndMT induction and fibrosis in vitro and in vivo. Non-cytotoxic concentrations of AGEs upregulated the protein expression of fibronectin, vimentin, and α-smooth muscle actin (α-SMA) (mesenchymal/myofibroblast markers) and downregulated the protein expression of vascular endothelial (VE)-cadherin and cluster of differentiation (CD) 31 (endothelial cell markers) in cultured mouse pancreatic islet endothelial cells, which was prevented by the AGE cross-link breaker alagebrium chloride. In streptozotocin-induced diabetic mice, the average islet area and islet immunoreactivities for insulin and CD31 were decreased and the islet immunoreactivities for AGEs and α-SMA and fibrosis were increased, which were prevented by the AGE inhibitor aminoguanidine. Immunofluorescence double staining showed that α-SMA-positive staining co-localized with CD31-positive staining in the diabetic islets, which was effectively prevented by aminoguanidine. These results demonstrate that AGEs can induce EndMT in islet endothelial cells and islet fibrosis in diabetic mice, suggesting that AGE-induced EndMT may contribute to islet fibrosis in diabetes.
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Affiliation(s)
- Pei-Shan Tsai
- Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chen-Yuan Chiu
- Center of Consultation, Center for Drug Evaluation, Taipei, Taiwan
| | - Meei-Ling Sheu
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
| | - Ching-Yao Yang
- Department of Surgery, College of Medicine and National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan
| | - Kuo-Cheng Lan
- Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
| | - Shing-Hwa Liu
- Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan; Department of Pediatrics, College of Medicine and Hospital, National Taiwan University, Taipei, Taiwan.
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18
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The vascular architecture of the pancreatic islets: A homage to August Krogh. Comp Biochem Physiol A Mol Integr Physiol 2021; 252:110846. [DOI: 10.1016/j.cbpa.2020.110846] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 11/09/2020] [Accepted: 11/10/2020] [Indexed: 01/15/2023]
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19
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Yabe SG, Fukuda S, Nishida J, Takeda F, Nashiro K, Okochi H. Efficient induction of pancreatic alpha cells from human induced pluripotent stem cells by controlling the timing for BMP antagonism and activation of retinoic acid signaling. PLoS One 2021; 16:e0245204. [PMID: 33428669 PMCID: PMC7799802 DOI: 10.1371/journal.pone.0245204] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Accepted: 12/23/2020] [Indexed: 01/15/2023] Open
Abstract
Diabetes mellitus is caused by breakdown of blood glucose homeostasis, which is maintained by an exquisite balance between insulin and glucagon produced respectively by pancreatic beta cells and alpha cells. However, little is known about the mechanism of inducing glucagon secretion from human alpha cells. Many methods for generating pancreatic beta cells from human pluripotent stem cells (hPSCs) have been reported, but only two papers have reported generation of pancreatic alpha cells from hPSCs. Because NKX6.1 has been suggested as a very important gene for determining cell fate between pancreatic beta and alpha cells, we searched for the factors affecting expression of NKX6.1 in our beta cell differentiation protocols. We found that BMP antagonism and activation of retinoic acid signaling at stage 2 (from definitive endoderm to primitive gut tube) effectively suppressed NKX6.1 expression at later stages. Using two different hPSCs lines, treatment with BMP signaling inhibitor (LDN193189) and retinoic acid agonist (EC23) at Stage 2 reduced NKX6.1 expression and allowed differentiation of almost all cells into pancreatic alpha cells in vivo after transplantation under a kidney capsule. Our study demonstrated that the cell fate of pancreatic cells can be controlled by adjusting the expression level of NKX6.1 with proper timing of BMP antagonism and activation of retinoic acid signaling during the pancreatic differentiation process. Our method is useful for efficient induction of pancreatic alpha cells from hPSCs.
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Affiliation(s)
- Shigeharu G Yabe
- Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Satsuki Fukuda
- Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Junko Nishida
- Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Fujie Takeda
- Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Kiyoko Nashiro
- Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Hitoshi Okochi
- Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
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20
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Lan T, Guo J, Bai X, Huang Z, Wei Z, Du G, Yan G, Weng L, Yi X. RGD-modified injectable hydrogel maintains islet beta-cell survival and function. J Appl Biomater Funct Mater 2020; 18:2280800020963473. [PMID: 33259245 DOI: 10.1177/2280800020963473] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
OBJECTIVE A potential solution for islet transplantation and drug discovery vis-à-vis treating diabetes is the production of functional islets in a three-dimensional extracellular matrix. Although several scaffold materials have been reported as viable candidates, a clinically applicable one that is injectable and can maintain long-term functionality and survival of islet pancreatic beta-cells (β-cells) is far from being established. RESULTS In the current study, we evaluated a ready-to-use and injectable hydrogel's impact on β-cells' function and viability, both in vitro and in vivo. We found that β-cells in high concentration with hydrogels functionalized via Arg-Gly-Asp (RGD) demonstrated better viability and insulin secretory capacity in vitro. Moreover, it is a biocompatible hydrogel that can maintain β-cell proliferation and vascularization without stimulating inflammation after subcutaneous injection. Meanwhile, modifying the hydrogel with RGD can maintain β-cells' secretion of insulin, regulating the blood glucose levels of mice with streptozotocin-induced diabetes. CONCLUSIONS Thus, these preliminary results indicate that this RGD-modified hydrogel is a potential extracellular matrix for islet transplantation at extrahepatic sites, and they also provide a reference for future tissue engineering study.
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Affiliation(s)
- Tianshu Lan
- Xiamen Medical College, Xiamen city, Fujian Province, China.,Key laboratory of functional and clinical translational medicine, Fujian province university, Xiamen Medical College, Xiamen city, China
| | - Jingyi Guo
- Xiamen Medical College, Xiamen city, Fujian Province, China
| | - Xiaoming Bai
- Xiamen Medical College, Xiamen city, Fujian Province, China
| | | | - Zhimin Wei
- Xiamen Medical College, Xiamen city, Fujian Province, China
| | - Guicheng Du
- Xiamen Medical College, Xiamen city, Fujian Province, China
| | - Guoliang Yan
- School of Medicine, Xiamen University, Xiamen city, Fujian Province, China
| | - Lebin Weng
- Xiamen Medical College, Xiamen city, Fujian Province, China
| | - Xue Yi
- Key laboratory of functional and clinical translational medicine, Fujian province university, Xiamen Medical College, Xiamen city, China
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21
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Fazio N, Cella CA, Del Re M, Laffi A, Rubino M, Zagami P, Spada F. Pharmacodynamics, clinical findings and approval status of current and emerging tyrosine-kinase inhibitors for pancreatic neuroendocrine tumors. Expert Opin Drug Metab Toxicol 2019; 15:993-1004. [PMID: 31794273 DOI: 10.1080/17425255.2019.1700951] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Introduction: Pancreatic neuroendocrine tumors (panNETs) represent a rare group of malignancies. For decades, chemotherapy, somatostatin analogs and interferon represented the only systemic therapies; however, over the latest years, new options were registered, including Everolimus, Sunitinib (SUN), and Peptide Receptor Radionuclide Therapy.Areas covered: This review discusses the role of tyrosine kinase inhibitors (TKIs) in advanced panNETs.Expert opinion: TKIs showed an antiangiogenic and antiproliferative impact on advanced panNETs. Sunitinib is the only TKI currently available in clinical practice, having been approved on the basis of relevant results of a specific panNET phase III trial. New TKIs, such as Cabozantinib, Lenvatinib, Pazopanib, Surufatinib are still on investigation in panNETs. Although some phase II studies with the new TKIs yielded better PFS and RR compared with SUN, different study designs and tumor populations may have induced selection biases. However, it was reported that panNETs resistant to SUN could respond to a new TKI, indicating a possible further therapeutic line in this context. The global investigation plan of TKIs in panNETs is not homogeneous and it is difficult to understand what kind of development this can have in the near future for clinical practice.
