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Tran HT, Rodprasert W, Padeta I, Oontawee S, Purbantoro SD, Thongsit A, Siriarchavatana P, Srisuwatanasagul S, Egusa H, Osathanon T, Sawangmake C. Establishment of subcutaneous transplantation platform for delivering induced pluripotent stem cell-derived insulin-producing cells. PLoS One 2025; 20:e0318204. [PMID: 39883721 PMCID: PMC11781742 DOI: 10.1371/journal.pone.0318204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Accepted: 01/10/2025] [Indexed: 02/01/2025] Open
Abstract
Potential trend of regenerative treatment for type I diabetes has been introduced for more than a decade. However, the technologies regarding insulin-producing cell (IPC) production and transplantation are still being developed. Here, we propose the potential IPC production protocol employing mouse gingival fibroblast-derived induced pluripotent stem cells (mGF-iPSCs) as a resource and the pre-clinical approved subcutaneous IPC transplantation platform for further clinical confirmation study. With a multi-step induction protocol, the functional and matured IPCs were generated by 13 days with a long-term survival capability. Further double encapsulation of mGF-iPSC-derived IPCs (mGF-iPSC-IPCs) could preserve the insulin secretion capacity and the transplantation potential of the generated IPCs. To address the potential on IPC transplantation, a 2-step subcutaneous transplantation procedure was established, comprising 1) vascularized subcutaneous pocket formation and 2) encapsulated IPC bead transplantation. The in vivo testing confirmed the safety and efficiency of the platform along with less inflammatory response which may help minimize tissue reaction and graft rejection. Further preliminary in vivo testing on subcutaneous IPC-bead transplantation in an induced type I diabetic mouse model showed beneficial trends on blood glucose control and survival rate sustainability of diabetic mice. Taken together, an established mGF-iPSC-IPC generation protocol in this study will be the potential backbone for developing the iPSC-derived IPC production employing human and animal cell resources. As well as the potential further development of IPC transplantation platform for diabetes treatment in human and veterinary practices using an established subcutaneous encapsulated IPC-bead transplantation platform presented in this study.
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Affiliation(s)
- Hong Thuan Tran
- Second Century Fund (C2F) Chulalongkorn University for Doctoral Scholarship, Chulalongkorn University, Bangkok, Thailand
- Faculty of Veterinary Science, The International Graduate Program of Veterinary Science and Technology (VST), Chulalongkorn University, Bangkok, Thailand
- Faculty of Veterinary Science, Veterinary Clinical Stem Cell and Bioengineering Research Unit, Chulalongkorn University, Bangkok, Thailand
- Faculty of Veterinary Science, Veterinary Stem Cell and Bioengineering Innovation Center (VSCBIC), Chulalongkorn University, Bangkok, Thailand
| | - Watchareewan Rodprasert
- Faculty of Veterinary Science, Veterinary Clinical Stem Cell and Bioengineering Research Unit, Chulalongkorn University, Bangkok, Thailand
- Faculty of Veterinary Science, Veterinary Stem Cell and Bioengineering Innovation Center (VSCBIC), Chulalongkorn University, Bangkok, Thailand
| | - Irma Padeta
- Second Century Fund (C2F) Chulalongkorn University for Doctoral Scholarship, Chulalongkorn University, Bangkok, Thailand
- Faculty of Veterinary Science, The International Graduate Program of Veterinary Science and Technology (VST), Chulalongkorn University, Bangkok, Thailand
- Faculty of Veterinary Science, Veterinary Clinical Stem Cell and Bioengineering Research Unit, Chulalongkorn University, Bangkok, Thailand
- Faculty of Veterinary Science, Veterinary Stem Cell and Bioengineering Innovation Center (VSCBIC), Chulalongkorn University, Bangkok, Thailand
| | - Saranyou Oontawee
- Faculty of Veterinary Science, Veterinary Clinical Stem Cell and Bioengineering Research Unit, Chulalongkorn University, Bangkok, Thailand
- Faculty of Veterinary Science, Veterinary Stem Cell and Bioengineering Innovation Center (VSCBIC), Chulalongkorn University, Bangkok, Thailand
| | - Steven dwi Purbantoro
- Second Century Fund (C2F) Chulalongkorn University for Doctoral Scholarship, Chulalongkorn University, Bangkok, Thailand
- Faculty of Veterinary Science, The International Graduate Program of Veterinary Science and Technology (VST), Chulalongkorn University, Bangkok, Thailand
- Faculty of Veterinary Science, Veterinary Clinical Stem Cell and Bioengineering Research Unit, Chulalongkorn University, Bangkok, Thailand
- Faculty of Veterinary Science, Veterinary Stem Cell and Bioengineering Innovation Center (VSCBIC), Chulalongkorn University, Bangkok, Thailand
| | - Anatcha Thongsit
- Faculty of Veterinary Science, Veterinary Clinical Stem Cell and Bioengineering Research Unit, Chulalongkorn University, Bangkok, Thailand
- Faculty of Veterinary Science, Veterinary Stem Cell and Bioengineering Innovation Center (VSCBIC), Chulalongkorn University, Bangkok, Thailand
| | - Parkpoom Siriarchavatana
- Faculty of Veterinary Science, Veterinary Clinical Stem Cell and Bioengineering Research Unit, Chulalongkorn University, Bangkok, Thailand
- Faculty of Veterinary Science, Veterinary Stem Cell and Bioengineering Innovation Center (VSCBIC), Chulalongkorn University, Bangkok, Thailand
- Faculty of Veterinary Medicine, Western University, Kanchanaburi, Thailand
| | - Sayamon Srisuwatanasagul
- Faculty of Veterinary Science, Department of Anatomy, Chulalongkorn University, Bangkok, Thailand
| | - Hiroshi Egusa
- Division of Molecular and Regenerative Prosthodontics, Center for Advanced Stem Cell and Regenerative Research, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Thanaphum Osathanon
- Faculty of Dentistry, Dental Stem Cell Biology Research Unit and Department of Anatomy, Chulalongkorn University, Bangkok, Thailand
- Faculty of Dentistry, Center of Excellence in Regenerative Dentistry, Chulalongkorn University, Bangkok, Thailand
| | - Chenphop Sawangmake
- Faculty of Veterinary Science, Veterinary Clinical Stem Cell and Bioengineering Research Unit, Chulalongkorn University, Bangkok, Thailand
- Faculty of Veterinary Science, Veterinary Stem Cell and Bioengineering Innovation Center (VSCBIC), Chulalongkorn University, Bangkok, Thailand
- Faculty of Veterinary Science, Department of Pharmacology, Chulalongkorn University, Bangkok, Thailand
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Yu X, Liu C, Kuang Z, Song S, Tian L, Wang Y. Islet organoids: a new hope for islet transplantation in diabetes. Front Immunol 2025; 15:1540209. [PMID: 39906747 PMCID: PMC11790636 DOI: 10.3389/fimmu.2024.1540209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Accepted: 12/26/2024] [Indexed: 02/06/2025] Open
Abstract
Diabetes mellitus, including Type 1 diabetes (T1D) and advanced Type 2 diabetes (T2D), remains a major global health challenge due to the destruction or dysfunction of insulin-producing β-cells. Islet transplantation offers a promising therapeutic strategy. However, it is limited by organ shortage globally and other risk factors. Recent advancements in organoid technology provide transformative solutions for islet regeneration. This review summarized three groundbreaking approaches: islet organoids differentiated from Procr+ pancreatic progenitor cells, chemically induced pluripotent stem cells (CiPSCs), and endoderm stem cells (EnSCs). Procr+ cells exhibit multipotency and potential for in vivo activation, offering a scalable and non-invasive strategy for β-cell regeneration. CiPSCs, reprogrammed via small molecules, enable personalized islet therapies with promising clinical outcomes, as demonstrated in T1D patients. EnSC-derived islets (E-islets) offer high differentiation efficiency and therapeutic efficacy, particularly for T2D patients with residual β-cell function. While each approach addresses specific challenges in islet transplantation, further research is needed to optimize scalability, immune compatibility, and long-term functionality. This review highlights the potential of organoid-based technologies to revolutionize diabetes treatment and pave the way for personalized, curative therapies.
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Affiliation(s)
- Xuemei Yu
- Department of Clinical Nutrition, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Chengkong Liu
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Zheng Kuang
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Siyuan Song
- Department of Neuroscience, Baylor College of Medicine, Houston, TX, United States
| | - Limin Tian
- Center for Geriatrics and Endocrinology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Yi Wang
- Center for Geriatrics and Endocrinology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
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Zhou M, Linn T, Petry SF. EndoC-βH3 pseudoislets are suitable for intraportal transplantation in diabetic mice. Islets 2024; 16:2406041. [PMID: 39298538 DOI: 10.1080/19382014.2024.2406041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 08/30/2024] [Accepted: 09/15/2024] [Indexed: 09/22/2024] Open
Abstract
BACKGROUND Islet or β-cell transplantation is a therapeutical approach to substitute the insulin-producing cells which are abolished in type 1 diabetes mellitus. The shortage of human islets as well as the complicated and costly isolation process limit the application of these techniques in daily clinical practice. EndoC-βH is a human β-cell line that readily forms aggregates termed pseudoislets, providing an alternative to primary human islets or β-cells. METHODS EndoC-βH3 cells were seeded and incubated to form pseudoislets. Their insulin secretion was analyzed by ELISA and compared with cell monolayers. Pseudoislets were transplanted into streptozotocin-treated NMRi nu/nu mice. Blood glucose was monitored before and after transplantation and compared with wild types. Grafts were analyzed by immunohistology. RESULTS This study shows that EndoC-βH cells are able to form pseudoislets by aggregation, leading to an enhanced glucose stimulated insulin secretion in vitro. These pseudoislets were then successfully transplanted into the livers of diabetic mice and produced insulin in vitro. Blood glucose levels of the streptozocin-treated recipient mice were significantly decreased when compared to pre-transplantation and matched the levels found in control mice. CONCLUSION We suggest pseudoislets aggregated from EndoC-βH cells as a valuable and promising model for islet transplantation research.
