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1
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Shang KM, Suzuki T, Kato H, Toyoda T, Tai YC, Komatsu H. Oxygen dynamics and delivery strategies to enhance beta cell replacement therapy. Am J Physiol Cell Physiol 2025; 328:C1667-C1684. [PMID: 40204281 DOI: 10.1152/ajpcell.00984.2024] [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: 12/13/2024] [Revised: 01/06/2025] [Accepted: 04/01/2025] [Indexed: 04/11/2025]
Abstract
Beta cell replacement therapy via pancreatic islet transplantation offers a promising treatment for type 1 diabetes as an alternative to insulin injections. However, posttransplantation oxygenation remains a critical challenge; isolated islets from donors lose vascularity and rely on slow oxygen diffusion for survival until revascularization occurs in the host tissue. This often results in significant hypoxia-induced acute graft loss. Overcoming the oxygenation barrier is crucial for advancing islet transplantation. This review is structured in three sections: the first examines oxygen dynamics in islet transplantation, focusing on factors affecting oxygen supply, including vascularity. It highlights oxygen dynamics specific to both transplant sites and islet grafts, with particular attention to extrahepatic sites such as subcutaneous tissue. The second section explores current oxygen delivery strategies, categorized into two main approaches: augmenting oxygen supply and enhancing effective oxygen solubility. The final section addresses key challenges, such as the lack of a clearly defined oxygen threshold for islet survival and the limited precision in measuring oxygen levels within small islet constructs. Recent advancements addressing these challenges are introduced. By deepening the understanding of oxygen dynamics and identifying current obstacles, this review aims to guide the development of innovative strategies for future research and clinical applications. These advancements are anticipated to enhance transplantation outcomes and bring us closer to a cure for type 1 diabetes.
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Affiliation(s)
- Kuang-Ming Shang
- Department of Medical Engineering, California Institute of Technology, Pasadena, California, United States
| | - Tomoharu Suzuki
- Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan
| | - Hiroyuki Kato
- Division of Transplant Surgery, Department of Surgery, University of California San Francisco, San Francisco, California, United States
| | - Taro Toyoda
- Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan
| | - Yu-Chong Tai
- Department of Medical Engineering, California Institute of Technology, Pasadena, California, United States
| | - Hirotake Komatsu
- Division of Transplant Surgery, Department of Surgery, University of California San Francisco, San Francisco, California, United States
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2
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Geng A, Yuan S, Yu QC, Zeng YA. The role of endothelial cells in pancreatic islet development, transplantation and culture. Front Cell Dev Biol 2025; 13:1558137. [PMID: 40330424 PMCID: PMC12052768 DOI: 10.3389/fcell.2025.1558137] [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: 01/09/2025] [Accepted: 03/03/2025] [Indexed: 05/08/2025] Open
Abstract
Endothelial cells (ECs) play pivotal roles in the development and maintenance of tissue homeostasis. During development, vasculature actively involves in organ morphogenesis and functional maturation, through the secretion of angiocrine factors and extracellular matrix components. Islets of Langerhans, essential functional units of glucose homeostasis, are embedded in a dense endothelial capillary network. Islet vasculature not only supplies nutrients and oxygen to endocrine cells but also facilitate the rapid delivery of pancreatic hormones to target tissues, thereby ensuring precise glucose regulation. Diabetes mellitus is a major disease burden and is caused by islet dysfunction or depletion, often accompanied by vessel loss and dysregulation. Therefore, elucidating the regulatory mechanisms of ECs within islets hold profound implications for diabetes therapy. This review provides an overview of recent research advancements on the functional roles of ECs in islet biology, transplantation, and in vitro islet organoid culture.
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Affiliation(s)
- Ajun Geng
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China
- New Cornerstone Science Laboratory, Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Shubo Yuan
- New Cornerstone Science Laboratory, Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Qing Cissy Yu
- New Cornerstone Science Laboratory, Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Yi Arial Zeng
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China
- New Cornerstone Science Laboratory, Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
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3
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Honarpisheh M, Lei Y, Follenzi A, Cucci A, Olgasi C, Berishvili E, Lebreton F, Bellofatto K, Piemonti L, Citro A, Campo F, Pignatelli C, Thaunat O, Kemter E, Kraetzl M, Wolf E, Seissler J, Wolf-van Buerck L, VANGUARD Consortium. Spheroids Composed of Reaggregated Neonatal Porcine Islets and Human Endothelial Cells Accelerate Development of Normoglycemia in Diabetic Mice. Cells 2025; 14:366. [PMID: 40072094 PMCID: PMC11898817 DOI: 10.3390/cells14050366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 01/13/2025] [Accepted: 02/28/2025] [Indexed: 03/15/2025] Open
Abstract
The engraftment of transplanted islets depends on the rapid establishment of a novel vascular network. The present study evaluated the effects of cord blood-derived blood outgrowth endothelial cells (BOECs) on the viability of neonatal porcine islets (NPIs) and the post-transplant outcome of grafted NPIs. Dispersed NPIs and human BOECs were reaggregated on microwell cell culture plates and tested for their anti-apoptotic and pro-angiogenic capacity by qRT-PCR and immunohistochemistry. The in vivo functionality was analyzed after transplantation into diabetic NOD-SCID IL2rγ-/- (NSG) mice. The spheroids, which contained reaggregated neonatal porcine islet cells (REPIs) and BOECs, exhibited enhanced viability and a significantly elevated gene expression of VEGFA, angiopoetin-1, heme oxygenase-1, and TNFAIP3 (A20) in vitro. The development of normoglycemia was significantly faster in animals transplanted with spheroids in comparison to the only REPI group (median 51.5 days versus 60 days) (p < 0.05). Furthermore, intragraft vascular density was substantially increased (p < 0.01). The co-transplantation of prevascularized REPI-BOEC spheroids resulted in superior angiogenesis and accelerated in vivo function. These findings may provide a novel tool to enhance the efficacy of porcine islet xenotransplantation.
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Affiliation(s)
- Mohsen Honarpisheh
- Medizinische Klinik und Poliklinik IV, Diabetes Zentrum, Klinikum der Universität München, LMU Munich, 80336 Munich, Germany; (M.H.); (Y.L.); (J.S.)
| | - Yutian Lei
- Medizinische Klinik und Poliklinik IV, Diabetes Zentrum, Klinikum der Universität München, LMU Munich, 80336 Munich, Germany; (M.H.); (Y.L.); (J.S.)
| | - Antonia Follenzi
- Department of Health Sciences, University of Piemonte Orientale, 28100 Novara, Italy; (A.F.); (A.C.)
| | - Alessia Cucci
- Department of Health Sciences, University of Piemonte Orientale, 28100 Novara, Italy; (A.F.); (A.C.)
| | - Cristina Olgasi
- Department of Translational Medicine, University of Piemonte Orientale, 28100 Novara, Italy;
| | - Ekaterine Berishvili
- Tissue Engineering and Organ Regeneration Lab, University of Geneva, Department of Surgery, CH-1211 Geneva, Switzerland; (E.B.); (F.L.); (K.B.)
| | - Fanny Lebreton
- Tissue Engineering and Organ Regeneration Lab, University of Geneva, Department of Surgery, CH-1211 Geneva, Switzerland; (E.B.); (F.L.); (K.B.)
| | - Kevin Bellofatto
- Tissue Engineering and Organ Regeneration Lab, University of Geneva, Department of Surgery, CH-1211 Geneva, Switzerland; (E.B.); (F.L.); (K.B.)
| | - Lorenzo Piemonti
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, 20132 Milan, Italy; (L.P.); (A.C.); (C.P.)