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Affiliation(s)
- Nicola Fazio
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy
| | - Chiara A Cella
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy
| | - Marzia Del Re
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy
| | - Alice Laffi
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy
| | - Manila Rubino
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy
| | - Paola Zagami
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy
| | - Francesca Spada
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy
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22
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Proshchina AE, Krivova YS, Barabanov VM, Saveliev SV. Pancreatic endocrine cell arrangement during human ontogeny. Acta Histochem 2019; 121:638-645. [PMID: 31146895 DOI: 10.1016/j.acthis.2019.05.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 05/17/2019] [Accepted: 05/22/2019] [Indexed: 12/19/2022]
Abstract
In the human pancreas, various forms of endocrine cell arrangement are found: single endocrine cells, endocrine cell clusters, and mantel, bipolar and mosaic cell (mixed) islets. Our aim was to analyse the distribution and dynamics of insulin-, glucagon- and somatostatin-containing cells within the various forms of endocrine pancreas arrangement during human prenatal development and in adults and to suggest a mechanism of change in the endocrine cell ratio in adult islets. Pancreatic autopsies derived from human foetuses from the 10th to the 40th weeks of development and from adults were examined using histological, immunohistochemical and morphometric methods. During development, the human endocrine pancreas undergoes not only de novo differentiation of endocrine cells and islet formation, but morphogenetic restructuring, which is revealed as a change of the α-, β- and δ-cell ratio in the islets. In particular, increased proportion of glucagon- and somatostatin-containing cells and decreased proportion of β-cells were shown in the largest mosaic islets in adults. Our results indicate that the distribution and proportion of α-, β- and δ-cells depend on the islets size and vascularisation. Studying of the mechanism of such restructuring may contribute to the development of new approaches in the treatment of diabetes mellitus.
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Jansson L, Carlsson PO. Pancreatic Blood Flow with Special Emphasis on Blood Perfusion of the Islets of Langerhans. Compr Physiol 2019; 9:799-837. [PMID: 30892693 DOI: 10.1002/cphy.c160050] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The pancreatic islets are more richly vascularized than the exocrine pancreas, and possess a 5- to 10-fold higher basal and stimulated blood flow, which is separately regulated. This is reflected in the vascular anatomy of the pancreas where islets have separate arterioles. There is also an insulo-acinar portal system, where numerous venules connect each islet to the acinar capillaries. Both islets and acini possess strong metabolic regulation of their blood perfusion. Of particular importance, especially in the islets, is adenosine and ATP/ADP. Basal and stimulated blood flow is modified by local endothelial mediators, the nervous system as well as gastrointestinal hormones. Normally the responses to the nervous system, especially the parasympathetic and sympathetic nerves, are fairly similar in endocrine and exocrine parts. The islets seem to be more sensitive to the effects of endothelial mediators, especially nitric oxide, which is a permissive factor to maintain the high basal islet blood flow. The gastrointestinal hormones with pancreatic effects mainly influence the exocrine pancreatic blood flow, whereas islets are less affected. A notable exception is incretin hormones and adipokines, which preferentially affect islet vasculature. Islet hormones can influence both exocrine and endocrine blood vessels, and these complex effects are discussed. Secondary changes in pancreatic and islet blood flow occur during several conditions. To what extent changes in blood perfusion may affect the pathogenesis of pancreatic diseases is discussed. Both type 2 diabetes mellitus and acute pancreatitis are conditions where we think there is evidence that blood flow may contribute to disease manifestations. © 2019 American Physiological Society. Compr Physiol 9:799-837, 2019.
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Affiliation(s)
- Leif Jansson
- Uppsala University, Department of Medical Cell Biology, Uppsala, Sweden
| | - Per-Ola Carlsson
- Uppsala University, Department of Medical Cell Biology, Uppsala, Sweden.,Uppsala University, Department of Medical Sciences, Uppsala, Sweden
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24
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Ren G, Rezaee M, Razavi M, Taysir A, Wang J, Thakor AS. Adipose tissue-derived mesenchymal stem cells rescue the function of islets transplanted in sub-therapeutic numbers via their angiogenic properties. Cell Tissue Res 2019; 376:353-364. [PMID: 30707291 DOI: 10.1007/s00441-019-02997-w] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Accepted: 01/17/2019] [Indexed: 02/07/2023]
Abstract
A significant proportion of islets are lost following transplantation due to hypoxia and inflammation. We hypothesize that adipose tissue-derived mesenchymal stem cells (AD-MSCs) can rescue a sub-therapeutic number of transplanted islets by helping them establish a new blood supply and reducing inflammation. Diabetic mice received syngeneic transplantation with 75 (minimal), 150 (sub-therapeutic), or 225 (therapeutic) islets, with or without 1 × 106 mouse AD-MSCs. Fasting blood glucose (FBG) values were measured over 6 weeks with tissue samples collected for islet structure and morphology (H&E, insulin/glucagon staining). Histological and immunohistochemical analyses of islets were also performed at 2 weeks in animals transplanted with a sub-therapeutic number of islets, with and without AD-MSCs, to determine new blood vessel formation, the presence of pro-angiogenic factors facilitating revascularization, and the degree of inflammation. AD-MSCs had no beneficial effect on FBG values when co-transplanted with a minimal or therapeutic number of islets. However, AD-MSCs significantly reduced FBG values and restored glycemic control in diabetic animals transplanted with a sub-therapeutic number of islets. Islets co-transplanted with AD-MSCs preserved their native morphology and organization and exhibited less aggregation when compared to islets transplanted alone. In the sub-therapeutic group, AD-MSCs significantly increased islet revascularization and the expression of angiogenic factors including hepatocyte growth factor (HGF) and angiopoietin-1 (Ang-1) while also reducing inflammation. AD-MSCs can rescue the function of islets when transplanted in a sub-therapeutic number, for at least 6 weeks, via their ability to maintain islet architecture while concurrently facilitating islet revascularization and reducing inflammation.
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Affiliation(s)
- Gang Ren
- Interventional Regenerative Medicine and Imaging Laboratory, Stanford University, Department of Radiology, Palo Alto, CA, 94034, USA
| | - Melika Rezaee
- Interventional Regenerative Medicine and Imaging Laboratory, Stanford University, Department of Radiology, Palo Alto, CA, 94034, USA.,Chicago Medical School, Rosalind Franklin University, North Chicago, IL, 60064, USA
| | - Mehdi Razavi
- Interventional Regenerative Medicine and Imaging Laboratory, Stanford University, Department of Radiology, Palo Alto, CA, 94034, USA
| | - Ahmed Taysir
- Interventional Regenerative Medicine and Imaging Laboratory, Stanford University, Department of Radiology, Palo Alto, CA, 94034, USA
| | - Jing Wang
- Interventional Regenerative Medicine and Imaging Laboratory, Stanford University, Department of Radiology, Palo Alto, CA, 94034, USA
| | - Avnesh S Thakor
- Interventional Regenerative Medicine and Imaging Laboratory, Stanford University, Department of Radiology, Palo Alto, CA, 94034, USA.
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25
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3D-Models of Insulin-Producing β-Cells: from Primary Islet Cells to Stem Cell-Derived Islets. Stem Cell Rev Rep 2018; 14:177-188. [PMID: 29181780 DOI: 10.1007/s12015-017-9783-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
There is a need for physiologically relevant assay platforms to provide functionally relevant models of diabetes, to accelerate the discovery of new treatment options and boost developments in drug discovery. In this review, we compare several 3D-strategies that have been used to increase the functional relevance of ex vivo human primary pancreatic islets and developments into the generation of stem cell derived pancreatic beta-cells (β-cells). Special attention will be given to recent approaches combining the use of extracellular matrix (ECM) scaffolds with pancreatic molecular memory, which can be used to improve yield and functionality of in vitro stem cell-derived pancreatic models. The ultimate goal is to develop scalable cell-based platforms for diabetes research and drug screening. This article will critically assess key aspects related to in vitro pancreatic 3D-ECM models and highlight the most promising approaches for future research.