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Affiliation(s)
- Mengmeng Zhou
- Clinical Research Unit and Working Group Experimental Diabetology and Islet Cell Biology, Medical Clinic and Polyclinic III, Center of Internal Medicine, Justus Liebig University, Gießen, Germany
| | - Thomas Linn
- Clinical Research Unit and Working Group Experimental Diabetology and Islet Cell Biology, Medical Clinic and Polyclinic III, Center of Internal Medicine, Justus Liebig University, Gießen, Germany
| | - Sebastian Friedrich Petry
- Clinical Research Unit and Working Group Experimental Diabetology and Islet Cell Biology, Medical Clinic and Polyclinic III, Center of Internal Medicine, Justus Liebig University, Gießen, Germany
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Rohban R, Martins CP, Esni F. Advanced therapy to cure diabetes: mission impossible is now possible? Front Cell Dev Biol 2024; 12:1484859. [PMID: 39629270 PMCID: PMC11611888 DOI: 10.3389/fcell.2024.1484859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Accepted: 11/04/2024] [Indexed: 12/07/2024] Open
Abstract
Cell and Gene therapy are referred to as advanced therapies that represent overlapping fields of regenerative medicine. They have similar therapeutic goals such as to modify cellular identity, improve cell function, or fight a disease. These two therapeutic avenues, however, possess major differences. While cell therapy involves introduction of new cells, gene therapy entails introduction or modification of genes. Furthermore, the aim of cell therapy is often to replace, or repair damaged tissue, whereas gene therapy is used typically as a preventive approach. Diabetes mellitus severely affects the quality of life of afflicted individuals and has various side effects including cardiovascular, ophthalmic disorders, and neuropathy while putting enormous economic pressure on both the healthcare system and the patient. In recent years, great effort has been made to develop cutting-edge therapeutic interventions for diabetes treatment, among which cell and gene therapies stand out. This review aims to highlight various cell- and gene-based therapeutic approaches leading to the generation of new insulin-producing cells as a topmost "panacea" for treating diabetes, while deliberately avoiding a detailed molecular description of these approaches. By doing so, we aim to target readers who are new to the field and wish to get a broad helicopter overview of the historical and current trends of cell- and gene-based approaches in β-cell regeneration.
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Affiliation(s)
- Rokhsareh Rohban
- Department of Internal Medicine, Division of Hematology, Medical University of Graz, Graz, Austria
| | - Christina P. Martins
- Department of Surgery, Division of Pediatric General and Thoracic Surgery, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
| | - Farzad Esni
- Department of Surgery, Division of Pediatric General and Thoracic Surgery, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
- Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA, United States
- UPMC Hillman Cancer Center, Pittsburgh, PA, United States
- McGowan Institute for regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States
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Huang Q, Zhu J. Regulatory T cell-based therapy in type 1 diabetes: Latest breakthroughs and evidence. Int Immunopharmacol 2024; 140:112724. [PMID: 39098233 DOI: 10.1016/j.intimp.2024.112724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 07/10/2024] [Accepted: 07/16/2024] [Indexed: 08/06/2024]
Abstract
Autoimmune diseases (ADs) are among the most significant health complications, with their incidence rising in recent years. Type 1 diabetes (T1D), an AD, targets the insulin-producing β cells in the pancreas, leading to chronic insulin deficiency in genetically susceptible individuals. Regulatory immune cells, particularly T-cells (Tregs), have been shown to play a crucial role in the pathogenesis of diabetes by modulating immune responses. In diabetic patients, Tregs often exhibit diminished effectiveness due to various factors, such as instability in forkhead box P3 (Foxp3) expression or abnormal production of the proinflammatory cytokine interferon-gamma (IFN-γ) by autoreactive T-cells. Consequently, Tregs represent a potential therapeutic target for diabetes treatment. Building on the successful clinical outcomes of chimeric antigen receptor (CAR) T-cell therapy in cancer treatment, particularly in leukemias, the concept of designing and utilizing CAR Tregs for ADs has emerged. This review summarizes the findings on Treg targeting in T1D and discusses the benefits and limitations of this treatment approach for patients suffering from T1D.
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Affiliation(s)
- Qiongxiao Huang
- Center for Reproductive Medicine, Department of Reproductive Endocrinology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, Zhejiang 310014, China
| | - Jing Zhu
- Center for Reproductive Medicine, Department of Reproductive Endocrinology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, Zhejiang 310014, China.
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Qi B, Ding Y, Zhang Y, Kou L, Zhao YZ, Yao Q. Biomaterial-assisted strategies to improve islet graft revascularization and transplant outcomes. Biomater Sci 2024; 12:821-836. [PMID: 38168805 DOI: 10.1039/d3bm01295f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2024]
Abstract
Islet transplantation holds significant promise as a curative approach for type 1 diabetes (T1D). However, the transition of islet transplantation from the experimental phase to widespread clinical implementation has not occurred yet. One major hurdle in this field is the challenge of insufficient vascularization and subsequent early loss of transplanted islets, especially in non-intraportal transplantation sites. The establishment of a fully functional vascular system following transplantation is crucial for the survival and secretion function of islet grafts. This vascular network not only ensures the delivery of oxygen and nutrients, but also plays a critical role in insulin release and the timely removal of metabolic waste from the grafts. This review summarizes recent advances in effective strategies to improve graft revascularization and enhance islet survival. These advancements include the local release and regulation of angiogenic factors (e.g., vascular endothelial growth factor, VEGF), co-transplantation of vascular fragments, and pre-vascularization of the graft site. These innovative approaches pave the way for the development of effective islet transplantation therapies for individuals with T1D.
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Affiliation(s)
- Boyang Qi
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
| | - Yang Ding
- The Second School of Medicine, Wenzhou Medical University, Wenzhou, China
| | - Ying Zhang
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
| | - Longfa Kou
- The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Ying-Zheng Zhao
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
| | - Qing Yao
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
- Cixi Biomedical Research Institute, Wenzhou Medical University, Zhejiang, China
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Mbituyimana B, Adhikari M, Qi F, Shi Z, Fu L, Yang G. Microneedle-based cell delivery and cell sampling for biomedical applications. J Control Release 2023; 362:692-714. [PMID: 37689252 DOI: 10.1016/j.jconrel.2023.09.013] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 08/16/2023] [Accepted: 09/04/2023] [Indexed: 09/11/2023]
Abstract
Cell-based therapeutics are novel therapeutic strategies that can potentially treat many presently incurable diseases through novel mechanisms of action. Cell therapies may benefit from the ease, safety, and efficacy of administering therapeutic cells. Despite considerable recent technological and biological advances, several barriers remain to the clinical translation and commercialization of cell-based therapies, including low patient compliance, personal handling inconvenience, poor biosafety, and limited biocompatibility. Microneedles (MNs) are emerging as a promising biomedical device option for improved cell delivery with little invasion, pain-free administration, and simplicity of disposal. MNs have shown considerable promise in treating a wide range of diseases and present the potential to improve cell-based therapies. In this review, we first summarized the latest advances in the various types of MNs developed for cell delivery and cell sampling. Emphasis was given to the design and fabrication of various types of MNs based on their structures and materials. Then we focus on the recent biomedical applications status of MNs-mediated cell delivery and sampling, including tissue repair (wound healing, heart repair, and endothelial repair), cancer treatment, diabetes therapy, cell sampling, and other applications. Finally, the current status of clinical application, potential perspectives, and the challenges for clinical translation are also highlighted.
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Affiliation(s)
- Bricard Mbituyimana
- Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China
| | - Manjila Adhikari
- Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China
| | - Fuyu Qi
- Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China
| | - Zhijun Shi
- Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.
| | - Lina Fu
- College of Medicine, Huanghuai University, Zhumadian, Henan 463000, China; Zhumadian Central Hospital, Zhumadian, Henan 463000, China.
| | - Guang Yang
- Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.
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Sionov RV, Ahdut-HaCohen R. A Supportive Role of Mesenchymal Stem Cells on Insulin-Producing Langerhans Islets with a Specific Emphasis on The Secretome. Biomedicines 2023; 11:2558. [PMID: 37761001 PMCID: PMC10527322 DOI: 10.3390/biomedicines11092558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 09/06/2023] [Accepted: 09/14/2023] [Indexed: 09/29/2023] Open
Abstract
Type 1 Diabetes (T1D) is a chronic autoimmune disease characterized by a gradual destruction of insulin-producing β-cells in the endocrine pancreas due to innate and specific immune responses, leading to impaired glucose homeostasis. T1D patients usually require regular insulin injections after meals to maintain normal serum glucose levels. In severe cases, pancreas or Langerhans islet transplantation can assist in reaching a sufficient β-mass to normalize glucose homeostasis. The latter procedure is limited because of low donor availability, high islet loss, and immune rejection. There is still a need to develop new technologies to improve islet survival and implantation and to keep the islets functional. Mesenchymal stem cells (MSCs) are multipotent non-hematopoietic progenitor cells with high plasticity that can support human pancreatic islet function both in vitro and in vivo and islet co-transplantation with MSCs is more effective than islet transplantation alone in attenuating diabetes progression. The beneficial effect of MSCs on islet function is due to a combined effect on angiogenesis, suppression of immune responses, and secretion of growth factors essential for islet survival and function. In this review, various aspects of MSCs related to islet function and diabetes are described.
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Affiliation(s)
- Ronit Vogt Sionov
- The Institute of Biomedical and Oral Research (IBOR), Faculty of Dental Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel
| | - Ronit Ahdut-HaCohen
- Department of Medical Neurobiology, Institute of Medical Research, Hadassah Medical School, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel;
- Department of Science, The David Yellin Academic College of Education, Jerusalem 9103501, Israel
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Fathi I, Inagaki A, Imura T, Koraitim T, Goto M. Pancreatic Islet Transplantation into the Submandibular Gland: Our Experimental Experience and a Review of the Relevant Literature. J Clin Med 2023; 12:jcm12113735. [PMID: 37297929 DOI: 10.3390/jcm12113735] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Revised: 05/25/2023] [Accepted: 05/26/2023] [Indexed: 06/12/2023] Open
Abstract
Pancreatic islet transplantation is a promising therapy for type 1 diabetes. Islet transplantation is clinically performed through intra-portal infusion, which is associated with several drawbacks, including poor engraftment. The histological resemblance between the submandibular gland and the pancreas renders it an attractive alternative site for islet transplantation. In this study, we refined the technique of islet transplantation into the submandibular gland to achieve good morphological features. Then, we transplanted 2600 islet equivalents into the submandibular glands of diabetic Lewis rats. Intra-portal islet transplantation was performed in diabetic rats as a control. Blood glucose levels were followed for 31 days, and an intravenous glucose tolerance test was performed. Immunohistochemistry was used to demonstrate the morphology of transplanted islets. Follow-up after transplantation showed that diabetes was cured in 2/12 rats in the submandibular group in comparison to 4/6 in the control group. The intravenous glucose tolerance test results of the submandibular and intra-portal groups were comparable. Immunohistochemistry showed large islet masses in the submandibular gland in all examined specimens with positive insulin staining. Our results show that submandibular gland tissue can support the islet function and engraftment but with considerable variability. Good morphological features were achieved using our refined technique. However, islet transplantation into rat submandibular glands did not demonstrate a clear advantage over conventional intra-portal transplantation.