- Department of Endocrinology, Università Vita-Salute San Raffaele, 20132 Milan, Italy
| | - Antonio Citro
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, 20132 Milan, Italy; (L.P.); (A.C.); (C.P.)
| | - Francesco Campo
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, 20132 Milan, Italy; (L.P.); (A.C.); (C.P.)
- Department of Endocrinology, Università Vita-Salute San Raffaele, 20132 Milan, Italy
| | - Cataldo Pignatelli
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, 20132 Milan, Italy; (L.P.); (A.C.); (C.P.)
| | - Olivier Thaunat
- Centre International de Recherche en Infectiologie, Université Claude Bernard Lyon I, 69364 Lyon, France;
- Department of Nephrology Transplantation and Clinical Immunology, Edouard Herriot Hospital, Hospices Civils de Lyon, 69003 Lyon, France
| | - Elisabeth Kemter
- Molecular Animal Breeding and Biotechnology, Gene Centre and Department of Veterinary Sciences, Ludwig-Maximilians-Universität München, 80539 Munich, Germany; (E.K.); (E.W.)
- German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
| | - Martin Kraetzl
- Molecular Animal Breeding and Biotechnology, Gene Centre and Department of Veterinary Sciences, Ludwig-Maximilians-Universität München, 80539 Munich, Germany; (E.K.); (E.W.)
| | - Eckhard Wolf
- Molecular Animal Breeding and Biotechnology, Gene Centre and Department of Veterinary Sciences, Ludwig-Maximilians-Universität München, 80539 Munich, Germany; (E.K.); (E.W.)
- German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
| | - Jochen Seissler
- Medizinische Klinik und Poliklinik IV, Diabetes Zentrum, Klinikum der Universität München, LMU Munich, 80336 Munich, Germany; (M.H.); (Y.L.); (J.S.)
| | - Lelia Wolf-van Buerck
- Medizinische Klinik und Poliklinik IV, Diabetes Zentrum, Klinikum der Universität München, LMU Munich, 80336 Munich, Germany; (M.H.); (Y.L.); (J.S.)
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Keshi E, Tang P, Lam T, Moosburner S, Haderer L, Reutzel-Selke A, Kloke L, Pratschke J, Sauer IM, Hillebrandt KH. Toward a 3D Printed Perfusable Islet Embedding Structure: Technical Notes and Preliminary Results. Tissue Eng Part C Methods 2023; 29:469-478. [PMID: 37528629 DOI: 10.1089/ten.tec.2023.0045] [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] [Indexed: 08/03/2023] Open
Abstract
To date, islet transplantation to treat type 1 diabetes mellitus remains unsuccessful in long-term follow-up, mainly due to failed engraftment and reconstruction of the islet niche. Alternative approaches, such as islet embedding structures (IESs) based on 3D printing have been developed. However, most of them have been implanted subcutaneously and only a few are intended for direct integration into the vascular system through anastomosis. In this study, we 3D printed a proof-of-concept IES using gelatin methacrylate biocompatible ink. This structure consisted of a branched vascular system surrounding both sides of a central cavity dedicated to islets of Langerhans. Furthermore, we designed a bioreactor optimized for these biological structures. This bioreactor allows seeding and perfusion experiments under sterile and physiological conditions. Preliminary experiments aimed to analyze if the vascular channel could successfully be seeded with mature endothelial cells and the central cavity with rat islets. Subsequently, the structures were used for a humanized model seeding human endothelial progenitor cells (huEPC) within the vascular architecture and human islets co-cultured with huEPC within the central cavity. The constructs were tested for hemocompatibility, suture strength, and anastomosability. The 3D printed IES appeared to be hemocompatible and anastomosable using an alternative cuff anastomosis in a simple ex vivo perfusion model. While rat islets alone could not successfully be embedded within the 3D printed structure for 3 days, human islets co-cultivated with huEPC successfully engrafted within the same time. This result emphasizes the importance of co-culture, nursing cells, and islet niche. In conclusion, we constructed a proof-of-concept 3D printed islet embedding device consisting of a vascular channel that is hemocompatible and perspectively anastomosable to clinical scale blood vessels. However, there are numerous limitations in this model that need to be overcome to transfer this technology to the bedside.
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Affiliation(s)
- Eriselda Keshi
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum, Experimental Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Peter Tang
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum, Experimental Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Tobias Lam
- Berlin Institute of Health (BIH), Berlin, Germany
| | - Simon Moosburner
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum, Experimental Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany
- Cellbricks GmbH, Berlin, Germany
| | - Luna Haderer
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum, Experimental Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany
- Cellbricks GmbH, Berlin, Germany
| | - Anja Reutzel-Selke
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum, Experimental Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Lutz Kloke
- Berlin Institute of Health (BIH), Berlin, Germany
| | - Johann Pratschke
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum, Experimental Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany
- Cluster of Excellence Matters of Activity. Image Space Material funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy-EXC 2025-390648296, Berlin, Germany
| | - Igor Maximilian Sauer
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum, Experimental Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany
- Cluster of Excellence Matters of Activity. Image Space Material funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy-EXC 2025-390648296, Berlin, Germany
| | - Karl Herbert Hillebrandt
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum, Experimental Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany
- Cellbricks GmbH, Berlin, Germany
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5
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Kale A, Rogers NM. No Time to Die-How Islets Meet Their Demise in Transplantation. Cells 2023; 12:cells12050796. [PMID: 36899932 PMCID: PMC10000424 DOI: 10.3390/cells12050796] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 02/27/2023] [Accepted: 03/01/2023] [Indexed: 03/08/2023] Open
Abstract
Islet transplantation represents an effective treatment for patients with type 1 diabetes mellitus (T1DM) and severe hypoglycaemia unawareness, capable of circumventing impaired counterregulatory pathways that no longer provide protection against low blood glucose levels. The additional beneficial effect of normalizing metabolic glycaemic control is the minimisation of further complications related to T1DM and insulin administration. However, patients require allogeneic islets from up to three donors, and the long-term insulin independence is inferior to that achieved with solid organ (whole pancreas) transplantation. This is likely due to the fragility of islets caused by the isolation process, innate immune responses following portal infusion, auto- and allo-immune-mediated destruction and β-cell exhaustion following transplantation. This review covers the specific challenges related to islet vulnerability and dysfunction that affect long-term cell survival following transplantation.