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26
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Grillo F, Florio T, Ferraù F, Kara E, Fanciulli G, Faggiano A, Colao A. Emerging multitarget tyrosine kinase inhibitors in the treatment of neuroendocrine neoplasms. Endocr Relat Cancer 2018; 25:R453-R466. [PMID: 29769293 DOI: 10.1530/erc-17-0531] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Accepted: 05/16/2018] [Indexed: 12/18/2022]
Abstract
In the last few years, the therapeutic approach for neuroendocrine neoplasms (NENs) has changed dramatically following the approval of several novel targeted treatments. The multitarget tyrosine kinase inhibitor (MTKI), sunitinib malate, has been approved by Regulatory Agencies in pancreatic NENs. The MTKI class, however, includes several other molecules (approved for other conditions), which are currently being studied in NENs. An in-depth review on the studies published on the MTKIs in neuroendocrine tumors such as axitinib, cabozantinib, famitinib, lenvatinib, nintedanib, pazopanib, sorafenib and sulfatinib was performed. Furthermore, we extensively searched on the Clinical Trial Registries databases worldwide, in order to collect information on the ongoing clinical trials related to this topic. Our systematic analysis on emerging MTKIs in the treatment of gastroenteropancreatic and lung NENs identifies in vitro and in vivo studies, which demonstrate anti-tumor activity of diverse MTKIs on neuroendocrine cells and tumors. Moreover, for the first time in the literature, we report an updated view concerning the upcoming clinical trials in this field: presently, phase I, II and III clinical trials are ongoing and will include, overall, a staggering 1667 patients. This fervid activity underlines the increasing interest of the scientific community in the use of emerging MTKIs in NEN treatment.
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Affiliation(s)
- Federica Grillo
- Pathology UnitDepartment of Surgical Sciences and Integrated Diagnostics (DISC), University of Genova, Genova, Italy
- Ospedale Policlinico San Martino IRCCSGenova, Italy
| | - Tullio Florio
- Pharmacology UnitDepartment of Internal Medicine (DIMI), University of Genova, Genova, Italy
| | - Francesco Ferraù
- Department of Human Pathology of Adulthood and ChildhoodUniversity of Messina, Messina, Italy
| | - Elda Kara
- Unit of EndocrinologyMetabolism, Diabetology and Nutrition, Azienda Sanitaria Universitaria Integrata di Udine, Ospedale Santa Maria della Misericordia, Udine, Italy
| | - Giuseppe Fanciulli
- Neuroendocrine Tumours UnitDepartment of Clinical and Experimental Medicine, University of Sassari - AOU Sassari, Sassari, Italy
| | - Antongiulio Faggiano
- Department of Clinical Medicine and SurgeryUniversity 'Federico II', Naples, Italy
| | - Annamaria Colao
- Department of Clinical Medicine and SurgeryUniversity 'Federico II', Naples, Italy
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27
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Xu T, Lv Z, Chen Q, Guo M, Wang X, Huang F. Vascular endothelial growth factor over-expressed mesenchymal stem cells-conditioned media ameliorate palmitate-induced diabetic endothelial dysfunction through PI-3K/AKT/m-TOR/eNOS and p38/MAPK signaling pathway. Biomed Pharmacother 2018; 106:491-498. [PMID: 29990837 DOI: 10.1016/j.biopha.2018.06.129] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Revised: 06/24/2018] [Accepted: 06/25/2018] [Indexed: 12/17/2022] Open
Abstract
In the pathogenesis of diabetes mellitus (DM), islet microvasculares are severely damaged due to glucolipotoxicity and other reasons. Vascular endothelial growth factor (VEGF) is an indispensable and specific angiogenic factor in the pathogenesis and treatment of diabetic islet microvascular disease. Mesenchymal stem cells (MSCs) are regarded as a promising treatment of diabetes because of their immunosuppressive effect and multipotential differentiation potency. In this study, we tested whether MSCs over-expressing VEGF conditioned medium (MSC-VEGF-CM) could ameliorate pancreatic islet endothelial cells (MS-1) dysfunction induced by a common diabetic inducer palmitate (PA). We found that cell survival and migration were restrained by PA and partly repaired by the pro-protected of MSC-VEGF-CM. Meanwhile, PI-3K/AKT/m-TOR/eNOS and p38/MAPK signaling pathways were also up-regulated. Though apoptosis-related proteins, caspase-3 and caspase-9, had no significantly suppressed between MSC-VEGF-CM and MSC-CM alone, the expression levels of vascular surface factors such as CD31, VE-cadherin, occludin and ICAM-1, were remarkably up-regulated by the pro-protected of MSC-VEGF-CM. Our data suggested that MSC-VEGF-CM had therapeutic effect on the PA-induced dysfunction through the re-activation of PI-3K/AKT/m-TOR/eNOS and p38/MAPK signaling pathways.
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Affiliation(s)
- Tianwei Xu
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Zhengbing Lv
- School of Life Science, Zhejiang Sci-Tech University, Hangzhou, China
| | - Qiuhua Chen
- Intensive Care Unit, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Nanjing, China
| | - Min Guo
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Xufang Wang
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Fengjie Huang
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, China.
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28
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De Robertis R, Paiella S, Cardobi N, Landoni L, Tinazzi Martini P, Ortolani S, De Marchi G, Gobbo S, Giardino A, Butturini G, Tortora G, Bassi C, D'Onofrio M. Tumor thrombosis: a peculiar finding associated with pancreatic neuroendocrine neoplasms. A pictorial essay. Abdom Radiol (NY) 2018; 43:613-619. [PMID: 28677005 DOI: 10.1007/s00261-017-1243-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
While abutment, encasement or vessel occlusion are identified in most patients with a pancreatic tumor, tumor thrombosis is an uncommon finding. In particular, there are no description in the literature of tumor thrombosis associated with ductal adenocarcinoma, the most common pancreatic tumor. On the other hand, surgical series reveal that tumor thrombosis is associated with about 5% of pancreatic neuroendocrine neoplasms (PanNENs), and literature data suggest that this finding is frequently underreported on pre-operative imaging examinations. Tumor thrombosis may be clinically relevant, causing splenoportomesenteric hypertension, possibly responsible for life-threatening upper gastrointestinal bleeding. Bland thrombosis caused by direct infiltration of peri-pancreatic vessels frequently determines surgical unresectability, even in neuroendocrine tumors; on the opposite, tumor thrombosis associated with PanNENs do not exclude surgery per se, even though both morbidity and mortality can be increased by such condition. Considering the favorable prognosis of PanNENs and the frequent need to treat tumor thrombosis in order to prevent complications or to relieve symptoms, it is of paramount importance for radiologists the knowledge of the variety of findings associated with tumor thrombosis in PanNENs.
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Affiliation(s)
- Riccardo De Robertis
- Department of Radiology, P. Pederzoli Hospital, Via Monte Baldo 24, 37019, Peschiera del Garda, Italy.
