Vessel Network Architecture of Adult Human Islets Promotes Distinct Cell-Cell Interactions In Situ and Is Altered After Transplantation.
Islet-cell hormone release is modulated by signals from endothelial and endocrine cells within the islet. However, models of intraislet vascularization and paracrine cell signaling are mostly based on the rodent pancreas. We assessed the architecture and endocrine cell interaction of the vascular network in unperturbed human islets in situ and their potential to re-establish their endogenous vascular network after transplantation in vivo. We prepared slices of fresh pancreas tissue obtained from nondiabetic patients undergoing partial pancreatectomy. In addition, we transplanted human donor islets into the anterior chamber of the mouse eye. Next, we performed three-dimensional in situ and in vivo imaging of islet cell and vessel architecture at cellular resolution and compared our findings with mouse and porcine islets. Our data reveal a significantly different vascular architecture with decreased vessel diameter, reduced vessel branching, and shortened total vessel network in human compared with mouse islets. Together with the distinct cellular arrangement in human islets, this limits β to endothelial cell interactions, facilitates connection of α and β cells, and promotes the formation of independent β-cell clusters within islets. Furthermore, our results show that the endogenous vascular network of islets is significantly altered after transplantation in a donor age-related mechanism. Thus, our study provides insight into the vascular architecture and cellular arrangement of human islets with apparent consequences for intercellular islet signaling. Moreover, our findings suggest that human islet engraftment after transplantation can be improved by using alternative, less mature islet-cell sources.
Paul Langerhans Institute Dresden of Helmholtz Zentrum München at the University Clinic Carl Gustav Carus of Technische Universität Dresden, Helmholtz Zentrum München, 85764 München-Neuherberg, Germany.|German Center for Diabetes Research, 85764 München-Neuherberg, Germany.|DFG-Center for Regenerative Therapies Dresden, Faculty of Medicine, University Clinic Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
Christian M
CM
Cohrs
Paul Langerhans Institute Dresden of Helmholtz Zentrum München at the University Clinic Carl Gustav Carus of Technische Universität Dresden, Helmholtz Zentrum München, 85764 München-Neuherberg, Germany.|German Center for Diabetes Research, 85764 München-Neuherberg, Germany.|DFG-Center for Regenerative Therapies Dresden, Faculty of Medicine, University Clinic Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
Chunguang
C
Chen
Paul Langerhans Institute Dresden of Helmholtz Zentrum München at the University Clinic Carl Gustav Carus of Technische Universität Dresden, Helmholtz Zentrum München, 85764 München-Neuherberg, Germany.|German Center for Diabetes Research, 85764 München-Neuherberg, Germany.|DFG-Center for Regenerative Therapies Dresden, Faculty of Medicine, University Clinic Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
Stephan R
SR
Jahn
Paul Langerhans Institute Dresden of Helmholtz Zentrum München at the University Clinic Carl Gustav Carus of Technische Universität Dresden, Helmholtz Zentrum München, 85764 München-Neuherberg, Germany.|German Center for Diabetes Research, 85764 München-Neuherberg, Germany.|DFG-Center for Regenerative Therapies Dresden, Faculty of Medicine, University Clinic Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
Julia
J
Stertmann
Paul Langerhans Institute Dresden of Helmholtz Zentrum München at the University Clinic Carl Gustav Carus of Technische Universität Dresden, Helmholtz Zentrum München, 85764 München-Neuherberg, Germany.|German Center for Diabetes Research, 85764 München-Neuherberg, Germany.|DFG-Center for Regenerative Therapies Dresden, Faculty of Medicine, University Clinic Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
Helena
H
Chmelova
Department of GI, Thoracic and Vascular Surgery, University Clinic Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
Jürgen
J
Weitz
Institute of Molecular Animal Breeding and Biotechnology, Ludwig-Maximilians-Universität München, 81377 Oberschleißheim, Germany.
Andrea
A
Bähr
Institute of Molecular Animal Breeding and Biotechnology, Ludwig-Maximilians-Universität München, 81377 Oberschleißheim, Germany.
Nikolai
N
Klymiuk
Paul Langerhans Institute Dresden of Helmholtz Zentrum München at the University Clinic Carl Gustav Carus of Technische Universität Dresden, Helmholtz Zentrum München, 85764 München-Neuherberg, Germany.|German Center for Diabetes Research, 85764 München-Neuherberg, Germany.|Department of Medicine III, University Clinic Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
Anja
A
Steffen
Paul Langerhans Institute Dresden of Helmholtz Zentrum München at the University Clinic Carl Gustav Carus of Technische Universität Dresden, Helmholtz Zentrum München, 85764 München-Neuherberg, Germany.|German Center for Diabetes Research, 85764 München-Neuherberg, Germany.|Department of Medicine III, University Clinic Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
Barbara
B
Ludwig
Department of Medicine III, University Clinic Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.|Division of Diabetes and Nutritional Sciences, King's College London, SE19NH London, United Kingdom.
Virginia
V
Kamvissi
German Center for Diabetes Research, 85764 München-Neuherberg, Germany.|Institute of Molecular Animal Breeding and Biotechnology, Ludwig-Maximilians-Universität München, 81377 Oberschleißheim, Germany.
Eckhard
E
Wolf
Paul Langerhans Institute Dresden of Helmholtz Zentrum München at the University Clinic Carl Gustav Carus of Technische Universität Dresden, Helmholtz Zentrum München, 85764 München-Neuherberg, Germany.|German Center for Diabetes Research, 85764 München-Neuherberg, Germany.|Department of Medicine III, University Clinic Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.|Division of Diabetes and Nutritional Sciences, King's College London, SE19NH London, United Kingdom.
Stefan R
SR
Bornstein
Paul Langerhans Institute Dresden of Helmholtz Zentrum München at the University Clinic Carl Gustav Carus of Technische Universität Dresden, Helmholtz Zentrum München, 85764 München-Neuherberg, Germany.|German Center for Diabetes Research, 85764 München-Neuherberg, Germany.|Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
Michele
M
Solimena
Paul Langerhans Institute Dresden of Helmholtz Zentrum München at the University Clinic Carl Gustav Carus of Technische Universität Dresden, Helmholtz Zentrum München, 85764 München-Neuherberg, Germany.|German Center for Diabetes Research, 85764 München-Neuherberg, Germany.|DFG-Center for Regenerative Therapies Dresden, Faculty of Medicine, University Clinic Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
Stephan
S
Speier
D000328:Adult; D000368:Aged; D000818:Animals; D002450:Cell Communication; D005260:Female; D006801:Humans; D050417:Insulin-Secreting Cells / Q000502:physiology*; D007515:Islets of Langerhans / Q000098:blood supply / Q000502:physiology*; D016381:Islets of Langerhans Transplantation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055806:Microvessels / Q000502:physiology*; D008875:Middle Aged; D013552:Swine