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Affiliation(s)
- Atharva Kale
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, NSW 2145, Australia
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia
| | - Natasha M. Rogers
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, NSW 2145, Australia
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia
- Renal and Transplant Unit, Westmead Hospital, Westmead, NSW 2145, Australia
- Correspondence:
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6
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Transplantation of Endothelial Progenitor Cells: Summary and prospect. Acta Histochem 2023; 125:151990. [PMID: 36587456 DOI: 10.1016/j.acthis.2022.151990] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 12/17/2022] [Accepted: 12/18/2022] [Indexed: 12/31/2022]
Abstract
Endothelial Progenitor Cells (EPCs) are precursor cells of endothelial cells (ECs), which can differentiate into vascular ECs, protect from endothelial dysfunction and tissue ischemia, and reduce vascular hyperplasia. Due to these functions, EPCs are used as a candidate cell source for transplantation strategies. In recent years, a great progress was achieved in EPCs biology research, and EPCs transplantation has become a research hotspot. At present, transplanted EPCs have been used to treat ischemic diseases due to their powerful vasculogenesis and beneficial paracrine effects. Although EPCs transplantation has been proved to play an important role, the clinical application of EPCs still faces many challenges. This review briefly summarized the basic characteristics of EPCs, the process of EPCs transplantation promoting the healing of ischemic tissue, and the ways to improve the efficiency of EPCs transplantation. In addition, the application of EPCs in neurological improvement, cardiovascular and respiratory diseases and the challenges and problems in clinical application of EPCs were also discussed. In the end, the application of EPCs transplantation in regenerative medicine and tissue engineering was discussed.
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7
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Ghezelayagh Z, Zabihi M, Kazemi Ashtiani M, Ghezelayagh Z, Lynn FC, Tahamtani Y. Recapitulating pancreatic cell-cell interactions through bioengineering approaches: the momentous role of non-epithelial cells for diabetes cell therapy. Cell Mol Life Sci 2021; 78:7107-7132. [PMID: 34613423 PMCID: PMC11072828 DOI: 10.1007/s00018-021-03951-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 09/09/2021] [Accepted: 09/23/2021] [Indexed: 12/11/2022]
Abstract
Over the past few years, extensive efforts have been made to generate in-vitro pancreatic micro-tissue, for disease modeling or cell replacement approaches in pancreatic related diseases such as diabetes mellitus. To obtain these goals, a closer look at the diverse cells participating in pancreatic development is necessary. Five major non-epithelial pancreatic (pN-Epi) cell populations namely, pancreatic endothelium, mesothelium, neural crests, pericytes, and stellate cells exist in pancreas throughout its development, and they are hypothesized to be endogenous inducers of the development. In this review, we discuss different pN-Epi cells migrating to and existing within the pancreas and their diverse effects on pancreatic epithelium during organ development mediated via associated signaling pathways, soluble factors or mechanical cell-cell interactions. In-vivo and in-vitro experiments, with a focus on N-Epi cells' impact on pancreas endocrine development, have also been considered. Pluripotent stem cell technology and multicellular three-dimensional organoids as new approaches to generate pancreatic micro-tissues have also been discussed. Main challenges for reaching a detailed understanding of the role of pN-Epi cells in pancreas development in utilizing for in-vitro recapitulation have been summarized. Finally, various novel and innovative large-scale bioengineering approaches which may help to recapitulate cell-cell interactions and are crucial for generation of large-scale in-vitro multicellular pancreatic micro-tissues, are discussed.
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Affiliation(s)
- Zahra Ghezelayagh
- Department of Developmental Biology, Faculty of Basic Sciences and Advanced Technologies in Biology, University of Science and Culture, ACECR, Tehran, Iran
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Mahsa Zabihi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Department of Genetics, Faculty of Basic Sciences and Advanced Technologies in Biology, University of Science and Culture, ACECR, Tehran, Iran
| | - Mohammad Kazemi Ashtiani
- Department of Cell Engineering, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Zeinab Ghezelayagh
- Department of Developmental Biology, Faculty of Basic Sciences and Advanced Technologies in Biology, University of Science and Culture, ACECR, Tehran, Iran
- Department of Embryology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Francis C Lynn
- Diabetes Research Group, BC Children's Hospital Research Institute, Vancouver, BC, Canada
- Department of Surgery and School of Biomedical Engineering , University of British Columbia, Vancouver, BC, Canada
| | - Yaser Tahamtani
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
- Reproductive Epidemiology Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran.
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8
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Li C, Lin L, Zhang L, Xu R, Chen X, Ji J, Li Y. Long noncoding RNA p21 enhances autophagy to alleviate endothelial progenitor cells damage and promote endothelial repair in hypertension through SESN2/AMPK/TSC2 pathway. Pharmacol Res 2021; 173:105920. [PMID: 34601081 DOI: 10.1016/j.phrs.2021.105920] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 09/22/2021] [Accepted: 09/28/2021] [Indexed: 12/11/2022]
Abstract
Vascular damage of hypertension has been the focus of hypertension treatment, and endothelial progenitor cells (EPCs) play an important role in the repair of vascular endothelial damage. Functional damage and decreased number of EPCs are observed in the peripheral circulation of hypertensive patients, but its mechanism is not yet elucidated. Here, we show that the number of EPCs in hypertensive patients is significantly lower than that of normal population, and the cell function decreases with a higher proportion of EPCs at later stages. A decrease in autophagy is responsible for the senescence and damage of EPCs induced by AngII. Moreover, lncRNA-p21 plays a critical regulator role in EPCs' senescence and dysfunction. Furthermore, lncRNA-p21 activates SESN2/AMPK/TSC2 pathway by promoting the transcriptional activity of p53 and enhances autophagy to protect against AngII-induced EPC damage. The data provide evidence that a reversal of decreased autophagy serves as the protective mechanism of EPC injury in hypertensive patients, and lncRNA-p21 is a new therapeutic target for vascular endothelial repair in hypertension.
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Affiliation(s)
- Chao Li
- Innovation Research Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China; Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Lin Lin
- Innovation Research Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Lei Zhang
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Ran Xu
- Tianqiao District People's Hospital, Jinan 250031, China
| | - Xiaoqing Chen
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Jingkang Ji
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Yunlun Li
- Innovation Research Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China; Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250000, China.
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9
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Akolpoglu MB, Inceoglu Y, Bozuyuk U, Sousa AR, Oliveira MB, Mano JF, Kizilel S. Recent advances in the design of implantable insulin secreting heterocellular islet organoids. Biomaterials 2020; 269:120627. [PMID: 33401104 DOI: 10.1016/j.biomaterials.2020.120627] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 12/14/2020] [Accepted: 12/18/2020] [Indexed: 12/11/2022]
Abstract
Islet transplantation has proved one of the most remarkable transmissions from an experimental curiosity into a routine clinical application for the treatment of type I diabetes (T1D). Current efforts for taking this technology one-step further are now focusing on overcoming islet donor shortage, engraftment, prolonged islet availability, post-transplant vascularization, and coming up with new strategies to eliminate lifelong immunosuppression. To this end, insulin secreting 3D cell clusters composed of different types of cells, also referred as heterocellular islet organoids, spheroids, or pseudoislets, have been engineered to overcome the challenges encountered by the current islet transplantation protocols. β-cells or native islets are accompanied by helper cells, also referred to as accessory cells, to generate a cell cluster that is not only able to accurately secrete insulin in response to glucose, but also superior in terms of other key features (e.g. maintaining a vasculature, longer durability in vivo and not necessitating immunosuppression after transplantation). Over the past decade, numerous 3D cell culture techniques have been integrated to create an engineered heterocellular islet organoid that addresses current obstacles. Here, we first discuss the different cell types used to prepare heterocellular organoids for islet transplantation and their contribution to the organoids design. We then introduce various cell culture techniques that are incorporated to prepare a fully functional and insulin secreting organoids with select features. Finally, we discuss the challenges and present a future outlook for improving clinical outcomes of islet transplantation.