| | - Salvatore Paiella
- Department of General and Pancreatic Surgery, Pancreas Institute, G.B. Rossi Hospital, Piazzale L.A. Scuro, 10, 37134, Verona, Italy
| | - Nicolò Cardobi
- Department of Radiology, P. Pederzoli Hospital, Via Monte Baldo 24, 37019, Peschiera del Garda, Italy
| | - Luca Landoni
- Department of General and Pancreatic Surgery, Pancreas Institute, G.B. Rossi Hospital, Piazzale L.A. Scuro, 10, 37134, Verona, Italy
| | - Paolo Tinazzi Martini
- Department of Radiology, P. Pederzoli Hospital, Via Monte Baldo 24, 37019, Peschiera del Garda, Italy
| | - Silvia Ortolani
- Department of Oncology, P. Pederzoli Hospital, Via Monte Baldo 24, 37019, Peschiera del Garda, Italy
| | - Giulia De Marchi
- Department of Gastroenterology, Pancreas Institute, G.B. Rossi Hospital, Piazzale L.A. Scuro, 10, 37134, Verona, Italy
| | - Stefano Gobbo
- Department of Pathology, P. Pederzoli Hospital, Via Monte Baldo 24, 37019, Peschiera del Garda, Italy
| | - Alessandro Giardino
- Department of Pancreatic Surgery, P. Pederzoli Hospital, Via Monte Baldo 24, 37019, Peschiera del Garda, Italy
| | - Giovanni Butturini
- Department of Pancreatic Surgery, P. Pederzoli Hospital, Via Monte Baldo 24, 37019, Peschiera del Garda, Italy
| | - Giampaolo Tortora
- Department of Medical Oncology, Pancreas Institute, G.B. Rossi Hospital, Piazzale L.A. Scuro, 10, 37134, Verona, Italy
| | - Claudio Bassi
- Department of General and Pancreatic Surgery, Pancreas Institute, G.B. Rossi Hospital, Piazzale L.A. Scuro, 10, 37134, Verona, Italy
| | - Mirko D'Onofrio
- Department of Radiology, Pancreas Institute, G.B. Rossi Hospital, Piazzale L.A. Scuro, 10, 37134, Verona, Italy
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29
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Narayanan S, Loganathan G, Dhanasekaran M, Tucker W, Patel A, Subhashree V, Mokshagundam S, Hughes MG, Williams SK, Balamurugan AN. Intra-islet endothelial cell and β-cell crosstalk: Implication for islet cell transplantation. World J Transplant 2017; 7:117-128. [PMID: 28507914 PMCID: PMC5409911 DOI: 10.5500/wjt.v7.i2.117] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Revised: 02/28/2017] [Accepted: 03/24/2017] [Indexed: 02/05/2023] Open
Abstract
The intra-islet microvasculature is a critical interface between the blood and islet endocrine cells governing a number of cellular and pathophysiological processes associated with the pancreatic tissue. A growing body of evidence indicates a strong functional and physical interdependency of β-cells with endothelial cells (ECs), the building blocks of islet microvasculature. Intra-islet ECs, actively regulate vascular permeability and appear to play a role in fine-tuning blood glucose sensing and regulation. These cells also tend to behave as “guardians”, controlling the expression and movement of a number of important immune mediators, thereby strongly contributing to the physiology of islets. This review will focus on the molecular signalling and crosstalk between the intra-islet ECs and β-cells and how their relationship can be a potential target for intervention strategies in islet pathology and islet transplantation.
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30
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Establishment, characterization and long-term culture of human endocrine pancreas-derived microvascular endothelial cells. Cytotherapy 2017; 19:141-152. [DOI: 10.1016/j.jcyt.2016.10.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Revised: 10/07/2016] [Accepted: 10/12/2016] [Indexed: 12/24/2022]
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31
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Kaviani M, Azarpira N. Insight into microenvironment remodeling in pancreatic endocrine tissue engineering: Biological and biomaterial approaches. Tissue Eng Regen Med 2016; 13:475-484. [PMID: 30603429 PMCID: PMC6170842 DOI: 10.1007/s13770-016-0014-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Revised: 02/03/2016] [Accepted: 02/05/2016] [Indexed: 01/04/2023] Open
Abstract
The treatment of diabetes mellitus, as a chronic and complicated disease, is a valuable purpose. Islet transplantation can provide metabolic stability and insulin independence in type 1 diabetes patients. Diet and insulin therapy are only diabetes controllers and cannot remove all of the diabetes complications. Moreover, islet transplantation is more promising treatment than whole pancreas transplantation because of lesser invasive surgical procedure and morbidity and mortality. According to the importance of extracellular matrix for islet viability and function, microenvironment remodeling of pancreatic endocrine tissue can lead to more success in diabetes treatment by pancreatic islets. Production of bioengineered pancreas and remodeling of pancreas extracellular matrix provide essential microenvironment for re-vascularization, re-innervation and signaling cascades triggering. Therefore, islets show better viability and function in these conditions. Researchers conduct various scaffolds with different biomaterials for the improvement of islet viability, function and transplantation outcome. The attention to normal pancreas anatomy, embryology and histology is critical to understand the pancreatic Langerhans islets niche and finally to achieve efficient engineered structure. Therefore, in the present study, the status and components of the islets niche is mentioned and fundamental issues related to the tissue engineering of this structure is considered. The purpose of this review article is summarization of recent progress in the endocrine pancreas tissue engineering and biomaterials and biological aspects of it.
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Affiliation(s)
- Maryam Kaviani
- Transplant Research Center, Shiraz University of Medical Sciences, Mohamad Rasulallah Research Tower, Khalili street, Shiraz, 7193635899 Iran
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Mohamad Rasulallah Research Tower, Khalili street, Shiraz, 7193635899 Iran
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32
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Lecomte MJ, Pechberty S, Machado C, Da Barroca S, Ravassard P, Scharfmann R, Czernichow P, Duvillié B. Aggregation of Engineered Human β-Cells Into Pseudoislets: Insulin Secretion and Gene Expression Profile in Normoxic and Hypoxic Milieu. CELL MEDICINE 2016; 8:99-112. [PMID: 28003935 DOI: 10.3727/215517916x692843] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Innovative treatments to cure type 1 diabetes are being actively researched. Among the different strategies, the replacement of β-cells has given promising results. Classically, islets from cadaveric donors are transplanted into diabetic patients, but recently phase I clinical trials that use stem cell-derived β-cells have been started. Such protocols require either an immunosuppressive treatment or the macroencapsulation of the β-cells. They involve cell aggregation and the exposure of the cells to hypoxia. Using an engineered human β-cell, we have addressed these two problems: a novel human β-cell line called EndoC-βH3 was cultured as single cells or aggregated clusters. EndoC-βH3 cells were also cultured at normal atmospheric oxygen tension (pO2 = 21%) or hypoxia (pO2 = 3%) in the presence or absence of modulators of the hypoxia-inducible factor 1α (HIF1α) pathway. Cell aggregation improved glucose-stimulated insulin secretion, demonstrating the benefit of cell-cell contacts. Low oxygen tension decreased β-cell viability and their sensitivity to glucose, but did not alter insulin production nor the insulin secretion capacity of the remaining cells. To investigate the role of HIF1α, we first used a HIF stabilizer at pO2 = 21%. This led to a mild decrease in cell viability, impaired glucose sensitivity, and altered insulin secretion. Finally, we used a HIF inhibitor on EndoC-βH3 pseudoislets exposed to hypoxia. Such treatment considerably decreased cell viability. In conclusion, aggregation of the EndoC-βH3 cells seems to be important to improve their function. A fraction of the EndoC-βH3 cells are resistant to hypoxia, depending on the level of activity of HIF1α. Thus, these cells represent a good human cell model for future investigations on islet cell transplantation analysis.
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Affiliation(s)
- Marie-José Lecomte
- Univercell-Biosolutions, Centre de recherche des Cordeliers , Paris , France
| | - Séverine Pechberty
- Univercell-Biosolutions, Centre de recherche des Cordeliers , Paris , France
| | - Cécile Machado
- Univercell-Biosolutions, Centre de recherche des Cordeliers , Paris , France
| | - Sandra Da Barroca
- Univercell-Biosolutions, Centre de recherche des Cordeliers , Paris , France
| | - Philippe Ravassard
- † Sorbonne Universités, UPMC Univ Paris 06, Inserm, CNRS, Institut du cerveau et de la moelle (ICM)-Hôpital Pitié-Salpêtrière , Paris , France
| | - Raphaël Scharfmann
- ‡INSERM U1016, Institut Cochin, Paris, France; §Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France
| | - Paul Czernichow
- Univercell-Biosolutions, Centre de recherche des Cordeliers , Paris , France
| | - Bertrand Duvillié
- ‡INSERM U1016, Institut Cochin, Paris, France; §Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France
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33
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Clarkin CE, Mahmoud M, Liu B, Sobamowo EO, King A, Arthur H, Jones PM, Wheeler-Jones CP. Modulation of endoglin expression in islets of langerhans by VEGF reveals a novel regulator of islet endothelial cell function. BMC Res Notes 2016; 9:362. [PMID: 27456002 PMCID: PMC4960785 DOI: 10.1186/s13104-016-2142-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Accepted: 06/30/2016] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Endoglin/CD105 is an auxiliary receptor for transforming growth factor-β with established roles in vascular remodelling. It has recently been shown that heterozygous endoglin deficiency in mice decreases insulin secretion in an animal model of obesity, highlighting a potential role for endoglin in the regulation of islet function. We have previously identified two different populations of endoglin expressing cells in human and mouse islets which are: (i) endothelial cells (ECs) and (ii) islet mesenchymal stromal cells. The contribution of islet EC endoglin expression to islet development and sensitivity to VEGF is unknown and is the focus of this study. RESULTS In vitro culture of mouse islets with VEGF164 for 48 h increased endoglin mRNA levels above untreated controls but VEGF did not modulate VEGFR2, CD31 or CD34 mRNA expression or islet viability. Removal of EC-endoglin expression in vivo reduced islet EC area but had no apparent effect on islet size or architecture. CONCLUSION EC-specific endoglin expression in islets is sensitive to VEGF and plays partial roles in driving islet vascular development, however such regulation appears to be distinct to mechanisms required to modulate islet viability and size.