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Affiliation(s)
- Ibrahim Fathi
- Division of Transplantation and Regenerative Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan
- Department of Surgery, Alexandria University, Alexandria 21131, Egypt
| | - Akiko Inagaki
- Division of Transplantation and Regenerative Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan
| | - Takehiro Imura
- Division of Transplantation and Regenerative Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan
| | - Tarek Koraitim
- Department of Surgery, Alexandria University, Alexandria 21131, Egypt
| | - Masafumi Goto
- Division of Transplantation and Regenerative Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan
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Teratani T, Kasahara N, Fujimoto Y, Sakuma Y, Miki A, Goto M, Sata N, Kitayama J. Mesenchymal Stem Cells Secretions Enhanced ATP Generation on Isolated Islets during Transplantation. Islets 2022; 14:69-81. [PMID: 35034568 PMCID: PMC8765074 DOI: 10.1080/19382014.2021.2022423] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
The success of islet transplantation in both basic research and clinical settings has proven that cell therapy has the potential to cure diabetes. Islets intended for transplantation are inevitably subjected to damage from a number of sources, including ischemic injury during removal and delivery of the donor pancreas, enzymatic digestion during islet isolation, and reperfusion injury after transplantation in the recipient. Here, we found that protein factors secreted by porcine adipose-tissue mesenchymal stem cells (AT-MSCs) were capable of activating preserved porcine islets. A conditioned medium was prepared from the supernatant obtained by culturing porcine AT-MSCs for 2 days in serum-free medium. Islets were preserved at 4°C in University of Wisconsin solution during transportation and then incubated at 37°C in RPMI-1620 medium with fractions of various molecular weights prepared from the conditioned medium. After treatment with certain fractions of the AT-MSC secretions, the intracellular ATP levels of the activated islets had increased to over 160% of their initial values after 4 days of incubation. Our novel system may be able to restore the condition of isolated islets after transportation or preservation and may help to improve the long-term outcome of islet transplantation.Abbreviations: AT-MSC, adipose-tissue mesenchymal stem cell; Cas-3, caspase-3; DAPI, 4,6-diamidino-2-phenylindole; DTZ, dithizone; ES cell, embryonic stem cell; FITC, fluorescein isothiocyanate; IEQ, islet equivalent; INS, insulin; iPS cell, induced pluripotent stem cell; Luc-Tg rat, luciferase-transgenic rat; PCNA, proliferating cell nuclear antigen; PDX1, pancreatic and duodenal homeobox protein-1; UW, University of Wisconsin; ZO1, zona occludens 1.
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Affiliation(s)
- Takumi Teratani
- Division of Translational Research, Jichi Medical University, Tochigi, Japan
- Department of Surgery, Jichi Medical University, Tochigi, Japan
- CONTACT Takumi Teratani Division of Clinical Investigation, Jichi Medical University, 3311-1, Yakushiji, Shimotsukeshi, Tochigi329-0498, Japan
| | - Naoya Kasahara
- Department of Surgery, Jichi Medical University, Tochigi, Japan
| | | | - Yasunaru Sakuma
- Department of Surgery, Jichi Medical University, Tochigi, Japan
| | - Atsushi Miki
- Department of Surgery, Jichi Medical University, Tochigi, Japan
| | - Masafumi Goto
- New Industry Creation Hatchery Center, Tohoku University, Miyagi, Japan
| | - Naohiro Sata
- Department of Surgery, Jichi Medical University, Tochigi, Japan
| | - Joji Kitayama
- Division of Translational Research, Jichi Medical University, Tochigi, Japan
- Department of Surgery, Jichi Medical University, Tochigi, Japan
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Synthesis of siRNA-Conjugated Dextran-Coated Iron Oxide Nanoparticles for Islet Protection During Transplantation and Noninvasive Imaging. Methods Mol Biol 2022; 2592:163-174. [PMID: 36507992 DOI: 10.1007/978-1-0716-2807-2_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Pancreatic islet transplantation (Tx) has a lifesaving potential for type 1 diabetes (T1D) patients. Islet damage during and after transplantation is one of the major reasons hampering its wide clinical application. Inability to monitor transplanted islets also severely limits our understanding of mechanisms regarding declining graft function after transplantation. Our team has proposed to use magnetic nanoparticles conjugated to siRNA (MN-siRNA) to label islets prior to transplantation with two goals in mind: to protect them from damage by silencing harmful genes and to monitor them after transplantation using noninvasive magnetic resonance imaging (MRI). This manuscript provides a step-by-step protocol for the synthesis and characterization of MN-siRNA probes.
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Kuang G, Zhang Q, Jia J, Yu Y. Freezing biological organisms for biomedical applications. SMART MEDICINE 2022; 1:e20220034. [PMID: 39188743 PMCID: PMC11235656 DOI: 10.1002/smmd.20220034] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 12/07/2022] [Indexed: 08/28/2024]
Abstract
Biological organisms play important roles in human health, either in a commensal or pathogenic manner. Harnessing inactivated organisms or living organisms is a promising way to treat diseases. As two types of freezing, cryoablation makes it simple to inactivate organisms that must be in a non-pathogenic state when needed, while cryopreservation is a facile way to address the problem of long-term storage challenged by living organism-based therapy. In this review, we present the latest studies of freezing biological organisms for biomedical applications. To begin with, the freezing strategies of cryoablation and cryopreservation, as well as their corresponding technical essentials, are illustrated. Besides, biomedical applications of freezing biological organisms are presented, including transplantation, tissue regeneration, anti-infection therapy, and anti-tumor therapy. The challenges and prospects of freezing living organisms for biomedical applications are well discussed. We believe that the freezing method will provide a potential direction for the standardization and commercialization of inactivated or living organism-based therapeutic systems, and promote the clinical application of organism-based therapy.
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Affiliation(s)
- Gaizhen Kuang
- Pharmaceutical Sciences LaboratoryÅbo Akademi UniversityTurkuFinland
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health)Wenzhou InstituteUniversity of Chinese Academy of SciencesWenzhouChina
| | - Qingfei Zhang
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health)Wenzhou InstituteUniversity of Chinese Academy of SciencesWenzhouChina
| | - Jinxuan Jia
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health)Wenzhou InstituteUniversity of Chinese Academy of SciencesWenzhouChina
| | - Yunru Yu
- Pharmaceutical Sciences LaboratoryÅbo Akademi UniversityTurkuFinland
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13
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Huang H, Shang Y, Li H, Feng Q, Liu Y, Chen J, Dong H. Co-transplantation of Islets-Laden Microgels and Biodegradable O 2-Generating Microspheres for Diabetes Treatment. ACS APPLIED MATERIALS & INTERFACES 2022; 14:38448-38458. [PMID: 35980755 DOI: 10.1021/acsami.2c07215] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Pancreatic islets transplantation is an optimal alternative to exogenous insulin injection for long-term effective type 1 diabetes treatment. However, direct islets transplantation without any protection can induce cell necrosis due to severe host immune rejection. Insufficient O2 supply induced by the lack of capillary network at the early stage of islets transplantation is another critical constraint limiting islets survival and insulin-secretion function. In this paper, we design a novel co-transplantation system composed of islets-laden nanocomposite microgels and O2-generating microspheres. In particular, nanocomposite microgels confer the encapsulated islets with simultaneous physical protection and chemical anti-inflammation/immunosuppression by covalently anchoring rapamycin-loaded cyclodextrin nanoparticles to microgel network. Meanwhile, O2-generating microspheres prepared by blending inorganic peroxides in biodegradable polycaprolactone and polylactic acid can generate in situ O2 gas and thus avoid hypoxia environment around transplanted islets. In vivo therapeutic effect of diabetic mice proves the reversion of the high blood glucose level back to normoglycemia and superior glucose tolerance for at least 90 days post co-transplantation. In brief, the localized drug and oxygen codelivery, as well as physical protection provided by our co-transplantation system, has the potential to overcome to a large extent the inflammatory, hypoxia, and host immune rejection after islets transplantation. This new strategy may have wider application in other cell replacement therapies.
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Affiliation(s)
- Hanhao Huang
- School of Materials Science and Engineering, South China University of Technology, Guangzhou 510006, China
- National Engineering Research Center for Tissue Restoration and Reconstruction (NERC-TRR), Guangzhou 510006, China
- Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education, South China University of Technology, Guangzhou 510006, P.R. China
| | - Yulian Shang
- National Engineering Research Center for Tissue Restoration and Reconstruction (NERC-TRR), Guangzhou 510006, China
- Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education, South China University of Technology, Guangzhou 510006, P.R. China
- School of Biomedical Science and Engineering, South China University of Technology, Guangzhou 510006, China
| | - Haofei Li
- School of Materials Science and Engineering, South China University of Technology, Guangzhou 510006, China
- National Engineering Research Center for Tissue Restoration and Reconstruction (NERC-TRR), Guangzhou 510006, China
- Guangdong Province Key Laboratory of Biomedical Engineering, South China University of Technology, Guangzhou 510641, China
| | - Qi Feng
- School of Materials Science and Engineering, South China University of Technology, Guangzhou 510006, China
- National Engineering Research Center for Tissue Restoration and Reconstruction (NERC-TRR), Guangzhou 510006, China
- Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education, South China University of Technology, Guangzhou 510006, P.R. China
| | - Yang Liu
- School of Materials Science and Engineering, South China University of Technology, Guangzhou 510006, China
- National Engineering Research Center for Tissue Restoration and Reconstruction (NERC-TRR), Guangzhou 510006, China
- Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education, South China University of Technology, Guangzhou 510006, P.R. China
| | - Junlin Chen
- School of Materials Science and Engineering, South China University of Technology, Guangzhou 510006, China
- National Engineering Research Center for Tissue Restoration and Reconstruction (NERC-TRR), Guangzhou 510006, China
- Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education, South China University of Technology, Guangzhou 510006, P.R. China
| | - Hua Dong
- School of Materials Science and Engineering, South China University of Technology, Guangzhou 510006, China
- National Engineering Research Center for Tissue Restoration and Reconstruction (NERC-TRR), Guangzhou 510006, China
- Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education, South China University of Technology, Guangzhou 510006, P.R. China
- Guangdong Province Key Laboratory of Biomedical Engineering, South China University of Technology, Guangzhou 510641, China
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14
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Xue Z, Mei D, Zhang L. Advances in single-cell nanoencapsulation and applications in diseases. J Microencapsul 2022; 39:481-494. [PMID: 35998209 DOI: 10.1080/02652048.2022.2111472] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/15/2022]
Abstract
Single-cell nanoencapsulation is a method of coating the surface of single cell with nanomaterials. In the early 20th century, with the introduction of various types of organic or inorganic nano-polymer materials, the selection of cell types, and the functional modification of the outer coating, this technology has gradually matured. Typical preparation methods include interfacial polycondensation, complex condensation, spray drying, microdroplet ejection, and layer-by-layer (LbL) self-assembly. The LbL assembly technology utilises nanomaterials with opposite charges deposited on cells by strong interaction (electrostatic interaction) or weak interaction (hydrogen bonding, hydrophobic interaction), which drives compounds to spontaneously form films with complete structure, stable performance and unique functions on cells. According to the needs of the disease, choosing appropriate cell types and biocompatible and biodegradable nanomaterials could achieve the purpose of promoting cell proliferation, immune isolation, reducing phagocytosis of the reticuloendothelial system, prolonging the circulation time in vivo, and avoiding repeated administration. Therefore, encapsulated cells could be utilised in various biomedical fields, such as cell catalysis, biotherapy, vaccine manufacturing and antitumor therapy. This article reviews cell nanoencapsulation therapies for diseases, including the various cell sources used, nanoencapsulation technology and the latest advances in preclinical and clinical research.