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Affiliation(s)
- M Birgul Akolpoglu
- Chemical and Biological Engineering, Koc University, Sariyer, 34450, Istanbul, Turkey
| | - Yasemin Inceoglu
- Chemical and Biological Engineering, Koc University, Sariyer, 34450, Istanbul, Turkey
| | - Ugur Bozuyuk
- Chemical and Biological Engineering, Koc University, Sariyer, 34450, Istanbul, Turkey
| | - Ana Rita Sousa
- Department of Chemistry, CICECO - Aveiro Institute of Materials. University of Aveiro. Campus Universitário de Santiago. 3810-193 Aveiro. Portugal
| | - Mariana B Oliveira
- Department of Chemistry, CICECO - Aveiro Institute of Materials. University of Aveiro. Campus Universitário de Santiago. 3810-193 Aveiro. Portugal.
| | - João F Mano
- Department of Chemistry, CICECO - Aveiro Institute of Materials. University of Aveiro. Campus Universitário de Santiago. 3810-193 Aveiro. Portugal
| | - Seda Kizilel
- Chemical and Biological Engineering, Koc University, Sariyer, 34450, Istanbul, Turkey.
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10
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Menger MM, Nalbach L, Roma LP, Körbel C, Wrublewsky S, Glanemann M, Laschke MW, Menger MD, Ampofo E. Erythropoietin accelerates the revascularization of transplanted pancreatic islets. Br J Pharmacol 2020; 177:1651-1665. [PMID: 31721150 DOI: 10.1111/bph.14925] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 10/30/2019] [Accepted: 11/03/2019] [Indexed: 01/31/2023] Open
Abstract
BACKGROUND AND PURPOSE Pancreatic islet transplantation is a promising therapeutic approach for Type 1 diabetes. A major prerequisite for the survival of grafted islets is a rapid revascularization after transplantation. Erythropoietin (EPO), the primary regulator of erythropoiesis, has been shown to promote angiogenesis. Therefore, we investigated in this study whether EPO improves the revascularization of transplanted islets. EXPERIMENTAL APPROACH Islets from FVB/N mice were transplanted into dorsal skinfold chambers of recipient animals, which were daily treated with an intraperitoneal injection of EPO (500 IU·kg-1 ) or vehicle (control) throughout an observation period of 14 days. In a second set of experiments, animals were only pretreated with EPO over a 6-day period prior to islet transplantation. The revascularization of the grafts was assessed by repetitive intravital fluorescence microscopy and immunohistochemistry. In addition, a streptozotocin-induced diabetic mouse model was used to study the effect of EPO-pretreatment on the endocrine function of the grafts. KEY RESULTS EPO treatment slightly accelerated the revascularization of the islet grafts. This effect was markedly more pronounced in EPO-pretreated animals, resulting in significantly higher numbers of engrafted islets and an improved perfusion of endocrine tissue without affecting systemic haematocrit levels when compared with controls. Moreover, EPO-pretreatment significantly accelerated the recovery of normoglycaemia in diabetic mice after islet transplantation. CONCLUSION AND IMPLICATIONS These findings demonstrate that, particularly, short-term EPO-pretreatment represents a promising therapeutic approach to improve the outcome of islet transplantation, without an increased risk of thromboembolic events.
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Affiliation(s)
- Maximilian M Menger
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany
| | - Lisa Nalbach
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany
| | - Leticia P Roma
- Biophysics Department, Center for Human and Molecular Biology, Saarland University, Homburg/Saar, Germany
| | - Christina Körbel
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany
| | - Selina Wrublewsky
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany
| | - Matthias Glanemann
- Department for General, Visceral, Vascular and Pediatric Surgery, Saarland University, Homburg/Saar, Germany
| | - Matthias W Laschke
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany
| | - Michael D Menger
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany
| | - Emmanuel Ampofo
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany
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11
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Vlahos AE, Kinney SM, Kingston BR, Keshavjee S, Won SY, Martyts A, Chan WC, Sefton MV. Endothelialized collagen based pseudo-islets enables tuneable subcutaneous diabetes therapy. Biomaterials 2020; 232:119710. [DOI: 10.1016/j.biomaterials.2019.119710] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 12/13/2019] [Accepted: 12/18/2019] [Indexed: 10/25/2022]
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12
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Lin L, Zhang L, Li XT, Ji JK, Chen XQ, Li YL, Li C. Rhynchophylline Attenuates Senescence of Endothelial Progenitor Cells by Enhancing Autophagy. Front Pharmacol 2020; 10:1617. [PMID: 32047439 PMCID: PMC6997466 DOI: 10.3389/fphar.2019.01617] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Accepted: 12/11/2019] [Indexed: 12/25/2022] Open
Abstract
The increase of blood pressure accelerates endothelial progenitor cells (EPCs) senescence, hence a significant reduction in the number of EPCs is common in patients with hypertension. Autophagy is a defense and stress regulation mechanism to assist cell homeostasis and organelle renewal. A growing number of studies have found that autophagy has a positive role in repairing vascular injury, but the potential mechanism between autophagy and senescence of EPCs induced by hypertension has rarely been studied. Therefore, in this study, we aim to explore the relationship between senescence and autophagy, and investigate the protective effect of rhynchophylline (Rhy) on EPCs. In angiotensin II (Ang II)-treated EPCs, enhancing autophagy through rapamycin mitigated Ang II-induced cell senescence, on the contrary, 3-methyladenine aggravated the senescence by weakening autophagy. Similarly, Rhy attenuated senescence and improved cellular function by rescuing the impaired autophagy in Ang II-treated EPCs. Furthermore, we found that Rhy promoted autophagy by activating AMP-activated protein kinase (AMPK) signaling pathway. Our results show that enhanced autophagy attenuates EPCs senescence and Rhy rescues autophagy impairment to protect EPCs against Ang II injury.
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Affiliation(s)
- Lin Lin
- Institute of Traditional Chinese Medicine Innovation, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Lei Zhang
- The First Faculty of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xin-Tong Li
- Institute of Education and Psychological Sciences, University of Jinan, Jinan, China
| | - Jing-Kang Ji
- Faculty of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xiao-Qing Chen
- Faculty of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yun-Lun Li
- Experiment Center, Shandong University of Traditional Chinese Medicine, Jinan, China.,Department of Cardiovascular, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Chao Li
- Institute of Traditional Chinese Medicine Innovation, Shandong University of Traditional Chinese Medicine, Jinan, China.,Experiment Center, Shandong University of Traditional Chinese Medicine, Jinan, China
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13
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Mathur T, Singh KA, R Pandian NK, Tsai SH, Hein TW, Gaharwar AK, Flanagan JM, Jain A. Organ-on-chips made of blood: endothelial progenitor cells from blood reconstitute vascular thromboinflammation in vessel-chips. LAB ON A CHIP 2019; 19:2500-2511. [PMID: 31246211 PMCID: PMC6650325 DOI: 10.1039/c9lc00469f] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2023]
Abstract
Development of therapeutic approaches to treat vascular dysfunction and thrombosis at disease- and patient-specific levels is an exciting proposed direction in biomedical research. However, this cannot be achieved with animal preclinical models alone, and new in vitro techniques, like human organ-on-chips, currently lack inclusion of easily obtainable and phenotypically-similar human cell sources. Therefore, there is an unmet need to identify sources of patient primary cells and apply them in organ-on-chips to increase personalized mechanistic understanding of diseases and to assess drugs. In this study, we provide a proof-of-feasibility of utilizing blood outgrowth endothelial cells (BOECs) as a disease-specific primary cell source to analyze vascular inflammation and thrombosis in vascular organ-chips or "vessel-chips". These blood-derived BOECs express several factors that confirm their endothelial identity. The vessel-chips are cultured with BOECs from healthy or diabetic patients and form an intact 3D endothelial lumen. Inflammation of the BOEC endothelium with exogenous cytokines reveals vascular dysfunction and thrombosis in vitro similar to in vivo observations. Interestingly, our study with vessel-chips also reveals that unstimulated BOECs of type 1 diabetic pigs show phenotypic behavior of the disease - high vascular dysfunction and thrombogenicity - when compared to control BOECs or normal primary endothelial cells. These results demonstrate the potential of organ-on-chips made from autologous endothelial cells obtained from blood in modeling vascular pathologies and therapeutic outcomes at a disease and patient-specific level.