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Affiliation(s)
- Claire E. Clarkin
- Diabetes Research Group, Division of Diabetes and Nutritional Sciences, School of Medicine, Kings College London, London, SE1 1UL UK
- Centre for Biological Sciences, University of Southampton, Building 85/Life Sciences, University Road, Southampton, SO17 1BJ UK
| | - Marwa Mahmoud
- Institute of Genetic Medicine, Newcastle University, London, NE1 3BZ UK
| | - Bo Liu
- Diabetes Research Group, Division of Diabetes and Nutritional Sciences, School of Medicine, Kings College London, London, SE1 1UL UK
| | - Emmanuel O. Sobamowo
- Centre for Biological Sciences, University of Southampton, Building 85/Life Sciences, University Road, Southampton, SO17 1BJ UK
| | - Aileen King
- Diabetes Research Group, Division of Diabetes and Nutritional Sciences, School of Medicine, Kings College London, London, SE1 1UL UK
| | - Helen Arthur
- Institute of Genetic Medicine, Newcastle University, London, NE1 3BZ UK
| | - Peter M. Jones
- Diabetes Research Group, Division of Diabetes and Nutritional Sciences, School of Medicine, Kings College London, London, SE1 1UL UK
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34
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Cigrovski Berković M, Čačev T, Catela Ivković T, Marout J, Ulamec M, Zjačić-Rotkvić V, Kapitanović S. High VEGF serum values are associated with locoregional spread of gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Mol Cell Endocrinol 2016; 425:61-68. [PMID: 26805636 DOI: 10.1016/j.mce.2016.01.013] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2015] [Revised: 01/13/2016] [Accepted: 01/16/2016] [Indexed: 11/18/2022]
Abstract
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are highly vascularized neoplasms, capable of synthethisizing VEGF-A, a key mediator of angiogenesis. In pancreatic neuroendocrine tumors (pNETs) VEGF expression is higher in benign and low-grade tumors and associated with good prognosis (neuroendocrine paradox) while the VEGF role in gastrointestinal NETs (GI-NETs) is still unclear. In this study, we examined the VEGF-1154A/G polymorphism in 145 GEP-NET patients and 150 controls. Next, we measured VEGF serum levels and VEGF tumor protein expression, comparing it with Ki67 and tumor grade. Patients' VEGF serum levels were compared with VEGF -1145A/G genotypes and metastatic status as well as with chromogranin A (CgA) and 5-hydroxyindolacetic acid (5-HIAA) in case of GI-NET patients. In this study GEP-NET patients had elevated VEGF serum values when compared to healthy controls (p = 0.0013). VEGF-1145G allele correlated with higher VEGF serum levels (p = 0.002). Patients with metastatic tumors had higher VEGF serum values when compared to patients without metastases (p = 0.033), and highest levels were observed in case of lymph node metastases (p = 0.008). VEGF-1145G allele was more frequent in non-functional GI-NET patients than in healthy controls (p = 0.041). CgA was superior to VEGF in tumor detection, while VEGF was superior to 5-HIAA. A correlation was observed between VEGF immunohistochemical staining and Ki-67 (p = 0.028). Tumours with weaker VEGF protein expression were more aggressive than tumours with stronger VEGF expression, confirming a "neuroendocrine paradox" in GI-NETs. Our results suggest the role of VEGF in GI-NETs locoregional spread.
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Affiliation(s)
- Maja Cigrovski Berković
- Department for Endocrinology, Diabetes and Metabolism, University Clinical Hospital Centre "Sestre milosrdnice", Zagreb, Croatia.
| | - Tamara Čačev
- Laboratory for Personalized Medicine, Division of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia
| | - Tina Catela Ivković
- Laboratory for Personalized Medicine, Division of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia
| | - Jasminka Marout
- Department for Endocrinology, Diabetes and Metabolism, University Clinical Hospital Centre "Sestre milosrdnice", Zagreb, Croatia
| | - Monika Ulamec
- Department for Clinical Pathology, University Clinical Hospital Centre "Sestre milosrdnice", Zagreb, Croatia
| | - Vanja Zjačić-Rotkvić
- Department for Endocrinology, Diabetes and Metabolism, University Clinical Hospital Centre "Sestre milosrdnice", Zagreb, Croatia
| | - Sanja Kapitanović
- Laboratory for Personalized Medicine, Division of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia
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35
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Takahashi Y, Takebe T, Taniguchi H. Engineering pancreatic tissues from stem cells towards therapy. Regen Ther 2016; 3:15-23. [PMID: 31245468 PMCID: PMC6581807 DOI: 10.1016/j.reth.2016.01.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Revised: 12/17/2015] [Accepted: 01/20/2016] [Indexed: 12/20/2022] Open
Abstract
Pancreatic islet transplantation is performed as a potential treatment for type 1 diabetes mellitus. However, this approach is significantly limited due to the critical shortage of islet sources. Recently, a number of publications have developed protocols for directed β-cell differentiation of pluripotent cells, such as embryonic stem (ES) or induced pluripotent stem (iPS) cells. Decades of studies have led to the development of modified protocols that recapitulate molecular developmental cues by combining various growth factors and small molecules with improved efficiency. However, the later step of pancreatic differentiation into functional β-cells has yet to be satisfactory in vitro, highlighting alternative approach by recapitulating spatiotemporal multicellular interaction in three-dimensional (3D) culture. Here, we summarize recent progress in the directed differentiation into pancreatic β-cells with a focus on both two-dimensional (2D) and 3D differentiation settings. We also discuss the potential transplantation strategies in combination with current bioengineering approaches towards diabetes therapy.
Transplantation of stem cell derived pancreatic progenitors is a possible approach for generating mature β-cell in vivo. Promise of 3-D (or 4-D) culture has started to be explored by reconstituting pancreatic tissue structures. Self-condensation culture is a basic technique of integrating multiple heterotypic lineages including vasculatures. Bioengineering approach has been combined for developing effective transplant strategies.