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Affiliation(s)
- Ziyang Xue
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Center of Rheumatoid Arthritis of Anhui Medical University, Hefei, China
| | - Dan Mei
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Center of Rheumatoid Arthritis of Anhui Medical University, Hefei, China
| | - Lingling Zhang
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Center of Rheumatoid Arthritis of Anhui Medical University, Hefei, China
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15
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Berney T, Andres A, Bellin MD, de Koning EJP, Johnson PRV, Kay TWH, Lundgren T, Rickels MR, Scholz H, Stock PG, White S, the International Islet Transplant Centers AghayanHamid R.AlejandroRodolfoAnazawaTakayukiAndresAxelArmanetMathieuBadetLionelBalamuruganAppakalai N.BartonFranca B.BellinMelena D.BenhamouPierre Y.BerishviliEkaterineBerneyThierryBertuzziFedericoBorotSophieBoscoDomenicoBottinoRitaBrendelMathias D.BuronFannyCaicedoLuis ArmandoCaseyJohnCattanPierreChoudharyPratikCoatesPatrick T.CongetIgnacioCooperMatthewde KoningEelco J.P.Dębska-ŚlizieńAlicjaDesaiChirag S.Dominguez-GilBeatrizDragoJulianEcheverriGabriel J.FedarukDzmitryGołębiewskaJustynaGossJohn A.HeringBernhard J.HyonSung H.JohnsonPaul R.V.JungHye S.KanakMazhar A.KandeelFouadKayThomasKenmochiTakashiKesslerLaurenceKeymeulenBartKhambaliaHusseinKhanKhalid M.KimJae H.KorsgrenOlleKudvaYogish C.LablancheSandrineLabriolaLeticiaLeeEun Y.LehmannRogerLudwigBarbaraLundrenTörbjörnLuoXunrongMaffiPaolaMarkmannJamesMattinaAlessandroMelocheMarkMokshagundamSri Prakash L.MorganKatherineMunchMarionNaziruddinBashooOdoricoJon S.OnacaNicholasParaskevasStevenPattouFrançoisPerninNadinePiemontiLorenzoRickelsMichael R.RicordiCamilloMuñoz RomoRaulSaudekFrantisekScholzHanneShapiroJames A.M.ShawJamesShimodaMasayukiStegallMark D.StockPeter G.VantyghemMarie-ChristineVentura-AguiarPedroWassmerCharles H.WebsterAngelaWhiteSteveWitkowskiPiotrWojtusciszynAnneWszolaMichalYoonKun-Ho. A Worldwide Survey of Activities and Practices in Clinical Islet of Langerhans Transplantation. Transpl Int 2022; 35:10507. [PMID: 36033644 PMCID: PMC9402897 DOI: 10.3389/ti.2022.10507] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Accepted: 05/30/2022] [Indexed: 11/19/2022]
Abstract
A global online survey was administered to 69 islet transplantation programs, covering 84 centers and 5 networks. The survey addressed questions on program organization and activity in the 2000–2020 period, including impact on activity of national health care coverage policies. We obtained full data from 55 institutions or networks worldwide and basic activity data from 6 centers. Additional data were obtained from alternative sources. A total of 94 institutions and 5 networks was identified as having performed islet allotransplantation. 4,365 islet allotransplants (2,608 in Europe, 1,475 in North America, 135 in Asia, 119 in Oceania, 28 in South America) were reported in 2,170 patients in the survey period. From 15 centers active at the start of the study period, the number of simultaneously active islet centers peaked at 54, to progressively decrease to 26 having performed islet allotransplants in 2020. Notably, only 16 centers/networks have done >100 islet allotransplants in the survey period. Types of transplants performed differed notably between North America and the rest of the world, in particular with respect to the near-absence of simultaneous islet-kidney transplantation. Absence of heath care coverage has significantly hampered transplant activity in the past years and the COVID-19 pandemic in 2020.
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Affiliation(s)
- Thierry Berney
- Division of Transplantation, Department of Surgery, University of Geneva Hospitals, Geneva, Switzerland,*Correspondence: Thierry Berney,
| | - Axel Andres
- Division of Transplantation, Department of Surgery, University of Geneva Hospitals, Geneva, Switzerland
| | - Melena D. Bellin
- Departments of Pediatrics and Surgery, University of Minnesota Medical Center, Minneapolis, MN, United States
| | | | - Paul R. V. Johnson
- Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - Thomas W. H. Kay
- Department of Medicine, St. Vincent’s Hospital, St. Vincent’s Institute of Medical Research, University of Melbourne, Melbourne, VIC, Australia
| | - Torbjörn Lundgren
- Department of Transplantation Surgery, Karolinska University Hospital, Stockholm, Sweden
| | - Michael R. Rickels
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
| | - Hanne Scholz
- Department of Transplant Medicine, Institute for Surgical Research, Oslo University Hospital, Oslo, Norway
| | - Peter G. Stock
- Division of Transplantation, Department of Surgery, University of California at San Francisco, San Francisco, CA, United States
| | - Steve White
- Department of HPB and Transplant Surgery, The Freeman Hospital, Newcastle Upon Tyne, United Kingdom
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Patel R, Parmar N, Rathwa N, Palit SP, Li Y, Garcia-Ocaña A, Begum R. A novel therapeutic combination of sitagliptin and melatonin regenerates pancreatic β-cells in mouse and human islets. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2022; 1869:119263. [PMID: 35364117 DOI: 10.1016/j.bbamcr.2022.119263] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 03/23/2022] [Accepted: 03/24/2022] [Indexed: 02/06/2023]
Abstract
Autoimmune-led challenge resulting in β-cell loss is responsible for the development of type 1 diabetes (T1D). Melatonin, a pineal hormone or sitagliptin, a dipeptidyl peptidase IV (DPP-IV) inhibitor, has increased β-cell mass in various diabetic models and has immunoregulatory property. Both β-cell regenerative capacity and melatonin secretion decrease with ageing. Thus, we aimed to investigate the therapeutic potential of melatonin combined with sitagliptin on β-cell regeneration under glucotoxic stress, in the streptozotocin-induced young and old diabetic mouse models, and euglycemic humanized islet transplant mouse model. Our results suggest that combination therapy of sitagliptin and melatonin show an additive effect in inducing mouse β-cell regeneration under glucotoxic stress, and in the human islet transplant mouse model. Further, in the young diabetic mouse model, the monotherapies induce β-cell transdifferentiation and reduce β-cell apoptosis whereas, in the old diabetic mouse model, melatonin and sitagliptin induce β-cell proliferation and β-cell transdifferentiation, and it also reduces β-cell apoptosis. Further, in both the models, combination therapy reduces fasting blood glucose levels, increases plasma insulin levels and glucose tolerance and promotes β-cell proliferation, β-cell transdifferentiation, and reduces β-cell apoptosis. It can be concluded that combination therapy is superior to monotherapies in ameliorating diabetic manifestations, and it can be used as a future therapy for β-cell regeneration in diabetes patients.
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Affiliation(s)
- Roma Patel
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara- 390002, Gujarat, India
| | - Nishant Parmar
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara- 390002, Gujarat, India
| | - Nirali Rathwa
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara- 390002, Gujarat, India
| | - Sayantani Pramanik Palit
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara- 390002, Gujarat, India
| | - Yansui Li
- Diabetes, Obesity and Metabolism Institute and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Adolfo Garcia-Ocaña
- Diabetes, Obesity and Metabolism Institute and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Rasheedunnisa Begum
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara- 390002, Gujarat, India.
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17
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Torres-Castro K, Azimi MS, Varhue WB, Honrado C, Peirce SM, Swami NS. Biophysical quantification of reorganization dynamics of human pancreatic islets during co-culture with adipose-derived stem cells. Analyst 2022; 147:2731-2738. [DOI: 10.1039/d2an00222a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Reorganization dynamics of human islets during co-culture with adipose stem cells depends on islet size and the heterogeneity can be assessed based on biomechanical opacity of individual islets.