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Affiliation(s)
- Tanmay Mathur
- Department of Biomedical Engineering, Texas A&M University, 101 Bizzell St, College Station, TX 77843, USA.
| | - Kanwar Abhay Singh
- Department of Biomedical Engineering, Texas A&M University, 101 Bizzell St, College Station, TX 77843, USA.
| | - Navaneeth K R Pandian
- Department of Biomedical Engineering, Texas A&M University, 101 Bizzell St, College Station, TX 77843, USA.
| | - Shu-Huai Tsai
- Department of Medical Physiology, Texas A&M University System Health Science Center, Temple, USA
| | - Travis W Hein
- Department of Medical Physiology, Texas A&M University System Health Science Center, Temple, USA
| | - Akhilesh K Gaharwar
- Department of Biomedical Engineering, Texas A&M University, 101 Bizzell St, College Station, TX 77843, USA. and Center for Remote Health Technologies and Systems, Texas A&M University, College Station, USA and Department of Materials Science and Engineering, Texas A&M University, College Station, USA
| | - Jonathan M Flanagan
- Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, USA
| | - Abhishek Jain
- Department of Biomedical Engineering, Texas A&M University, 101 Bizzell St, College Station, TX 77843, USA.
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14
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Abstract
PURPOSE OF REVIEW Pancreatic islet cell transplantation is currently the only curative cell therapy for type 1 diabetes mellitus. However, its potential to treat many more patients is limited by several challenges. The emergence of 3D bioprinting technology from recent advances in 3D printing, biomaterials, and cell biology has provided the means to overcome these challenges. RECENT FINDINGS 3D bioprinting allows for the precise fabrication of complex 3D architectures containing spatially distributed cells, biomaterials (bioink), and bioactive factors. Different strategies to capitalize on this ability have been investigated for the 3D bioprinting of pancreatic islets. In particular, with co-axial bioprinting technology, the co-printability of islets with supporting cells such as endothelial progenitor cells and regulatory T cells, which have been shown to accelerate revascularization of islets and improve the outcome of various transplantations, respectively, has been achieved. 3D bioprinting of islets for generation of an artificial pancreas is a newly emerging field of study with a vast potential to improve islet transplantation.
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Affiliation(s)
- Juewan Kim
- Department of Molecular & Cellular Biology, School of Biological Sciences, The University of Adelaide, Adelaide, South Australia, 5005, Australia
| | - Kyungwon Kang
- Discipline of Medicine, School of Medicine, The University of Adelaide, Adelaide, South Australia, 5000, Australia
| | - Christopher J Drogemuller
- Discipline of Medicine, School of Medicine, The University of Adelaide, Adelaide, South Australia, 5000, Australia
- Central Northern Adelaide Renal and Transplantation Service (CNARTS), The Royal Adelaide Hospital, Adelaide, South Australia, 5000, Australia
| | - Gordon G Wallace
- Intelligent Polymer Research Institute, ARC Centre of Excellence for Electromaterial Science, University of Wollongong, Wollongong, New South Wales, 2522, Australia
| | - P Toby Coates
- Discipline of Medicine, School of Medicine, The University of Adelaide, Adelaide, South Australia, 5000, Australia.
- Central Northern Adelaide Renal and Transplantation Service (CNARTS), The Royal Adelaide Hospital, Adelaide, South Australia, 5000, Australia.
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15
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Liu X, Carter SD, Renes MJ, Kim J, Rojas‐Canales DM, Penko D, Angus C, Beirne S, Drogemuller CJ, Yue Z, Coates PT, Wallace GG. Development of a Coaxial 3D Printing Platform for Biofabrication of Implantable Islet-Containing Constructs. Adv Healthc Mater 2019; 8:e1801181. [PMID: 30633852 DOI: 10.1002/adhm.201801181] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 12/19/2018] [Indexed: 12/19/2022]
Abstract
Over the last two decades, pancreatic islet transplantations have become a promising treatment for Type I diabetes. However, although providing a consistent and sustained exogenous insulin supply, there are a number of limitations hindering the widespread application of this approach. These include the lack of sufficient vasculature and allogeneic immune attacks after transplantation, which both contribute to poor cell survival rates. Here, these issues are addressed using a biofabrication approach. An alginate/gelatin-based bioink formulation is optimized for islet and islet-related cell encapsulation and 3D printing. In addition, a custom-designed coaxial printer is developed for 3D printing of multicellular islet-containing constructs. In this work, the ability to fabricate 3D constructs with precise control over the distribution of multiple cell types is demonstrated. In addition, it is shown that the viability of pancreatic islets is well maintained after the 3D printing process. Taken together, these results represent the first step toward an improved vehicle for islet transplantation and a potential novel strategy to treat Type I diabetes.