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Key Words
- 2D, two-dimensional
- 3D, three-dimensional
- BMP, bone morphogenic protein
- Diabetes
- ES, embryonic stem
- FGF, fibroblast growth factors
- Heterotypic cellular interaction
- IBMIR, instant blood-mediated reaction
- ILV, indolactam V
- Ngn3, neurogenin 3
- PEG, polyethylene glycol
- PI3K, phosphatidylinositol-3 kinase
- PIPAAm, poly-N-isopropylacrylamide
- PVA, polyvinyl alcohol
- Pancreas
- Pdx1, pancreatic and duodenal homeobox 1
- Ptf1a, pancreatic transcription factor 1a
- Regenerative medicine
- VEGF, vascular endothelial growth factor
- Vascularization
- iPS, induced pluripotent stem
- iPS/ES cell
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Affiliation(s)
- Yoshinobu Takahashi
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Kanazawa-ku 3-9, Yokohama, Kanagawa, 236-0004, Japan
| | - Takanori Takebe
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Kanazawa-ku 3-9, Yokohama, Kanagawa, 236-0004, Japan.,Advanced Medical Research Center, Yokohama City University, Kanazawa-ku 3-9, Yokohama, Kanagawa, 236-0004, Japan.,PRESTO, Japan Science and Technology Agency, 4-1-8, Honcho, Kawaguchi, Saitama, 332-0012, Japan.,Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, 3333 Burnet Avenue, Cincinnati, OH, 45229- 3039, USA
| | - Hideki Taniguchi
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Kanazawa-ku 3-9, Yokohama, Kanagawa, 236-0004, Japan.,Advanced Medical Research Center, Yokohama City University, Kanazawa-ku 3-9, Yokohama, Kanagawa, 236-0004, Japan
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Cooper TT, Hess DA. The IsletCore Program: Improving the Supply of Human Islets to Satisfy the Demand for Research. See article in Endocrinology 2016;157:560-569. Endocrinology 2016; 157:997-1002. [PMID: 26919514 DOI: 10.1210/en.2016-1061] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Affiliation(s)
- Tyler T Cooper
- Molecular Medicine Research Group, Krembil Centre for Stem Cell Biology, Robarts Research Institute, and Department of Physiology and Pharmacology, Western University Canada, London, Ontario, Canada N6A 3K7
| | - David A Hess
- Molecular Medicine Research Group, Krembil Centre for Stem Cell Biology, Robarts Research Institute, and Department of Physiology and Pharmacology, Western University Canada, London, Ontario, Canada N6A 3K7
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Feng ZC, Popell A, Li J, Silverstein J, Oakie A, Yee SP, Wang R. c-Kit Receptor Signaling Regulates Islet Vasculature, β-Cell Survival, and Function In Vivo. Diabetes 2015; 64:3852-66. [PMID: 26253609 DOI: 10.2337/db15-0054] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2015] [Accepted: 07/25/2015] [Indexed: 11/13/2022]
Abstract
The receptor tyrosine kinase c-Kit plays an integral role in maintaining β-cell mass and function. Although c-Kit receptor signaling promotes angiogenesis in multiple cell types, its role in islet vasculature is unknown. This study examines the effects of c-Kit-mediated vascular endothelial growth factor isoform A (VEGF-A) and islet vascularization on β-cell function and survival using in vitro cell culture and in vivo mouse models. In cultured INS-1 cells and primary islets, c-Kit regulates VEGF-A expression via the Akt/mammalian target of rapamycin (mTOR) signaling pathway. Juvenile mice with mutated c-Kit (c-Kit(Wv/+)) showed impaired islet vasculature and β-cell dysfunction, while restoring c-Kit expression in β-cells of c-Kit(Wv/+) mice rescued islet vascular defects through modulation of the Akt/mTOR/VEGF-A pathway, indicating that c-Kit signaling in β-cells is a required regulator for maintaining normal islet vasculature. Furthermore, β-cell-specific c-Kit overexpression (c-KitβTg) in aged mice showed significantly increased islet vasculature and β-cell function, but, when exposed to a long-term high-fat diet, c-Kit signaling in c-KitβTg mice induced substantial vascular remodeling, which resulted in increased islet inflammatory responses and β-cell apoptosis. These results suggest that c-Kit-mediated VEGF-A action in β-cells plays a pivotal role in maintaining islet vascularization and function.
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Affiliation(s)
- Zhi-Chao Feng
- Children's Health Research Institute, University of Western Ontario, London, Ontario, Canada Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
| | - Alex Popell
- Children's Health Research Institute, University of Western Ontario, London, Ontario, Canada Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
| | - Jinming Li
- Children's Health Research Institute, University of Western Ontario, London, Ontario, Canada Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
| | - Jenna Silverstein
- Children's Health Research Institute, University of Western Ontario, London, Ontario, Canada Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
| | - Amanda Oakie
- Children's Health Research Institute, University of Western Ontario, London, Ontario, Canada Department of Pathology, University of Western Ontario, London, Ontario, Canada
| | - Siu-Pok Yee
- Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, CT
| | - Rennian Wang
- Children's Health Research Institute, University of Western Ontario, London, Ontario, Canada Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada Department of Medicine, University of Western Ontario, London, Ontario, Canada
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38
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Lan KC, Chiu CY, Kao CW, Huang KH, Wang CC, Huang KT, Tsai KS, Sheu ML, Liu SH. Advanced glycation end-products induce apoptosis in pancreatic islet endothelial cells via NF-κB-activated cyclooxygenase-2/prostaglandin E2 up-regulation. PLoS One 2015; 10:e0124418. [PMID: 25898207 PMCID: PMC4405342 DOI: 10.1371/journal.pone.0124418] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2014] [Accepted: 03/13/2015] [Indexed: 12/23/2022] Open
Abstract
Microvascular complications eventually affect nearly all patients with diabetes. Advanced glycation end-products (AGEs) resulting from hyperglycemia are a complex and heterogeneous group of compounds that accumulate in the plasma and tissues in diabetic patients. They are responsible for both endothelial dysfunction and diabetic vasculopathy. The aim of this study was to investigate the cytotoxicity of AGEs on pancreatic islet microvascular endothelial cells. The mechanism underlying the apoptotic effect of AGEs in pancreatic islet endothelial cell line MS1 was explored. The results showed that AGEs significantly decreased MS1 cell viability and induced MS1 cell apoptosis in a dose-dependent manner. AGEs dose-dependently increased the expressions of cleaved caspase-3, and cleaved poly (ADP-ribose) polymerase in MS1 cells. Treatment of MS1 cells with AGEs also resulted in increased nuclear factor (NF)-κB-p65 phosphorylation and cyclooxygenase (COX)-2 expression. However, AGEs did not affect the expressions of endoplasmic reticulum (ER) stress-related molecules in MS1 cells. Pretreatment with NS398 (a COX-2 inhibitor) to inhibit prostaglandin E2 (PGE2) production reversed the induction of cleaved caspase-3, cleaved PARP, and MS1 cell viability. Moreover, AGEs significantly increased the receptor for AGEs (RAGE) protein expression in MS1 cells, which could be reversed by RAGE neutralizing antibody. RAGE Neutralizing antibody could also reverse the induction of cleaved caspase-3 and cleaved PARP and decreased cell viability induced by AGEs. These results implicate the involvement of NF-κB-activated COX-2/PGE2 up-regulation in AGEs/RAGE-induced islet endothelial cell apoptosis and cytotoxicity. These findings may provide insight into the pathological processes within the pancreatic islet microvasculature induced by AGEs accumulation.
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Affiliation(s)
- Kuo-Cheng Lan
- Department of Emergency Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Chen-Yuan Chiu
- Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chia-Wei Kao
- Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Kuo-How Huang
- Department of Urology, College of Medicine and Hospital, National Taiwan University, Taipei, Taiwan
| | - Ching-Chia Wang
- Department of Pediatrics, College of Medicine and Hospital, National Taiwan University, Taipei, Taiwan
| | - Kuo-Tong Huang
- Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Keh-Sung Tsai
- Departments of Laboratory Medicine, College of Medicine and Hospital, National Taiwan University, Taipei, Taiwan
| | - Meei-Ling Sheu
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
| | - Shing Hwa Liu
- Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan
- Department of Pediatrics, College of Medicine and Hospital, National Taiwan University, Taipei, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
- * E-mail:
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Phelps EA, Templeman KL, Thulé PM, García AJ. Engineered VEGF-releasing PEG-MAL hydrogel for pancreatic islet vascularization. Drug Deliv Transl Res 2015; 5:125-36. [PMID: 25787738 PMCID: PMC4366610 DOI: 10.1007/s13346-013-0142-2] [Citation(s) in RCA: 85] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Biofunctionalized polyethylene glycol maleimide (PEG-MAL) hydrogels were engineered as a platform to deliver pancreatic islets to the small bowel mesentery and promote graft vascularization. VEGF, a potent stimulator of angiogenesis, was incorporated into the hydrogel to be released in an on-demand manner through enzymatic degradation. PEG-MAL hydrogel enabled extended in vivo release of VEGF. Isolated rat islets encapsulated in PEG-MAL hydrogels remained viable in culture and secreted insulin. Islets encapsulated in PEG-MAL matrix and transplanted to the small bowel mesentery of healthy rats grafted to the host tissue and revascularized by 4 weeks. Addition of VEGF release to the PEG-MAL matrix greatly augmented the vascularization response. These results establish PEG-MAL engineered matrices as a vascular-inductive cell delivery vehicle and warrant their further investigation as islet transplantation vehicles in diabetic animal models.
