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      Controlled Heterotypic Pseudo-Islet Assembly of Human β-Cells and Human Umbilical Vein Endothelial Cells Using Magnetic Levitation

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          Abstract

          β-Cell functionality and survival are highly dependent on the cells' microenvironment and cell–cell interactions. Since the pancreas is a highly vascularized organ, the crosstalk between β-cells and endothelial cells (ECs) is vital to ensure proper function. To understand the interaction of pancreatic β-cells with vascular ECs, we sought to investigate the impact of the spatial distribution on the interaction of human cell line-based β-cells (EndoC-βH3) and human umbilical vein endothelial cells (HUVECs). We focused on the evaluation of three major spatial distributions, which can be found within human islets in vivo, in tissue-engineered heterotypic cell spheroids, so-called pseudo-islets, by controlling the aggregation process using magnetic levitation. We report that heterotypic spheroids formed by spontaneous aggregation cannot be maintained in culture due to HUVEC disassembly over time. In contrast, magnetic levitation allows the formation of stable heterotypic spheroids with defined spatial distribution and significantly facilitated HUVEC integration. To the best of our knowledge, this is the first study that introduces a human-only cell line-based in vitro test system composed of a coculture of β-cells and ECs with a successful stimulation of β-cell secretory function monitored by a glucose-stimulated insulin secretion assays. In addition, we systematically investigate the impact of the spatial distribution on cocultures of human β-cells and ECs, showing that the architecture of pseudo-islets significantly affects β-cell functionality.

          Impact statement

          Tissue engineering of coculture systems containing β-cells and endothelial cells (ECs) is a promising technique to stimulate β-cell functionality. In this study, we analyzed human pancreatic islet tissue and revealed three different native distributions of β-cells and ECs. We successfully recreated these distributions in vitro by employing magnetic levitation of human β-cells and ECs, forming controlled heterotypic pseudo-islets, which enabled us to identify a significant impact of the pseudo-islet architecture on insulin secretion.

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          Most cited references68

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          Recent advances in three-dimensional multicellular spheroid culture for biomedical research.

          Many types of mammalian cells can aggregate and differentiate into 3-D multicellular spheroids when cultured in suspension or a nonadhesive environment. Compared to conventional monolayer cultures, multicellular spheroids resemble real tissues better in terms of structural and functional properties. Multicellular spheroids formed by transformed cells are widely used as avascular tumor models for metastasis and invasion research and for therapeutic screening. Many primary or progenitor cells on the other hand, show significantly enhanced viability and functional performance when grown as spheroids. Multicellular spheroids in this aspect are ideal building units for tissue reconstruction. Here we review the current understanding of multicellular spheroid formation mechanisms, their biomedical applications, and recent advances in spheroid culture, manipulation, and analysis techniques.
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            Pancreatic regulation of glucose homeostasis

            In order to ensure normal body function, the human body is dependent on a tight control of its blood glucose levels. This is accomplished by a highly sophisticated network of various hormones and neuropeptides released mainly from the brain, pancreas, liver, intestine as well as adipose and muscle tissue. Within this network, the pancreas represents a key player by secreting the blood sugar-lowering hormone insulin and its opponent glucagon. However, disturbances in the interplay of the hormones and peptides involved may lead to metabolic disorders such as type 2 diabetes mellitus (T2DM) whose prevalence, comorbidities and medical costs take on a dramatic scale. Therefore, it is of utmost importance to uncover and understand the mechanisms underlying the various interactions to improve existing anti-diabetic therapies and drugs on the one hand and to develop new therapeutic approaches on the other. This review summarizes the interplay of the pancreas with various other organs and tissues that maintain glucose homeostasis. Furthermore, anti-diabetic drugs and their impact on signaling pathways underlying the network will be discussed.
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              Pancreatic exocrine duct cells give rise to insulin-producing beta cells during embryogenesis but not after birth.

              A longstanding unsettled question is whether pancreatic beta cells originate from exocrine duct cells. We have now used genetic labeling to fate map embryonic and adult pancreatic duct cells. We show that Hnf1beta+ cells of the trunk compartment of the early branching pancreas are precursors of acinar, duct, and endocrine lineages. Hnf1beta+ cells subsequent form the embryonic duct epithelium, which gives rise to both ductal and endocrine lineages, but not to acinar cells. By the end of gestation, the fate of Hnf1beta+ duct cells is further restrained. We provide compelling evidence that the ductal epithelium does not make a significant contribution to acinar or endocrine cells during neonatal growth, during a 6 month observation period, or during beta cell growth triggered by ligation of the pancreatic duct or by cell-specific ablation with alloxan followed by EGF/gastrin treatment. Thus, once the ductal epithelium differentiates it has a restricted plasticity, even under regenerative settings. 2009 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Tissue Eng Part A
                Tissue Eng Part A
                tea
                Tissue Engineering. Part A
                Mary Ann Liebert, Inc., publishers (140 Huguenot Street, 3rd FloorNew Rochelle, NY 10801USA )
                1937-3341
                1937-335X
                April 2020
                16 April 2020
                16 April 2020
                : 26
                : 7-8
                : 387-399
                Affiliations
                [ 1 ]Department of Women's Health, Research Institute for Women's Health, Eberhard Karls University Tübingen, Tübingen, Germany.
                [ 2 ]Department of Anatomy, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland.
                [ 3 ]The Natural and Medical Sciences Institute (NMI) at the University of Tübingen, Reutlingen, Germany.
                [ 4 ]Cluster of Excellence iFIT (EXC 2180) “Image-Guided and Functionally Instructed Tumor Therapies,” Eberhard Karls University Tübingen, Tübingen, Germany.
                [ 5 ]Department of Medicine/Cardiology, Cardiovascular Research Laboratories, University of California, Los Angeles, California.
                Author notes
                [*]Address correspondence to: Katja Schenke-Layland, MSc, PhD, Department of Women's Health, Research Institute for Women's Health, Eberhard Karls University Tübingen, Silcherstr. 7/1, Tübingen 72076, Germany katja.schenke-layland@ 123456med.uni-tuebingen.de katja.schenke-layland@ 123456nmi.de
                Article
                10.1089/ten.tea.2019.0158
                10.1089/ten.tea.2019.0158
                7187983
                31680653
                906b8bbf-7a37-4739-8a5a-7f180a77d544
                © Max Urbanczyk et al., 2019; Published by Mary Ann Liebert, Inc.

                This Open Access article is distributed under the terms of the Creative Commons License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : Received: June 13, 2019
                : Accepted: October 4, 2019
                Page count
                Figures: 6, References: 75, Pages: 13
                Categories
                Original Articles

                diabetes,islets,β-cells,insulin,endothelial cells,3d
                diabetes, islets, β-cells, insulin, endothelial cells, 3d

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