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Affiliation(s)
- Xiao Liu
- Intelligent Polymer Research Institute ARC Centre of Excellence for Electromaterials Science University of Wollongong Wollongong 2522 Australia
| | - Sarah‐Sophia D. Carter
- Intelligent Polymer Research Institute ARC Centre of Excellence for Electromaterials Science University of Wollongong Wollongong 2522 Australia
- Department of Orthopedics University Medical Center Utrecht Utrecht 3508 GA The Netherlands
| | - Max Jurie Renes
- Intelligent Polymer Research Institute ARC Centre of Excellence for Electromaterials Science University of Wollongong Wollongong 2522 Australia
- Department of Orthopedics University Medical Center Utrecht Utrecht 3508 GA The Netherlands
| | - Juewan Kim
- Department of Molecular & Cellular Biology School of Biological Sciences University of Adelaide Adelaide 5005 Australia
| | - Darling Macarena Rojas‐Canales
- Department of Medicine University of Adelaide Adelaide 5000 Australia
- Central Northern Adelaide Renal and Transplantation Service Royal Adelaide Hospital Adelaide 5000 Australia
| | - Daniella Penko
- Department of Medicine University of Adelaide Adelaide 5000 Australia
- Central Northern Adelaide Renal and Transplantation Service Royal Adelaide Hospital Adelaide 5000 Australia
| | - Cameron Angus
- Intelligent Polymer Research Institute ARC Centre of Excellence for Electromaterials Science University of Wollongong Wollongong 2522 Australia
| | - Stephen Beirne
- Intelligent Polymer Research Institute ARC Centre of Excellence for Electromaterials Science University of Wollongong Wollongong 2522 Australia
| | - Christopher John Drogemuller
- Department of Medicine University of Adelaide Adelaide 5000 Australia
- Central Northern Adelaide Renal and Transplantation Service Royal Adelaide Hospital Adelaide 5000 Australia
| | - Zhilian Yue
- Intelligent Polymer Research Institute ARC Centre of Excellence for Electromaterials Science University of Wollongong Wollongong 2522 Australia
| | - Patrick T. Coates
- Department of Medicine University of Adelaide Adelaide 5000 Australia
- Central Northern Adelaide Renal and Transplantation Service Royal Adelaide Hospital Adelaide 5000 Australia
| | - Gordon G. Wallace
- Intelligent Polymer Research Institute ARC Centre of Excellence for Electromaterials Science University of Wollongong Wollongong 2522 Australia
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16
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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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17
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Perez-Basterrechea M, Esteban MM, Vega JA, Obaya AJ. Tissue-engineering approaches in pancreatic islet transplantation. Biotechnol Bioeng 2018; 115:3009-3029. [PMID: 30144310 DOI: 10.1002/bit.26821] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 08/08/2018] [Accepted: 08/14/2018] [Indexed: 12/15/2022]
Abstract
Pancreatic islet transplantation is a promising alternative to whole-pancreas transplantation as a treatment of type 1 diabetes mellitus. This technique has been extensively developed during the past few years, with the main purpose of minimizing the complications arising from the standard protocols used in organ transplantation. By using a variety of strategies used in tissue engineering and regenerative medicine, pancreatic islets have been successfully introduced in host patients with different outcomes in terms of islet survival and functionality, as well as the desired normoglycemic control. Here, we describe and discuss those strategies to transplant islets together with different scaffolds, in combination with various cell types and diffusible factors, and always with the aim of reducing host immune response and achieving islet survival, regardless of the site of transplantation.
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Affiliation(s)
- Marcos Perez-Basterrechea
- Unidad de Terapia Celular y Medicina Regenerativa, Servicio de Hematología y Hemoterapia, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain.,Plataforma de Terapias Avanzadas, Instituto de Investigación Biosanitaria del Principado de Asturias (ISPA), Oviedo, Spain
| | - Manuel M Esteban
- Departamento de Biología Funcional, Universidad de Oviedo, Oviedo, Spain
| | - Jose A Vega
- Departamento de Morfología y Biología Celular, Universidad de Oviedo, Oviedo, Spain.,Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Santiago, Chile
| | - Alvaro J Obaya
- Departamento de Biología Funcional, Universidad de Oviedo, Oviedo, Spain
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18
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Grapensparr L, Christoffersson G, Carlsson PO. Bioengineering with Endothelial Progenitor Cells Improves the Vascular Engraftment of Transplanted Human Islets. Cell Transplant 2018; 27:948-956. [PMID: 29862837 PMCID: PMC6050913 DOI: 10.1177/0963689718759474] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Revised: 01/18/2018] [Accepted: 01/22/2018] [Indexed: 11/16/2022] Open
Abstract
Pancreatic islets isolated for transplantation are disconnected from their vascular supply and need to establish a new functional network posttransplantation. Due to poor revascularization, prevailing hypoxia with correlating increased apoptosis rates in experimental studies can be observed for months posttransplantation. Endothelial progenitor cells (EPCs) are bone marrow-derived cells that promote neovascularization. The present study tested the hypothesis that EPCs, isolated from human umbilical cord blood, could be coated to human islet surfaces and be used to promote islet vascular engraftment. Control or EPC bioengineered human islets were transplanted into the renal subcapsular space of nonobese diabetic/severe combined immunodeficiency mice. Four weeks posttransplantation, graft blood perfusion and oxygen tension were measured using laser Doppler flowmetry and Clark microelectrodes, respectively. Vessel functionality was also assessed by in vivo confocal imaging. The vascular density and the respective contribution of human and recipient endothelium were assessed immunohistochemically by staining for human and mouse CD31. Islet grafts with EPCs had substantially higher blood perfusion and oxygen tension than control transplants. Furthermore, analysis of the vascular network of the grafts revealed that grafts containing EPC bioengineered islets had a superior vascular density compared with control grafts, with functional chimeric blood vessels. We conclude that a simple procedure of surface coating with EPCs provides a possibility to improve the vascular engraftment of transplanted human islets. Established protocols are also easily applicable for intraportal islet transplantation in order to obtain a novel directed cellular therapy at the site of implantation in the liver.
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Affiliation(s)
- Liza Grapensparr
- Department of Medical Cell Biology, Uppsala University, Uppsala,
Sweden
| | | | - Per-Ola Carlsson
- Department of Medical Cell Biology, Uppsala University, Uppsala,
Sweden
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
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19
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Modular tissue engineering for the vascularization of subcutaneously transplanted pancreatic islets. Proc Natl Acad Sci U S A 2017; 114:9337-9342. [PMID: 28814629 DOI: 10.1073/pnas.1619216114] [Citation(s) in RCA: 97] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
The transplantation of pancreatic islets, following the Edmonton Protocol, is a promising treatment for type I diabetics. However, the need for multiple donors to achieve insulin independence reflects the large loss of islets that occurs when islets are infused into the portal vein. Finding a less hostile transplantation site that is both minimally invasive and able to support a large transplant volume is necessary to advance this approach. Although the s.c. site satisfies both these criteria, the site is poorly vascularized, precluding its utility. To address this problem, we demonstrate that modular tissue engineering results in an s.c. vascularized bed that enables the transplantation of pancreatic islets. In streptozotocin-induced diabetic SCID/beige mice, the injection of 750 rat islet equivalents embedded in endothelialized collagen modules was sufficient to restore and maintain normoglycemia for 21 days; the same number of free islets was unable to affect glucose levels. Furthermore, using CLARITY, we showed that embedded islets became revascularized and integrated with the host's vasculature, a feature not seen in other s.c. STUDIES Collagen-embedded islets drove a small (albeit not significant) shift toward a proangiogenic CD206+MHCII-(M2-like) macrophage response, which was a feature of module-associated vascularization. While these results open the potential for using s.c. islet delivery as a treatment option for type I diabetes, the more immediate benefit may be for the exploration of revascularized islet biology.