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Affiliation(s)
- Edward A. Phelps
- Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332
- Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Drive, Atlanta, GA 30332
| | - Kellie L. Templeman
- Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332
- Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Drive, Atlanta, GA 30332
| | - Peter M. Thulé
- Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Drive, Atlanta, GA 30332
- Division of Endocrinology, Metabolism and Lipids, Emory University School of Medicine, Atlanta Veterans Affairs Medical Center, 1670 Clairmont Road NE, Decatur, GA 30033
| | - Andrés J. García
- Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332
- Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Drive, Atlanta, GA 30332
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40
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Rozance PJ, Anderson M, Martinez M, Fahy A, Macko AR, Kailey J, Seedorf GJ, Abman SH, Hay WW, Limesand SW. Placental insufficiency decreases pancreatic vascularity and disrupts hepatocyte growth factor signaling in the pancreatic islet endothelial cell in fetal sheep. Diabetes 2015; 64:555-64. [PMID: 25249573 PMCID: PMC4303968 DOI: 10.2337/db14-0462] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Hepatocyte growth factor (HGF) and vascular endothelial growth factor A (VEGFA) are paracrine hormones that mediate communication between pancreatic islet endothelial cells (ECs) and β-cells. Our objective was to determine the impact of intrauterine growth restriction (IUGR) on pancreatic vascularity and paracrine signaling between the EC and β-cell. Vessel density was less in IUGR pancreata than in controls. HGF concentrations were also lower in islet EC-conditioned media (ECCM) from IUGR, and islets incubated with control islet ECCM responded by increasing insulin content, which was absent with IUGR ECCM. The effect of ECCM on islet insulin content was blocked with an inhibitory anti-HGF antibody. The HGF receptor was not different between control and IUGR islets, but VEGFA was lower and the high-affinity VEGF receptor was higher in IUGR islets and ECs, respectively. These findings show that paracrine actions from ECs increase islet insulin content, and in IUGR ECs, secretion of HGF was diminished. Given the potential feed-forward regulation of β-cell VEGFA and islet EC HGF, these two growth factors are highly integrated in normal pancreatic islet development, and this regulation is decreased in IUGR fetuses, resulting in lower pancreatic islet insulin concentrations and insulin secretion.
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Affiliation(s)
- Paul J Rozance
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO Perinatal Research Center, University of Colorado School of Medicine, Aurora, CO
| | - Miranda Anderson
- School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ
| | - Marina Martinez
- School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ
| | - Anna Fahy
- School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ
| | - Antoni R Macko
- School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ
| | - Jenai Kailey
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO Perinatal Research Center, University of Colorado School of Medicine, Aurora, CO
| | - Gregory J Seedorf
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO Pediatric Heart Lung Center, University of Colorado School of Medicine, Aurora, CO
| | - Steven H Abman
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO Pediatric Heart Lung Center, University of Colorado School of Medicine, Aurora, CO
| | - William W Hay
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO Pediatric Heart Lung Center, University of Colorado School of Medicine, Aurora, CO
| | - Sean W Limesand
- School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ
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41
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Geron E, Boura-Halfon S, Schejter ED, Shilo BZ. The Edges of Pancreatic Islet β Cells Constitute Adhesive and Signaling Microdomains. Cell Rep 2015; 10:317-325. [PMID: 25600867 DOI: 10.1016/j.celrep.2014.12.031] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Revised: 11/11/2014] [Accepted: 12/12/2014] [Indexed: 10/24/2022] Open
Abstract
Pancreatic islet β cells are organized in rosette-like structures around blood vessels and exhibit an artery-to-vein orientation, but they do not display the typical epithelial polarity. It is unclear whether these cells present a functional asymmetry related to their spatial organization. Here, we identify murine β cell edges, the sites at which adjacent cell faces meet at a sharp angle, as surface microdomains of cell-cell adhesion and signaling. The edges are marked by enrichment of F-actin and E-cadherin and are aligned between neighboring cells. The edge organization is E-cadherin contact dependent and correlates with insulin secretion capacity. Edges display elevated levels of glucose transporters and SNAP25 and extend numerous F-actin-rich filopodia. A similar β cell edge organization was observed in human islets. When stimulated, β cell edges exhibit high calcium levels. In view of the functional importance of intra-islet communication, the spatial architecture of their edges may prove fundamental for coordinating physiological insulin secretion.
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Affiliation(s)
- Erez Geron
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Sigalit Boura-Halfon
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Eyal D Schejter
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Ben-Zion Shilo
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
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42
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Dolenšek J, Rupnik MS, Stožer A. Structural similarities and differences between the human and the mouse pancreas. Islets 2015; 7:e1024405. [PMID: 26030186 PMCID: PMC4589993 DOI: 10.1080/19382014.2015.1024405] [Citation(s) in RCA: 226] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2014] [Revised: 02/20/2015] [Accepted: 02/23/2015] [Indexed: 02/08/2023] Open
Abstract
Mice remain the most studied animal model in pancreas research. Since the findings of this research are typically extrapolated to humans, it is important to understand both similarities and differences between the 2 species. Beside the apparent difference in size and macroscopic organization of the organ in the 2 species, there are a number of less evident and only recently described differences in organization of the acinar and ductal exocrine tissue, as well as in the distribution, composition, and architecture of the endocrine islets of Langerhans. Furthermore, the differences in arterial, venous, and lymphatic vessels, as well as innervation are potentially important. In this article, the structure of the human and the mouse pancreas, together with the similarities and differences between them are reviewed in detail in the light of conceivable repercussions for basic research and clinical application.
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Affiliation(s)
- Jurij Dolenšek
- Institute of Physiology; Faculty of Medicine; University of Maribor; Maribor, Slovenia
| | - Marjan Slak Rupnik
- Institute of Physiology; Faculty of Medicine; University of Maribor; Maribor, Slovenia
- Centre for Open Innovations and Research Core@UM; University of Maribor; Maribor, Slovenia
- Institute of Physiology; Center for Physiology and Pharmacology; Medical University of Vienna; Vienna, Austria
| | - Andraž Stožer
- Institute of Physiology; Faculty of Medicine; University of Maribor; Maribor, Slovenia
- Centre for Open Innovations and Research Core@UM; University of Maribor; Maribor, Slovenia
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43
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Affiliation(s)
- Peter In't Veld
- Diabetes Research Center, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium,
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44
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Yu Y, Wang X, Nyberg SL. Potential and Challenges of Induced Pluripotent Stem Cells in Liver Diseases Treatment. J Clin Med 2014; 3:997-1017. [PMID: 26237490 PMCID: PMC4449640 DOI: 10.3390/jcm3030997] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Revised: 08/22/2014] [Accepted: 08/26/2014] [Indexed: 01/14/2023] Open
Abstract
Tens of millions of patients are affected by liver disease worldwide. Many of these patients can benefit from cell therapy involving living metabolically active cells, either by treatment of their liver disease, or by prevention of their disease phenotype. Cell therapies, including hepatocyte transplantation and bioartificial liver (BAL) devices, have been proposed as therapeutic alternatives to the shortage of transplantable livers. Both BAL and hepatocyte transplantation are cellular therapies that avoid use of a whole liver. Hepatocytes are also widely used in drug screening and liver disease modelling. However, the demand for human hepatocytes, heavily outweighs their availability by conventional means. Induced pluripotent stem cells (iPSCs) technology brings together the potential benefits of embryonic stem cells (ESCs) (i.e., self-renewal, pluripotency) and addresses the major ethical and scientific concerns of ESCs: embryo destruction and immune-incompatibility. It has been shown that hepatocyte-like cells (HLCs) can be generated from iPSCs. Furthermore, human iPSCs (hiPSCs) can provide an unlimited source of human hepatocytes and hold great promise for applications in regenerative medicine, drug screening and liver diseases modelling. Despite steady progress, there are still several major obstacles that need to be overcome before iPSCs will reach the bedside. This review will focus on the current state of efforts to derive hiPSCs for potential use in modelling and treatment of liver disease.