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Affiliation(s)
- Karina Torres-Castro
- Department of Electrical & Computer Engineering, University of Virginia, Charlottesville, Virginia-22904, USA
| | - Mohammad S. Azimi
- Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia-22904, USA
| | - Walter B. Varhue
- Department of Electrical & Computer Engineering, University of Virginia, Charlottesville, Virginia-22904, USA
| | - Carlos Honrado
- Department of Electrical & Computer Engineering, University of Virginia, Charlottesville, Virginia-22904, USA
| | - Shayn M. Peirce
- Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia-22904, USA
| | - Nathan S. Swami
- Department of Electrical & Computer Engineering, University of Virginia, Charlottesville, Virginia-22904, USA
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18
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Samojlik MM, Stabler CL. Designing biomaterials for the modulation of allogeneic and autoimmune responses to cellular implants in Type 1 Diabetes. Acta Biomater 2021; 133:87-101. [PMID: 34102338 PMCID: PMC9148663 DOI: 10.1016/j.actbio.2021.05.039] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 05/05/2021] [Accepted: 05/20/2021] [Indexed: 12/15/2022]
Abstract
The effective suppression of adaptive immune responses is essential for the success of allogeneic cell therapies. In islet transplantation for Type 1 Diabetes, pre-existing autoimmunity provides an additional hurdle, as memory autoimmune T cells mediate both an autoantigen-specific attack on the donor beta cells and an alloantigen-specific attack on the donor graft cells. Immunosuppressive agents used for islet transplantation are generally successful in suppressing alloimmune responses, but dramatically hinder the widespread adoption of this therapeutic approach and fail to control memory T cell populations, which leaves the graft vulnerable to destruction. In this review, we highlight the capacity of biomaterials to provide local and nuanced instruction to suppress or alter immune pathways activated in response to an allogeneic islet transplant. Biomaterial immunoisolation is a common approach employed to block direct antigen recognition and downstream cell-mediated graft destruction; however, immunoisolation alone still permits shed donor antigens to escape into the host environment, resulting in indirect antigen recognition, immune cell activation, and the creation of a toxic graft site. Designing materials to decrease antigen escape, improve cell viability, and increase material compatibility are all approaches that can decrease the local release of antigen and danger signals into the implant microenvironment. Implant materials can be further enhanced through the local delivery of anti-inflammatory, suppressive, chemotactic, and/or tolerogenic agents, which serve to control both the innate and adaptive immune responses to the implant with a benefit of reduced systemic effects. Lessons learned from understanding how to manipulate allogeneic and autogenic immune responses to pancreatic islets can also be applied to other cell therapies to improve their efficacy and duration. STATEMENT OF SIGNIFICANCE: This review explores key immunologic concepts and critical pathways mediating graft rejection in Type 1 Diabetes, which can instruct the future purposeful design of immunomodulatory biomaterials for cell therapy. A summary of immunological pathways initiated following cellular implantation, as well as current systemic immunomodulatory agents used, is provided. We then outline the potential of biomaterials to modulate these responses. The capacity of polymeric encapsulation to block some powerful rejection pathways is covered. We also highlight the role of cellular health and biocompatibility in mitigating immune responses. Finally, we review the use of bioactive materials to proactively modulate local immune responses, focusing on key concepts of anti-inflammatory, suppressive, and tolerogenic agents.
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Affiliation(s)
- Magdalena M Samojlik
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA
| | - Cherie L Stabler
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA; University of Florida Diabetes Institute, Gainesville, FL, USA; Graduate Program in Biomedical Sciences, College of Medicine, University of Florida, Gainesville, FL, USA.
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19
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Hashemi J, Barati G, Bibak B. Decellularized Matrix Bioscaffolds: Implementation of Native Microenvironment in Pancreatic Tissue Engineering. Pancreas 2021; 50:942-951. [PMID: 34643609 DOI: 10.1097/mpa.0000000000001868] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
ABSTRACT Type 1 diabetes is an autoimmune disease, and its incidence is usually estimated in the range of 5% to 10%. Currently, the administration of exogenous insulin is the standard of care therapy. However, this therapy is not effective in some patients who may develop some chronic complications. Islet transplantation into the liver is another therapy with promising outcomes; however, the long-term efficacy of this therapeutic option is limited to a small number of patients. Because native extracellular matrix (ECM) components provide a suitable microenvironment for islet functions, engineering a 3-dimensional construct that recapitulates the native pancreatic environment could address these obstacles. Many attempts have been conducted to mimic an in vivo microenvironment to increase the survival of islets or islet-like clusters. With the advent of decellularization technology, it is possible to use a native ECM in organ engineering. Pancreatic decellularized bioscaffold provides proper cell-cell and cell-ECM interactions and retains growth factors that are critical in the determination of cell fate within a native organ. This review summarizes the current knowledge of decellularized matrix technology and addresses its possible limitations before use in the clinic.
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Affiliation(s)
- Javad Hashemi
- From the Department of Pathobiology and Laboratory Sciences, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd
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20
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Yamanaka T, Nakayama-Iwatsuki K, Fujimoto S, Hirono N, Negishi J, Tamada Y, Hirabayashi M, Hochi S. All-in-One Silk Fibroin Sponge as the Vitrification Cryodevice of Rat Pancreatic Islets and the VEGF-Embedded Scaffold for Subrenal Transplantation. Transplant Proc 2021; 53:1744-1750. [PMID: 34052022 DOI: 10.1016/j.transproceed.2021.04.012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Accepted: 04/05/2021] [Indexed: 12/19/2022]
Abstract
Islet transplantation is a promising option for the clinical treatment of insulin-dependent diabetes, but a reliable islet cryopreservation/transplantation protocol should be established to overcome the donor shortage. The current study reports that a silk fibroin (SF) sponge disk can be used as a cryodevice for vitrification of large quantity pancreatic islets and the scaffold for subsequent subrenal transplantation in a rat model. The marginal islet mass (550 islet equivalents [IEQs]) on an SF sponge disk was vitrified-warmed and transplanted beneath the kidney capsule of a streptozotocin-induced diabetic rat with or without vascular endothelial growth factor (VEGF). Subrenal transplantation (no scaffold) of 550 IEQ fresh islets and post-warm islets vitrified on a nylon mesh device resulted in achieving euglycemia of recipient rats at 60% and 0%, respectively. Transplantation of 550 IEQ islets vitrified-warmed on an SF sponge disk failed to achieve euglycemia of recipient rats (0%), but the VEGF inclusion in the SF sponge disk contributed to acquiring the euglycemic recipients (33%). All cured recipient rats regained hyperglycemia after nephrectomy, and the histopathologic analysis exhibited a well-developing blood vessel network into the islet engrafts. Thus, an SF sponge disc was successively available as the cryodevice for islet vitrification, the transporter of the angiogenic VEGF, and the scaffold for subrenal transplantation in the rat model.
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Affiliation(s)
- Takahiro Yamanaka
- Graduate School of Medicine, Science and Technology, Shinshu University, Ueda, Nagano, Japan
| | - Kenyu Nakayama-Iwatsuki
- Graduate School of Science and Technology, Shinshu University, Ueda, Nagano, Japan; Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, Okazaki, Aichi, Japan
| | - Sora Fujimoto
- Faculty of Textile Science and Technology, Shinshu University, Ueda, Nagano, Japan
| | - Naoki Hirono
- Faculty of Textile Science and Technology, Shinshu University, Ueda, Nagano, Japan
| | - Jun Negishi
- Graduate School of Medicine, Science and Technology, Shinshu University, Ueda, Nagano, Japan; Graduate School of Science and Technology, Shinshu University, Ueda, Nagano, Japan; Faculty of Textile Science and Technology, Shinshu University, Ueda, Nagano, Japan
| | - Yasushi Tamada
- Graduate School of Medicine, Science and Technology, Shinshu University, Ueda, Nagano, Japan; Graduate School of Science and Technology, Shinshu University, Ueda, Nagano, Japan; Faculty of Textile Science and Technology, Shinshu University, Ueda, Nagano, Japan
| | - Masumi Hirabayashi
- Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, Okazaki, Aichi, Japan; School of Life Science, The Graduate University of Advanced Studies, Okazaki, Aichi, Japan
| | - Shinichi Hochi
- Graduate School of Medicine, Science and Technology, Shinshu University, Ueda, Nagano, Japan; Graduate School of Science and Technology, Shinshu University, Ueda, Nagano, Japan; Faculty of Textile Science and Technology, Shinshu University, Ueda, Nagano, Japan.
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21
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Nakayama-Iwatsuki K, Yanagisawa K, Tanaka D, Hirabayashi M, Negishi J, Hochi S. Acellular matrix derived from rat liver improves the functionality of rat pancreatic islets before or after vitrification. Cryobiology 2021; 100:90-95. [PMID: 33757759 DOI: 10.1016/j.cryobiol.2021.03.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 02/26/2021] [Accepted: 03/16/2021] [Indexed: 12/18/2022]
Abstract
Cryopreservation of pancreatic islets can overcome the severe shortage of islet donors in clinical islet transplantation, but the impaired quality of post-warm islets need improvement. This present study was conducted to investigate whether the pre- or post-treatment of rat islets with liver decellularized matrix (LDM) for vitrification can improve the viability (FDA/PI double staining) and the functionality (glucose-stimulated insulin secretion [GSIS] assay). Rat LDM was prepared by high-hydrostatic pressure, lyophilization, and re-suspension in saline. Co-culturing of isolated islets with 0 (control), 30, 60, or 90 μg/ml LDM for 24 h resulted in the comparable viability among the 4 groups (98.7-99.6%) and the higher insulin secretion potential in 30 and 60 μg/ml LDM treatment groups than the control group (stimulation index [SI]: 12.1 and 12.7, respectively, vs. 6.5 in the control group, P < 0.05). When the islets co-cultured with 60 μg/ml LDM were vitrified-warmed on a nylon mesh cryodevice, the viability and the GSIS of the post-warm islets were not improved. Post-treatment of vitrified-warmed islets with 60 μg/ml LDM during the recovery culture for 12 h resulted in the comparable clearance of degenerating cell debris from the post-warm islets, while their insulin secretion potential was improved (SI: 5.0 vs. 3.5 in the control group, P < 0.05). These findings indicate that the components in LDM can enhance the insulin secretion potential of rat islets suffering damage by enzymatic stress during the islet isolation process or by cryoinjuries during the vitrification-warming process.
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Affiliation(s)
- Kenyu Nakayama-Iwatsuki
- Graduate School of Science and Technology, Shinshu University, Ueda, Nagano, 386-8567, Japan; National Institute for Physiological Sciences, Okazaki, Aichi, 444-8787, Japan
| | - Kotaro Yanagisawa
- Graduate School of Science and Technology, Shinshu University, Ueda, Nagano, 386-8567, Japan
| | - Dan Tanaka
- Graduate School of Science and Technology, Shinshu University, Ueda, Nagano, 386-8567, Japan
| | - Masumi Hirabayashi
- National Institute for Physiological Sciences, Okazaki, Aichi, 444-8787, Japan; School of Life Science, The Graduate University for Advanced Studies, Okazaki, Aichi, 444-8787, Japan
| | - Jun Negishi
- Graduate School of Science and Technology, Shinshu University, Ueda, Nagano, 386-8567, Japan; Faculty of Textile Science and Technology, Shinshu University, Ueda, Nagano, 386-8567, Japan
| | - Shinichi Hochi
- Graduate School of Science and Technology, Shinshu University, Ueda, Nagano, 386-8567, Japan; Faculty of Textile Science and Technology, Shinshu University, Ueda, Nagano, 386-8567, Japan.