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20
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Mahou R, Zhang DK, Vlahos AE, Sefton MV. Injectable and inherently vascularizing semi-interpenetrating polymer network for delivering cells to the subcutaneous space. Biomaterials 2017; 131:27-35. [PMID: 28371625 DOI: 10.1016/j.biomaterials.2017.03.032] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Revised: 03/20/2017] [Accepted: 03/21/2017] [Indexed: 12/22/2022]
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21
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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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22
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Barba-Gutierrez DA, Daneri-Navarro A, Villagomez-Mendez JJA, Kanamune J, Robles-Murillo AK, Sanchez-Enriquez S, Villafan-Bernal JR, Rivas-Carrillo JD. Facilitated Engraftment of Isolated Islets Coated With Expanded Vascular Endothelial Cells for Islet Transplantation. Transplant Proc 2016; 48:669-72. [PMID: 27110026 DOI: 10.1016/j.transproceed.2016.02.036] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Diabetes is complex disease, which involves primary metabolic changes followed by immunological and vascular pathophysiological adjustments. However, it is mostly characterized by an unbalanced decreased number of the β-cells unable to maintain the metabolic requirements and failure to further regenerate newly functional pancreatic islets. The objective of this study was to analyze the properties of the endothelial cells to facilitate the islet cells engraftment after islet transplantation. METHODS We devised a co-cultured engineer system to coat isolated islets with vascular endothelial cells. To assess the cell integration of cell-engineered islets, we stained them for endothelial marker CD31 and nuclei counterstained with DAPI dye. We comparatively performed islet transplantations into streptozotocin-induced diabetic mice and recovered the islet grafts for morphometric analyses on days 3, 7, 10, and 30. Blood glucose levels were measured continuously after islet transplantation to monitor the functional engraftment and capacity to achieve metabolic control. RESULTS Cell-engineered islets showed a well-defined rounded shape after co-culture when compared with native isolated islets. Furthermore, the number of CD31-positive cells layered on the islet surface showed a direct proportion with engraftment capacities and less TUNEL-positive cells on days 3 and 7 after transplantation. CONCLUSIONS We observed that vascular endothelial cells could be functional integrated into isolated islets. We also found that islets that are coated with vascular endothelial cells increased their capacity to engraft. These findings indicate that islets coated with endothelial cells have a greater capacity of engraftment and thus establish a definitely vascular network to support the metabolic requirements.
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Affiliation(s)
- D Alonso Barba-Gutierrez
- Department of Physiology, Laboratory of Immunology, Tissue Engineering and Transplant, University Center for Health Sciences, University of Guadalajara, Mexico
| | - A Daneri-Navarro
- Department of Physiology, Laboratory of Immunology, Tissue Engineering and Transplant, University Center for Health Sciences, University of Guadalajara, Mexico
| | - J Jesus Alejandro Villagomez-Mendez
- Department of Physiology, Laboratory of Immunology, Tissue Engineering and Transplant, University Center for Health Sciences, University of Guadalajara, Mexico
| | - J Kanamune
- Department of Organ Reconstruction, Field of Clinical Application, Institute for Frontier Medical Sciences, Kyoto University, Japan
| | | | - S Sanchez-Enriquez
- Department of Molecular Biology and Genomics, University Center for Health Sciences, University of Guadalajara, Mexico
| | - J Rafael Villafan-Bernal
- Department of Surgery, Center of Health Sciences, Autonomous University of Aguascalientes, Mexico
| | - J D Rivas-Carrillo
- Department of Physiology, Laboratory of Immunology, Tissue Engineering and Transplant, University Center for Health Sciences, University of Guadalajara, Mexico.
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23
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Lu J, Xia Q, Zhou Q. How to make insulin-producing pancreatic β cells for diabetes treatment. SCIENCE CHINA-LIFE SCIENCES 2016; 60:239-248. [DOI: 10.1007/s11427-016-0211-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/24/2016] [Accepted: 09/20/2016] [Indexed: 12/21/2022]
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24
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Qin G, Chen Y, Li H, Xu S, Li Y, Sun J, Rao W, Chen C, Du M, He K, Ye Y. Melittin inhibits tumor angiogenesis modulated by endothelial progenitor cells associated with the SDF-1α/CXCR4 signaling pathway in a UMR-106 osteosarcoma xenograft mouse model. Mol Med Rep 2016; 14:57-68. [PMID: 27177128 PMCID: PMC4918564 DOI: 10.3892/mmr.2016.5215] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Accepted: 01/29/2016] [Indexed: 12/31/2022] Open
Abstract
Endothelial progenitor cells (EPCs) are important in tumor angiogenesis. Stromal cell-derived factor-1α (SDF-1α) and its receptor C-X-C chemokine receptor type 4 (CXCR4) are key in stem cell homing. Melittin, a component of bee venom, exerts antitumor activity, however, the underlying mechanisms remain to be elucidated. The present study aimed to assess the effects of melittin on EPCs and angiogenesis in a mouse model of osteosarcoma. UMR-106 cells and EPCs were treated with various concentrations of melittin and cell viability was determined using the MTT assay. EPC adherence, migration and tube forming ability were assessed. Furthermore, SDF-1α, AKT and extracellular signal-regulated kinase (ERK)1/2 expression levels were detected by western blotting. Nude mice were inoculated with UMR-106 cells to establish an osteosarcoma mouse model. The tumors were injected with melittin, and its effects were assessed by immunohistochemistry and immunofluorescence. Melittin decreased the viability of UMR-106 cells and EPCs. In addition, it decreased EPC adhesion, migration and tube formation when compared with control and SDF-1α-treated cells. Melittin decreased the expression of phosphorylated (p)-AKT, p-ERK1/2, SDF-1α and CXCR4 in UMR-106 cells and EPCs when compared with the control. The proportions of cluster of differentiation (CD)34/CD133 double-positive cells were 16.4±10.4% in the control, and 7.0±4.4, 2.9±1.2 and 1.3±0.3% in tumors treated with 160, 320 and 640 µg/kg melittin per day, respectively (P<0.05). At 11 days, melittin reduced the tumor size when compared with that of the control (control, 4.8±1.3 cm3; melittin, 3.2±0.6, 2.6±0.5, and 2.0±0.2 cm3 for 160, 320 and 640 µg/kg, respectively; all P<0.05). Melittin decreased the microvessel density, and SDF-1α and CXCR4 protein expression levels in the tumors. Melittin may decrease the effect of osteosarcoma on EPC-mediated angiogenesis, possibly via inhibition of the SDF-1α/CXCR4 signaling pathway.
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Affiliation(s)
- Gang Qin
- Department of Orthopedics, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, Guangxi 530023, P.R. China
| | - Yongqiang Chen
- Department of Orthopedics, Shanghai Municipal Hospital of Traditional Chinese Medicine Affiliated to Shanghai TCM University, Shanghai 200071, P.R. China
| | - Haidong Li
- Department of Orthopedics, Shanghai Municipal Hospital of Traditional Chinese Medicine Affiliated to Shanghai TCM University, Shanghai 200071, P.R. China
| | - Suyang Xu
- Department of Orthopedics, Shanghai Municipal Hospital of Traditional Chinese Medicine Affiliated to Shanghai TCM University, Shanghai 200071, P.R. China
| | - Yumei Li
- Department of Orthopedics, Shanghai Municipal Hospital of Traditional Chinese Medicine Affiliated to Shanghai TCM University, Shanghai 200071, P.R. China
| | - Jian Sun
- Department of Orthopedics, Shanghai Municipal Hospital of Traditional Chinese Medicine Affiliated to Shanghai TCM University, Shanghai 200071, P.R. China
| | - Wu Rao
- Department of Orthopedics, Shanghai Municipal Hospital of Traditional Chinese Medicine Affiliated to Shanghai TCM University, Shanghai 200071, P.R. China
| | - Chaowei Chen
- Department of Orthopedics, Shanghai Municipal Hospital of Traditional Chinese Medicine Affiliated to Shanghai TCM University, Shanghai 200071, P.R. China
| | - Mindong Du
- Department of Orthopedics, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, Guangxi 530023, P.R. China
| | - Kaiyi He
- Department of Orthopedics, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, Guangxi 530023, P.R. China
| | - Yong Ye
- College of Pharmacy, Guangxi Medical University, Nanning, Guangxi 530000, P.R. China
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Del Toro-Arreola A, Robles-Murillo AK, Daneri-Navarro A, Rivas-Carrillo JD. The role of endothelial cells on islet function and revascularization after islet transplantation. Organogenesis 2016; 12:28-32. [PMID: 27002241 DOI: 10.1080/15476278.2016.1165378] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Islet transplantation has become a widely accepted therapeutic option for selected patients with type 1 diabetes mellitus. However, in order to achieve insulin independence a great number of islets are often pooled from 2 to 4 pancreata donors. Mostly, it is due to the massive loss of islets immediately after transplant. The endothelium plays a key role in the function of native islets and during the revascularization process after islet transplantation. However, if a delayed revascularization occurs, even the remaining islets will also undergo to cell death and late graft dysfunction. Therefore, it is essential to understand how the signals are released from endothelial cells, which might regulate both differentiation of pancreatic progenitors and thereby maintenance of the graft function. New strategies to facilitate islet engraftment and a prompt revascularization could be designed to intervene and might lead to improve future results of islet transplantation.