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Affiliation(s)
- Yue Yu
- Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, Nanjing, Jiangsu Province 210029, China.
- Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province 210029, China.
| | - Xuehao Wang
- Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, Nanjing, Jiangsu Province 210029, China.
- Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province 210029, China.
| | - Scott L Nyberg
- Division of Experimental Surgery, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
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Karakaxas D, Gazouli M, Liakakos T, Vaiopoulou A, Apessou D, Papaparaskeva K, Patapis P, Dervenis C. Pancreatic neuroendocrine tumors: current opinions on a rare, but potentially curable neoplasm. Eur J Gastroenterol Hepatol 2014; 26:826-835. [PMID: 24987821 DOI: 10.1097/meg.0000000000000138] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Pancreatic neuroendocrine tumors (PNETs) share a unique genetic identity, functional behavior, and clinical course. Compared with tumors of the exocrine pancreas, they are rare and show a different biologic behavior and prognosis. On the basis of data from recent studies, all PNETs, outside of small insulinomas, should be considered potentially malignant and treated accordingly. Untreated tumors have a high possibility to grow locally into adjacent structures or spread to distant organs. Although surgical excision irrespective of tumor functioning or nonfunctioning state remains the cornerstone of therapy, providing the best disease-free and survival rates to date, the understanding of the genetic nature of the disease yields new 'targets' to consider in drug development. The aim of this review is to summarize all recent advances of genetic research and new drug development in terms of PNETs, especially their genetic identity and subsequent alterations leading to the development of near or total malignant activity, and the new medical treatment strategies of this potentially curable disease on the basis of therapeutical agents acting, where possible, at the genetic level.
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Affiliation(s)
- Dimitrios Karakaxas
- aSurgical Department-HPB Surgical Unit, Konstantopouleion Agia Olga General Hospital bLaboratory of Biology, Department of Basic Medical Science, School of Medicine, University of Athens cThird Department of Surgery, University of Athens School of Medicine, Attikon University Hospital, Athens, Greece
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46
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Figliuzzi M, Bonandrini B, Silvani S, Remuzzi A. Mesenchymal stem cells help pancreatic islet transplantation to control type 1 diabetes. World J Stem Cells 2014; 6:163-172. [PMID: 24772243 PMCID: PMC3999774 DOI: 10.4252/wjsc.v6.i2.163] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 12/20/2013] [Accepted: 03/04/2014] [Indexed: 02/06/2023] Open
Abstract
Islet cell transplantation has therapeutic potential to treat type 1 diabetes, which is characterized by autoimmune destruction of insulin-producing pancreatic islet β cells. It represents a minimal invasive approach for β cell replacement, but long-term blood control is still largely unachievable. This phenomenon can be attributed to the lack of islet vasculature and hypoxic environment in the immediate post-transplantation period that contributes to the acute loss of islets by ischemia. Moreover, graft failures continue to occur because of immunological rejection, despite the use of potent immunosuppressive agents. Mesenchymal stem cells (MSCs) have the potential to enhance islet transplantation by suppressing inflammatory damage and immune mediated rejection. In this review we discuss the impact of MSCs on islet transplantation and focus on the potential role of MSCs in protecting islet grafts from early graft failure and from autoimmune attack.
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Esposito A, Palmisano A, Maffi P, Malosio ML, Nano R, Canu T, De Cobelli F, Piemonti L, Ironi G, Secchi A, Del Maschio A. Liver perfusion changes occurring during pancreatic islet engraftment: a dynamic contrast-enhanced magnetic resonance study. Am J Transplant 2014; 14:202-9. [PMID: 24219129 DOI: 10.1111/ajt.12501] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2013] [Revised: 07/26/2013] [Accepted: 09/07/2013] [Indexed: 01/25/2023]
Abstract
The aim of this study was to investigate liver microvascular adaptation following the intraportal infusion of pancreatic islets (pancreatic islet transplantation [islet-tx]) in diabetic patients using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). DCE-MRI was performed before and 7 days after islet-tx in six diabetic patients. Initial area under curve (AUC60) and volume transfer coefficient (Ktrans) were assessed as markers of liver perfusion. Clinical and metabolic monthly follow-up was performed in all patients, considering fasting C-peptide and β-score as main indices of graft function. High variability in the response of liver microvasculature to islet infusion was observed: two patients showed a significant reduction in liver perfusion after transplantation (pt.2: AUC60 = -23.4%, Ktrans = -31.7%; pt.4: AUC60 = -23.7%, Ktrans = -27.9%); three patients did not show any significant variation of liver perfusion and one patient showed a significant increase (pt.3: AUC60 = +31%, Ktrans = +42.8%). Interestingly, a correlation between DCE-MRI parameters and indices of graft function was observed and, in particular, both patients with DCE-MRI evidence of posttransplantation liver perfusion reduction experienced premature graft failure. Our preliminary study demonstrated that DCE-MRI may identify different adaptive responses of liver microvasculature in patients submitted to islet-tx. These different responses could have an impact on islet engraftment, although reported findings need confirmation from larger studies.
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Affiliation(s)
- A Esposito
- Department of Radiology and Experimental Imaging Center, San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
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Synergism of a natural plant product, oleanolic acid with calcineurin inhibitor in prolonging islet allograft survival. Transpl Immunol 2013; 29:64-70. [DOI: 10.1016/j.trim.2013.09.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2013] [Revised: 09/03/2013] [Accepted: 09/04/2013] [Indexed: 11/19/2022]
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Paget MB, Murray HE, Bailey CJ, Downing R. Pre-transplant signal induction for vascularisation in human islets. Diab Vasc Dis Res 2013; 10:536-45. [PMID: 24062164 DOI: 10.1177/1479164113504770] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Human islet transplant success is partially impaired by slow revascularisation. Our study investigated the potential for rotational cell culture (RC) of human islets combined with thiazolidinedione (TZD) stimulation of peroxisome proliferator-activated receptor gamma (PPARγ) to upregulate vascular endothelial growth factor (VEGF) expression in the islets. Four groups of human islets were studied: static culture (SC) with and without 25 mmol/L TZD and RC with and without 25 mmol/L TZD. These were assessed for insulin secretion and soluble VEGF-A release. Both proteins were quantified by enzyme-linked immunosorbent assay (ELISA), supported with qualitative immunofluorescence staining. RC + TZD increased insulin secretion by >20% (p < 0.05-0.001) in response to 16.7 mmol/L glucose and 16.7 mmol/L glucose + 10 mmol/L theophylline (G + T). This effect was seen at all time intervals compared with SC and without addition of TZD. Soluble VEGF-A release was significantly augmented by RC and TZD exposure with an increased effect of >30% (p < 0.001) at 72 h under both SC and RC conditions. RC supplemented with a TZD enhances and prolongs the release of insulin and soluble VEGF-A by isolated human islets.
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Affiliation(s)
- Michelle B Paget
- Islet Research Laboratory, Worcestershire Clinical Research Unit, Worcestershire Acute Hospitals NHS Trust, Worcester, UK
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Wei R, Yang J, Hong TP. Relationship between vascular endothelial cells and pancreatic islet development and stem cell differentiation. Shijie Huaren Xiaohua Zazhi 2013; 21:2493-2499. [DOI: 10.11569/wcjd.v21.i25.2493] [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] [Indexed: 02/06/2023] Open
Abstract
As the main components of the pancreatic islet niche, endothelial cells participate in many processes of pancreatic development, including pancreatic cell fate decision, endocrine pancreatic cell differentiation and proliferation, and spatial distribution of the pancreas. On different occasions, endothelial cells play disparate roles by cross-talking with islet cells to influence endocrine pancreatic cell differentiation and islet morphology and function. Cytokines such as hepatocyte growth factor and sphingosine-1-phosphate as well as the extracellular matrixes such as laminin and collagen Ⅳ, which are produced and/or secreted by endothelial cells, play important roles in the regulation of islet development and function. Furthermore, endothelial cells are involved in the balance between self-renewal and differentiation of stem cells. Application of endothelial cells to induce the differentiation of stem cells into functional islet cells may be one of the most promising approaches to cell replacement therapy for diabetes.
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