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22
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Alcazar O, Alvarez A, Ricordi C, Linetsky E, Buchwald P. The Effect of Recovery Warm-up Time Following Cold Storage on the Dynamic Glucose-stimulated Insulin Secretion of Isolated Human Islets. Cell Transplant 2021; 29:963689720908278. [PMID: 32223315 PMCID: PMC7444215 DOI: 10.1177/0963689720908278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Standardized islet characterization assays that can provide results in a timely manner are essential for successful islet cell transplantation. A critical component of islet cell quality is β-cell function, and perifusion-based assessments of dynamic glucose-stimulated insulin secretion (GSIS) are the most informative method to assess this, as they provide the most complex in vitro evaluation of GSIS. However, protocols used vary considerably among centers and investigators as they often use different low- and high-glucose concentrations, exposure-times, flow-rates, oxygen concentrations, islet numbers, analytical methods, measurement units, and instruments, which result in different readouts and make comparisons across platforms difficult. Additionally, the conditions of islet storage and shipment prior to assessment may also affect islet function. Establishing improved standardized protocols for perifusion GSIS assays should be an integral part of the ongoing effort to increase the rigor of human islet studies. Here, we performed detailed evaluation of GSIS of human islets using a fully automated multichannel perifusion instrument following various warm-up recovery times after cold storage that corresponds to current shipping conditions (8°C). We found that recovery times shorter than 18 h (overnight) resulted in impaired insulin secretion. While the effects were relatively moderate on second-phase insulin secretion, first-phase peaks were restored only following 18-h incubation. Hence, the biphasic profile of dynamic GSIS was considerably affected when islets were not allowed to recover for a sufficient time after being maintained in cold. Accordingly, while cold storage might improve islet cell survival during shipment and prolong the length of culture, functional assessments should be performed only after allowing for at least overnight recovery at physiological temperatures.
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Affiliation(s)
- Oscar Alcazar
- Diabetes Research Institute, Miller School of Medicine, University of Miami, FL, USA
| | - Alejandro Alvarez
- Diabetes Research Institute, Miller School of Medicine, University of Miami, FL, USA
| | - Camillo Ricordi
- Diabetes Research Institute, Miller School of Medicine, University of Miami, FL, USA.,Department of Surgery, Division of Cellular Transplantation, cGMP Advanced Cell and Biologic Manufacturing Facility, Miller School of Medicine, University of Miami, FL, USA
| | - Elina Linetsky
- Diabetes Research Institute, Miller School of Medicine, University of Miami, FL, USA.,Department of Surgery, Division of Cellular Transplantation, cGMP Advanced Cell and Biologic Manufacturing Facility, Miller School of Medicine, University of Miami, FL, USA
| | - Peter Buchwald
- Diabetes Research Institute, Miller School of Medicine, University of Miami, FL, USA.,Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, FL, USA
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23
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Primavera R, Razavi M, Kevadiya BD, Wang J, Vykunta A, Di Mascolo D, Decuzzi P, Thakor AS. Enhancing islet transplantation using a biocompatible collagen-PDMS bioscaffold enriched with dexamethasone-microplates. Biofabrication 2021; 13. [PMID: 33455953 DOI: 10.1088/1758-5090/abdcac] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 01/15/2021] [Indexed: 01/01/2023]
Abstract
Islet transplantation is a promising approach to enable type 1 diabetic patients to attain glycemic control independent of insulin injections. However, up to 60% of islets are lost immediately following transplantation. To improve this outcome, islets can be transplanted within bioscaffolds, however, synthetic bioscaffolds induce an intense inflammatory reaction which can have detrimental effects on islet function and survival. In the present study, we first improved the biocompatibility of polydimethylsiloxane (PDMS) bioscaffolds by coating them with collagen. To reduce the inflammatory response to PDMS bioscaffolds, we then enriched the bioscaffolds with dexamethasone-loaded microplates (DEX-µScaffolds). These DEX-microplates have the ability to release DEX in a sustained manner over 7 weeks within a therapeutic range that does not affect the glucose responsiveness of the islets but which minimizes inflammation in the surrounding microenvironment. The bioscaffold showed excellent mechanical properties that enabled it to resist pore collapse thereby helping to facilitate islet seeding and its handling for implantation, and subsequent engraftment, within the epididymal fat pad (EFP). Following the transplantation of islets into the EFP of diabetic mice using DEX-µScaffolds there was a return in basal blood glucose to normal values by day 4, with normoglycemia maintained for 30 days. Furthermore, these animals demonstrated a normal dynamic response to glucose challenges with histological evidence showing reduced pro-inflammatory cytokines and fibrotic tissue surrounding DEX-µScaffolds at the transplantation site. In contrast, diabetic animals transplanted with either islets alone or islets in bioscaffolds without DEX microplates were not able to regain glycemic control during basal conditions with overall poor islet function. Taken together, our data show that coating PDMS bioscaffolds with collagen, and enriching them with DEX-microplates, significantly prolongs and enhances islet function and survival.
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Affiliation(s)
- Rosita Primavera
- Radiology, Stanford University School of Medicine, 3155 Porter Drive, Stanford, California, 94305-5119, UNITED STATES
| | - Mehdi Razavi
- University of Central Florida, 6900 Lake Nona Blvd, Orlando, Florida, 32827, UNITED STATES
| | - Bhavesh D Kevadiya
- PEN, University of Nebraska Medical Center, Lab-3064,DRC-1,department of pharmacology and experimental neuroscience, Omaha, Nebraska, 68198, UNITED STATES
| | - Jing Wang
- Radiology, Stanford University School of Medicine, 3155 Porter Drive, Stanford, California, 94304, UNITED STATES
| | - Akshara Vykunta
- Radiology, Stanford University School of Medicine, 3155 Porter Drive, Stanford, California, 94304, UNITED STATES
| | - Daniele Di Mascolo
- Central Research Labs Genova, Istituto Italiano di Tecnologia, Via Morego, 30, Genova, Liguria, 16163, ITALY
| | - Paolo Decuzzi
- Istituto Italiano di Tecnologia, Via Morego, 30, Genova, Liguria, 16163, ITALY
| | - Avnesh S Thakor
- Radiology, Stanford University School of Medicine, 3155 Porter Drive, Stanford, California, 94304, UNITED STATES
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24
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Velluto D, Bojadzic D, De Toni T, Buchwald P, Tomei AA. Drug-Integrating Amphiphilic Nanomaterial Assemblies: 1. Spatiotemporal control of cyclosporine delivery and activity using nanomicelles and nanofibrils. J Control Release 2021; 329:955-970. [PMID: 33086102 PMCID: PMC7904645 DOI: 10.1016/j.jconrel.2020.10.026] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 10/12/2020] [Accepted: 10/15/2020] [Indexed: 12/13/2022]
Abstract
Immunomodulatory therapies are limited by unavoidable side effects as well as poor solubility, stability, and pharmacokinetic properties. Nanomaterial-based drug delivery may overcome these limitations by increasing drug solubility, site-targeting, and duration of action. Here, we prepared innovative drug-integrating amphiphilic nanomaterial assemblies (DIANA) with tunable hydrophobicity, size, and morphology, and we evaluated their ability to deliver cyclosporine A (CsA) for immunomodulatory applications. We synthesized amphiphilic block copolymers made of poly(ethylene glycol)-poly(propylene sulfide) (PEG-PPS) and poly(ethylene glycol)-oligo(ethylene sulfide) (PEG-OES) that can self-assemble into solid core nanomicelles (nMIC, with ≈20 nm diameter) and nanofibrils (nFIB, with ≈5 nm diameter and > 500 nm length), respectively. nMIC and nFIB displayed good CsA encapsulation efficiency (up to 4.5 and 2 mg/mL, respectively in aqueous solution), superior to many other solubilization methods, and provided sustained release (>14 and > 7 days for the nMIC and nFIB) without compromising CsA's pharmacological activity. Treatment of insulin-secreting cells with unloaded DIANAs did not impair cell viability and functionality. Both CsA-loaded DIANAs inhibited the proliferation and activation of insulin-reactive cytotoxic T cells in vitro. Subcutaneous injections of CsA-loaded DIANAs in mice provided CsA sustained release, decreasing alloantigen-induced immune responses in the draining lymph node at lower doses and reduced administration frequency than unformulated CsA. While nMIC solubilized higher amounts and provided more sustained release of CsA in vitro, nFIB enhanced cellular uptake and promoted local retention due to slower trafficking in vivo. DIANAs provide a versatile platform for a local immune suppression regimen that can be applied to allogeneic cell transplantation.
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Affiliation(s)
- Diana Velluto
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Damir Bojadzic
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL, USA; Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Teresa De Toni
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL, USA; Department of Biomedical Engineering, University of Miami, Miami, FL, USA
| | - Peter Buchwald
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL, USA; Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, FL, USA.
| | - Alice A Tomei
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL, USA; Department of Biomedical Engineering, University of Miami, Miami, FL, USA; Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, USA; Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA.
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25
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Pomposelli T, Wang P, Takeuchi K, Miyake K, Ariyoshi Y, Watanabe H, Chen X, Shimizu A, Robertson N, Yamada K, Moore A. Protection of Pancreatic Islets Using Theranostic Silencing Nanoparticles in a Baboon Model of Islet Transplantation. Diabetes 2020; 69:2414-2422. [PMID: 32855170 PMCID: PMC7576559 DOI: 10.2337/db20-0517] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Accepted: 08/24/2020] [Indexed: 12/15/2022]
Abstract
The long-term success of pancreatic islet transplantation (Tx) as a cure for type 1 diabetes remains limited. Islet loss after Tx related to apoptosis, inflammation, and other factors continues to limit Tx efficacy. In this project, we demonstrate a novel approach aimed at protecting islets before Tx in nonhuman primates (NHPs) (baboons) by silencing a gene (caspase-3) responsible for induction of apoptosis. This was done using siRNA (siCas-3) conjugated to magnetic nanoparticles (MNs). In addition to serving as carriers for siCas-3, these nanoparticles also act as reporters for MRI, so islets labeled with MN-siCas-3 can be monitored in vivo after Tx. In vitro studies showed the antiapoptotic effect of MN-siCas-3 on islets in culture, resulting in minimal islet loss. For in vivo studies, donor baboon islets were labeled with MN-siCas-3 and infused into recipient diabetic subjects. A dramatic reduction in insulin requirements was observed in animals transplanted with even a marginal number of labeled islets compared with controls. By demonstrating the protective effect of MN-siCas-3 in the challenging NHP model, this study proposes a novel strategy to minimize the number of donor islets required from either cadaveric or living donors.