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Affiliation(s)
- Alicia Del Toro-Arreola
- a Department of Physiology, Laboratory of Immunology, Tissue Engineering and Transplant , University Center for Health Sciences, University of Guadalajara , Mexico
| | | | - Adrian Daneri-Navarro
- a Department of Physiology, Laboratory of Immunology, Tissue Engineering and Transplant , University Center for Health Sciences, University of Guadalajara , Mexico
| | - Jorge David Rivas-Carrillo
- a Department of Physiology, Laboratory of Immunology, Tissue Engineering and Transplant , University Center for Health Sciences, University of Guadalajara , Mexico
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26
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Buitinga M, Janeczek Portalska K, Cornelissen DJ, Plass J, Hanegraaf M, Carlotti F, de Koning E, Engelse M, van Blitterswijk C, Karperien M, van Apeldoorn A, de Boer J. Coculturing Human Islets with Proangiogenic Support Cells to Improve Islet Revascularization at the Subcutaneous Transplantation Site. Tissue Eng Part A 2016; 22:375-85. [PMID: 26871862 DOI: 10.1089/ten.tea.2015.0317] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
While subcutaneous tissue has been proposed as a clinically relevant site for pancreatic islet transplantation, a major issue of concern remains, which is its poor vascular state. In an effort to overcome this limitation, we present an efficient and reproducible method to form human composite islets (CIs) with proangiogenic cell types in a controlled manner using nonadherent agarose microwell templates. In this study, we assessed the three-dimensional structure, function, and angiogenic potential of human CIs with human mesenchymal stromal cells (hMSCs), with or without human umbilical vein endothelial cells (HUVECs), and preconditioned hMSCs (PC-hMSCs) in EGM-2 under shear stress. Distinct cellular rearrangements could be observed in CIs, but islet functionality was maintained. In vitro angiogenesis assays found significantly enhanced sprout formation in case of CIs. In particular, the number of sprouts emanating from CIs with PC-hMSCs was significantly increased compared to other conditions. Subsequent in vivo assessment confirmed the proangiogenic potential of CIs. However, in contrast to our in vitro angiogenesis assays, CIs with hMSCs and HUVECs exhibited a higher in vivo angiogenic potential compared to control islets or islets combined with hMSCs or PC-hMSCs. These findings highlight the importance and necessity of verifying in vitro studies with in vivo models to reliably predict, in this case, revascularization outcomes. Regardless, we demonstrate here the therapeutic potential of CIs with proangiogenic support cells to enhance islet revascularization at a clinically relevant, although poorly vascularized, transplantation site.
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Affiliation(s)
- Mijke Buitinga
- 1 Department of Developmental BioEngineering, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente , Enschede, The Netherlands
| | - Karolina Janeczek Portalska
- 2 Department of Tissue Regeneration, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente , Enschede, The Netherlands
| | - Dirk-Jan Cornelissen
- 1 Department of Developmental BioEngineering, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente , Enschede, The Netherlands
| | - Jacqueline Plass
- 1 Department of Developmental BioEngineering, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente , Enschede, The Netherlands
| | - Maaike Hanegraaf
- 3 Department of Nephrology, Leiden University Medical Center , Leiden, The Netherlands
| | - Françoise Carlotti
- 3 Department of Nephrology, Leiden University Medical Center , Leiden, The Netherlands
| | - Eelco de Koning
- 3 Department of Nephrology, Leiden University Medical Center , Leiden, The Netherlands .,4 Department of Endocrinology, Leiden University Medical Center , Leiden, The Netherlands .,5 Hubrecht Institute-Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht , Utrecht, The Netherlands
| | - Marten Engelse
- 3 Department of Nephrology, Leiden University Medical Center , Leiden, The Netherlands
| | - Clemens van Blitterswijk
- 6 Department of Complex Tissue Regeneration, Institute for Technology Inspired Regenerative Medicine (MERLN), Maastricht University , Maastricht, The Netherlands
| | - Marcel Karperien
- 1 Department of Developmental BioEngineering, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente , Enschede, The Netherlands
| | - Aart van Apeldoorn
- 1 Department of Developmental BioEngineering, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente , Enschede, The Netherlands
| | - Jan de Boer
- 7 Laboratory for Cell Biology-Inspired Tissue Engineering, Institute for Technology Inspired Regenerative Medicine (MERLN) , Maastricht, The Netherlands
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27
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Talavera-Adame D, Dafoe DC. Endothelium-derived essential signals involved in pancreas organogenesis. World J Exp Med 2015; 5:40-49. [PMID: 25992319 PMCID: PMC4436939 DOI: 10.5493/wjem.v5.i2.40] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2014] [Revised: 03/18/2015] [Accepted: 04/14/2015] [Indexed: 02/06/2023] Open
Abstract
Endothelial cells (ECs) are essential for pancreas differentiation, endocrine specification, and endocrine function. They are also involved in the physiopathology of type 1 and type 2 diabetes. During embryogenesis, aortic ECs provide specific factors that maintain the expression of key genes for pancreas development such as pancreatic and duodenal homeobox-1. Other unknown factors are also important for pancreatic endocrine specification and formation of insulin-producing beta cells. Endocrine precursors proliferate interspersed with ductal cells and exocrine precursors and, at some point of development, these endocrine precursors migrate to pancreatic mesenchyme and start forming the islets of Langerhans. By the end of the gestation and close to birth, these islets contain immature beta cells with the capacity to express vascular endothelial growth factor and therefore to recruit ECs from the surrounding microenvironment. ECs in turn produce factors that are essential to maintain insulin secretion in pancreatic beta cells. Once assembled, a cross talk between endocrine cells and ECs maintain the integrity of islets toward an adequate function during the whole life of the adult individual. This review will focus in the EC role in the differentiation and maturation of pancreatic beta cells during embryogenesis as well as the current knowledge about the involvement of endothelium to derive pancreatic beta cells in vitro from mouse or human pluripotent stem cells.
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