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Affiliation(s)
- Thomas Pomposelli
- Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY
| | - Ping Wang
- Precision Health Program, Michigan State University, East Lansing, MI
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI
| | - Kazuhiro Takeuchi
- Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY
| | - Katsunori Miyake
- Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY
| | - Yuichi Ariyoshi
- Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY
| | - Hironosuke Watanabe
- Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY
| | - Xiaojuan Chen
- Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY
| | - Akira Shimizu
- Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY
| | - Neil Robertson
- Precision Health Program, Michigan State University, East Lansing, MI
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI
| | - Kazuhiko Yamada
- Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY
| | - Anna Moore
- Precision Health Program, Michigan State University, East Lansing, MI
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI
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26
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Yu M, Agarwal D, Korutla L, May CL, Wang W, Griffith NN, Hering BJ, Kaestner KH, Velazquez OC, Markmann JF, Vallabhajosyula P, Liu C, Naji A. Islet transplantation in the subcutaneous space achieves long-term euglycaemia in preclinical models of type 1 diabetes. Nat Metab 2020; 2:1013-1020. [PMID: 32895576 PMCID: PMC7572844 DOI: 10.1038/s42255-020-0269-7] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 07/21/2020] [Indexed: 01/19/2023]
Abstract
The intrahepatic milieu is inhospitable to intraportal islet allografts1-3, limiting their applicability for the treatment of type 1 diabetes. Although the subcutaneous space represents an alternate, safe and easily accessible site for pancreatic islet transplantation, lack of neovascularization and the resulting hypoxic cell death have largely limited the longevity of graft survival and function and pose a barrier to the widespread adoption of islet transplantation in the clinic. Here we report the successful subcutaneous transplantation of pancreatic islets admixed with a device-free islet viability matrix, resulting in long-term euglycaemia in diverse immune-competent and immuno-incompetent animal models. We validate sustained normoglycaemia afforded by our transplantation methodology using murine, porcine and human pancreatic islets, and also demonstrate its efficacy in a non-human primate model of syngeneic islet transplantation. Transplantation of the islet-islet viability matrix mixture in the subcutaneous space represents a simple, safe and reproducible method, paving the way for a new therapeutic paradigm for type 1 diabetes.
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Affiliation(s)
- Ming Yu
- Division of Transplantation, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Divyansh Agarwal
- Division of Transplantation, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
- Medical Scientist Training Program, Genomics and Computational Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
| | - Laxminarayana Korutla
- Division of Transplantation, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Catherine L May
- Institute for Diabetes, Obesity & Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
- Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA
| | - Wei Wang
- Division of Transplantation, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | | | - Bernhard J Hering
- Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, MN, USA
| | - Klaus H Kaestner
- Institute for Diabetes, Obesity & Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Omaida C Velazquez
- Division of Vascular Surgery, DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - James F Markmann
- Division of Transplant Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | | | - Chengyang Liu
- Division of Transplantation, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
| | - Ali Naji
- Division of Transplantation, Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
- Institute for Diabetes, Obesity & Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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27
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The MEK Inhibitor Trametinib Suppresses Major Histocompatibility Antigen-mismatched Rejection Following Pancreatic Islet Transplantation. Transplant Direct 2020; 6:e591. [PMID: 32851124 PMCID: PMC7423917 DOI: 10.1097/txd.0000000000001045] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 06/19/2020] [Accepted: 07/04/2020] [Indexed: 11/26/2022] Open
Abstract
Background. Potential adverse effects, such as functional impairment of islets, render conventional immunosuppressive drugs unsuitable for use in islet transplantation. In addition, as a single therapy, they cannot prolong islet allograft survival. Here, we investigated the utility of the mitogen-activated protein kinase inhibitor trametinib and asked whether it ameliorates acute rejection of transplanted islets without the need for conventional immunosuppressants. Methods. Islets from fully major histocompatibility complex-mismatched BALB/c mice were transplanted into streptozotocin-induced diabetic C57BL/6 mice via the portal vein. These mice received trametinib or vehicle (orally) for 28 days. Isolated islets from BALB/c mice were incubated in vitro with different concentrations of trametinib to determine viability and function. Results. Trametinib (0.1 and 0.3 mg/kg) prolonged graft survival significantly (P = 0.0007 and P = 0.005, respectively) when compared with vehicle. Histologic analyses revealed that cellular infiltration of the graft by lymphocytes was inhibited significantly on day 7 (P < 0.05). In addition, trametinib suppressed functional differentiation of naive CD4+ T cells in recipients. Expression of mRNA encoding inflammatory cytokines interleukin (IL)-2, tumor necrosis factor α, and interferon γ in recipients treated with trametinib was also inhibited (P < 0.001, P < 0.05, and P < 0.01, respectively). Trametinib also increased production of IL-4 and IL-10 (P < 0.05 and P = 0.20, respectively). In vitro, islets incubated with different concentrations of trametinib exhibited no harmful effects with respect to viability and function. Conclusions. Trametinib delayed islet graft rejection by inhibiting functional differentiation of naive CD4+ T cells and regulating inflammatory cytokines. Trametinib might be a promising candidate for maintenance immunosuppressive therapy after allogeneic islet transplantation.
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28
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Nakamura T, Fujikura J, Anazawa T, Ito R, Ogura M, Okajima H, Uemoto S, Inagaki N. Long-term outcome of islet transplantation on insulin-dependent diabetes mellitus: An observational cohort study. J Diabetes Investig 2020; 11:363-372. [PMID: 31390159 PMCID: PMC7078128 DOI: 10.1111/jdi.13128] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 07/17/2019] [Accepted: 07/29/2019] [Indexed: 12/13/2022] Open
Abstract
AIMS/INTRODUCTION To investigate the long-term efficacy and safety of islet transplantation (ITx) compared with multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII). MATERIALS AND METHODS Among 619 patients diagnosed as insulin-dependent diabetes mellitus or type 1 diabetes at Kyoto University, Kyoto, Japan, seven patients were selected as the ITx group and 26 age-matched patients with no endogenous insulin secretion were selected as the MDI/CSII group. Hemoglobin A1c, aspartate aminotransferase/alanine aminotransferase (AST/ALT) and creatinine were assessed retrospectively at 1, 2, 5 and 10 years for both groups; serum C-peptide immunoreactivity was assessed for the ITx group. Major clinical events were also assessed. RESULTS Hemoglobin A1c improvement in ITx was significant at 1 year (8.4% [7.8-9.9%] at baseline to 7.1% [6.3-7.4%] in ITx vs 8.2% [7.4-9.8%] at baseline to 8.1% [7.3-9.5%] in MDI/CSII, P < 0.01 between groups), and was maintained at 2 years (7.4% [6.3-8.2%] vs 8.4% [7.4-9.6%], P = 0.11). The increase of stimulated C-peptide immunoreactivity was significant at 1 year (0.57 ng/mL [0.26-0.99 ng/mL], P < 0.05 from baseline) and 2 years (0.43 ng/mL [0.19-0.67 ng/mL], P < 0.05), although it became insignificant thereafter. There was no significant difference in AST/ALT or creatinine at 10 years, although a transient AST/ALT elevation was observed in ITx. In regard to clinical events, the occurrence of severe hypoglycemia was 14% vs 31% (relative risk 0.46, P = 0.64), that of infectious disease was 43% vs 12% (relative risk 3.71, P = 0.09) and digestive symptoms was 43% vs 7.7% (relative risk 5.57, P = 0.05) in ITx vs MDI/CSII, respectively. No patient died in either group. CONCLUSIONS The present findings showed that ITx was considered to contribute to the reduction of hypoglycemia and better glycemic control with tolerable, but attention-requiring, risks over a period of 10 years compared with MDI/CSII.
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Affiliation(s)
- Toshihiro Nakamura
- Department of Diabetes, Endocrinology and NutritionGraduate School of MedicineKyoto UniversityKyotoJapan
| | - Junji Fujikura
- Department of Diabetes, Endocrinology and NutritionGraduate School of MedicineKyoto UniversityKyotoJapan
| | - Takayuki Anazawa
- Division of Hepato‐Biliary‐Pancreatic Surgery and TransplantationGraduate School of MedicineKyoto UniversityKyotoJapan
| | - Ryo Ito
- Department of Diabetes, Endocrinology and NutritionGraduate School of MedicineKyoto UniversityKyotoJapan
| | - Masahito Ogura
- Department of Diabetes, Endocrinology and NutritionGraduate School of MedicineKyoto UniversityKyotoJapan
| | - Hideaki Okajima
- Division of Hepato‐Biliary‐Pancreatic Surgery and TransplantationGraduate School of MedicineKyoto UniversityKyotoJapan
| | - Shinji Uemoto
- Division of Hepato‐Biliary‐Pancreatic Surgery and TransplantationGraduate School of MedicineKyoto UniversityKyotoJapan
| | - Nobuya Inagaki
- Department of Diabetes, Endocrinology and NutritionGraduate School of MedicineKyoto UniversityKyotoJapan
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29
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Raffin C, Vo LT, Bluestone JA. T reg cell-based therapies: challenges and perspectives. Nat Rev Immunol 2020; 20:158-172. [PMID: 31811270 PMCID: PMC7814338 DOI: 10.1038/s41577-019-0232-6] [Citation(s) in RCA: 473] [Impact Index Per Article: 94.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/07/2019] [Indexed: 12/25/2022]
Abstract
Cellular therapies using regulatory T (Treg) cells are currently undergoing clinical trials for the treatment of autoimmune diseases, transplant rejection and graft-versus-host disease. In this Review, we discuss the biology of Treg cells and describe new efforts in Treg cell engineering to enhance specificity, stability, functional activity and delivery. Finally, we envision that the success of Treg cell therapy in autoimmunity and transplantation will encourage the clinical use of adoptive Treg cell therapy for non-immune diseases, such as neurological disorders and tissue repair.
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Affiliation(s)
- Caroline Raffin
- Sean N. Parker Autoimmune Research Laboratory, Diabetes Center, University of California, San Francisco, San Francisco, CA, USA
| | - Linda T Vo
- Sean N. Parker Autoimmune Research Laboratory, Diabetes Center, University of California, San Francisco, San Francisco, CA, USA
| | - Jeffrey A Bluestone
- Sean N. Parker Autoimmune Research Laboratory, Diabetes Center, University of California, San Francisco, San Francisco, CA, USA.
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30
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Zheng L, Wang Y, Yang B, Zhang B, Wu Y. Islet Transplantation Imaging in vivo. Diabetes Metab Syndr Obes 2020; 13:3301-3311. [PMID: 33061492 PMCID: PMC7520574 DOI: 10.2147/dmso.s263253] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Accepted: 07/29/2020] [Indexed: 12/31/2022] Open
Abstract
Although islet transplantation plays an effective and powerful role in the treatment of diabetes, a large amount of islet grafts are lost at an early stage due to instant blood-mediated inflammatory reactions, immune rejection, and β-cell toxicity resulting from immunosuppressive agents. Timely intervention based on the viability and function of the transplanted islets at an early stage is crucial. Various islet transplantation imaging techniques are available for monitoring the conditions of post-transplanted islets. Due to the development of various imaging modalities and the continuous study of contrast agents, non-invasive islet transplantation imaging in vivo has made great progress. The tracing and functional evaluation of transplanted islets in vivo have thus become possible. However, most studies on contrast agent and imaging modalities are limited to animal experiments, and long-term toxicity and stability need further evaluation. Accordingly, the clinical application of the current achievements still requires a large amount of effort. In this review, we discuss the contrast agents for MRI, SPECT/PET, BLI/FI, US, MPI, PAI, and multimodal imaging. We further summarize the advantages and limitations of various molecular imaging methods.
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Affiliation(s)
- Lei Zheng
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou310000, People’s Republic of China
| | - Yinghao Wang
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou310000, People’s Republic of China
| | - Bin Yang
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou310000, People’s Republic of China
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou310000, People’s Republic of China
| | - Bo Zhang
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou310000, People’s Republic of China
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou310000, People’s Republic of China
- Correspondence: Bo Zhang; Yulian Wu Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou310000, People’s Republic of China Tel/Fax +86 571 87783563 Email ;
| | - Yulian Wu
- Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou310000, People’s Republic of China
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou310000, People’s Republic of China
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31
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Carnosine, pancreatic protection, and oxidative stress in type 1 diabetes. Diabetes 2020. [DOI: 10.1016/b978-0-12-815776-3.00020-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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32
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Luckring EJ, Parker PD, Hani H, Grace MH, Lila MA, Pierce JG, Adin CA. In Vitro Evaluation of a Novel Synthetic Bilirubin Analog as an Antioxidant and Cytoprotective Agent for Pancreatic Islet Transplantation. Cell Transplant 2020; 29:963689720906417. [PMID: 32323568 PMCID: PMC7444211 DOI: 10.1177/0963689720906417] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 01/23/2020] [Accepted: 01/24/2020] [Indexed: 11/30/2022] Open
Abstract
Bilirubin is a natural cytoprotective agent and physiologic doses have proven to be beneficial in various models of organ and cellular transplantation. Recently, we showed that bilirubin has protective effects in models of pancreatic islet transplantation, preventing cell death associated with islet stress and suppressing the release of damage-associated molecular patterns. Despite these promising therapeutic attributes, the natural bilirubin used in these research studies is animal-derived (porcine), making it unsuitable for clinical application. In the current study, we synthesized two bilirubin analogs that can be produced without the use of animal-derived products. Antioxidant activity for the analogs was measured using the ferric-reducing-ability-of-plasma (FRAP) and 2,2V-azinobis(3-ethylbenzothiazoline-6-sulfonate) (ABTS) assays. Dose-dependent cytotoxicity and cytoprotective effects were then demonstrated in isolated rat islets. Compound 1 showed similar antioxidant activity to natural bilirubin. Dose-dependent cytotoxicity was seen following treatment with Compound 1 and natural bilirubin at doses >40 μM, resulting in significantly increased cell death when compared to control islets (P < 0.05) or islets treated with doses ≤20 μM (P < 0.05). Following hypoxic challenge, islet cell death was reduced in islets treated with Compound 1 at 10 μM (17.27% ± 0.26%) compared to natural bilirubin at 10 μM (51.36% ± 0.71%; P < 0.0001) or 20 μM (59.02% ± 0.83%; P < 0.0001) and control islets (36.51% ± 0.44%; P < 0.0001). Compound 1 was found to have promising antioxidant and cytoprotective effects, limiting islet cell death in a model of islet transplantation hypoxic stress. Compound 1 may serve as a synthetic drug lead for clinical islet transplantation and further evaluation of this molecule and its analogs is warranted.
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Affiliation(s)
- Emilee J. Luckring
- Department of Veterinary Clinical Sciences, North Carolina
State University, Raleigh, NC, USA
| | - Patrick D. Parker
- Department of Chemistry and Comparative Medicine Institute,
North Carolina State University, Raleigh, NC, USA
| | - Homayoun Hani
- Department of Cell Biology and Physiology, University of
North Carolina, Chapel Hill, NC, USA
| | - Mary H. Grace
- Plants for Human Health Institute, Department of Food,
Bioprocessing, and Nutrition Sciences and Comparative Medicine Institute,
North Carolina State University, Kannapolis, NC, USA
| | - Mary A. Lila
- Plants for Human Health Institute, Department of Food,
Bioprocessing, and Nutrition Sciences and Comparative Medicine Institute,
North Carolina State University, Kannapolis, NC, USA
| | - Joshua G. Pierce
- Department of Chemistry and Comparative Medicine Institute,
North Carolina State University, Raleigh, NC, USA
| | - Christopher A. Adin
- Department of Small Animal Clinical Sciences, University of
Florida, Gainesville, FL, USA
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Coentro JQ, De Pieri A, Gaspar D, Tsiapalis D, Zeugolis DI, Bayon Y. Translational Research Symposium-collaborative efforts as driving forces of healthcare innovation. JOURNAL OF MATERIALS SCIENCE. MATERIALS IN MEDICINE 2019; 30:133. [PMID: 31792698 DOI: 10.1007/s10856-019-6339-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Accepted: 11/16/2019] [Indexed: 06/10/2023]
Abstract
The 5th Translational Research Symposium was organised at the annual meeting of the European Society for Biomaterials 2018, Maastricht, the Netherlands, with emphasis on the future of emerging and smart technologies for healthcare in Europe. Invited speakers from academia and industry highlighted the vision and expectations of healthcare in Europe beyond 2020 and the perspectives of innovation stakeholders, such as small and medium enterprises, large companies and Universities. The aim of the present article is to summarise and explain the main statements made during the symposium, with particular attention on the need to identify unmet clinical needs and their efficient translation into healthcare solutions through active collaborations between all the participants involved in the value chain.
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Affiliation(s)
- João Q Coentro
- Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), National University of Galway Ireland (NUI Galway), Galway, Ireland
- Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), National University of Galway Ireland (NUI Galway), Galway, Ireland
| | - Andrea De Pieri
- Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), National University of Galway Ireland (NUI Galway), Galway, Ireland
- Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), National University of Galway Ireland (NUI Galway), Galway, Ireland
- Proxy Biomedical, Spiddal, Galway, Ireland
| | - Diana Gaspar
- Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), National University of Galway Ireland (NUI Galway), Galway, Ireland
- Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), National University of Galway Ireland (NUI Galway), Galway, Ireland
| | - Dimitrios Tsiapalis
- Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), National University of Galway Ireland (NUI Galway), Galway, Ireland
- Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), National University of Galway Ireland (NUI Galway), Galway, Ireland
| | - Dimitrios I Zeugolis
- Regenerative, Modular & Developmental Engineering Laboratory (REMODEL), National University of Galway Ireland (NUI Galway), Galway, Ireland
- Science Foundation Ireland (SFI) Centre for Research in Medical Devices (CÚRAM), National University of Galway Ireland (NUI Galway), Galway, Ireland
| | - Yves Bayon
- Medtronic, Sofradim Production, Trevoux, France.
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Cheng Y, Zhang Y, Yu Y, Zhao G, Zhao Y, He X. Cold-Responsive Nanocapsules Enable the Sole-Cryoprotectant-Trehalose Cryopreservation of β Cell-Laden Hydrogels for Diabetes Treatment. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2019; 15:e1904290. [PMID: 31833664 DOI: 10.1002/smll.201904290] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/03/2019] [Revised: 09/17/2019] [Indexed: 05/27/2023]
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Ishida N, Ishiyama K, Saeki Y, Tanaka Y, Ohdan H. Cotransplantation of preactivated mesenchymal stem cells improves intraportal engraftment of islets by inhibiting liver natural killer cells in mice. Am J Transplant 2019; 19:2732-2745. [PMID: 30859713 DOI: 10.1111/ajt.15347] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Revised: 02/10/2019] [Accepted: 03/03/2019] [Indexed: 01/25/2023]
Abstract
The activation of natural killer (NK) cells in the liver inhibits engraftment of intraportally transplanted islets. We attempted to modulate the activity of NK cells by cotransplanting mesenchymal stem cells (MSCs) with islets in mice. We first investigated the ability of MSCs to secrete prostaglandin E2 , a predominant inhibitor of NK cell function, in various combinations of inflammatory cytokines. Notably, we found that prostaglandin E2 production was partially delayed in MSCs activated by inflammatory cytokines in vitro, whereas liver NK cells were activated early after islet transplant in vivo. Accordingly, preactivated MSCs, but not naive MSCs, substantially suppressed the expression of activation markers in liver NK cells after cotransplant with islets. Similarly, cotransplant with preactivated MSCs, but not naive MSCs, markedly improved the survival of islet grafts. These results highlight MSC cotransplant as an effective and clinically feasible method for enhancing engraftment efficiency.
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Affiliation(s)
- Nobuki Ishida
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kohei Ishiyama
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.,Department of Surgery, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure, Japan
| | - Yoshihiro Saeki
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuka Tanaka
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hideki Ohdan
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
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Stevens M, Oltean S. Modulation of the Apoptosis Gene Bcl-x Function Through Alternative Splicing. Front Genet 2019; 10:804. [PMID: 31552099 PMCID: PMC6743414 DOI: 10.3389/fgene.2019.00804] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 07/31/2019] [Indexed: 01/09/2023] Open
Abstract
Apoptosis plays a vital role in cell homeostasis during development and disease. Bcl-x, a member of the Bcl-2 family of proteins, is a mitochondrial transmembrane protein that functions to regulate the intrinsic apoptosis pathway. An alternative splicing (AS) event in exon 2 of Bcl-x results in two isoforms of Bcl-x with antagonistic effects on cell survival: Bcl-xL (long isoform), which is anti-apoptotic, and Bcl-xS (short isoform), which is pro-apoptotic. Bcl-xL is the most abundant Bcl-x protein and functions to inhibit apoptosis by a number of different mechanisms including inhibition of Bax. In contrast, Bcl-xS can directly bind to and inhibit the anti-apoptotic Bcl-xL and Bcl-2 proteins, resulting in the release of the pro-apoptotic Bak. There are multiple splice factors and signaling pathways that influence the Bcl-xL/Bcl-xS splicing ratio, including serine/arginine-rich (SR) proteins, heterogeneous nuclear ribonucleoproteins (hnRNPs), transcription factors, and cytokines. Dysregulation of the AS of Bcl-x has been implicated in cancer and diabetes. In cancer, the upregulation of Bcl-xL expression in tumor cells can result in resistance to chemotherapeutic agents. On the other hand, dysregulation of Bcl-x AS to promote Bcl-xS expression has been shown to be detrimental to pancreatic β-cells in diabetes, resulting in β-cell apoptosis. Therefore, manipulation of the splice factor, transcription factor, and signaling pathways that modulate this splicing event is fast emerging as a therapeutic avenue in the treatment of cancer and diabetes.
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Affiliation(s)
- Megan Stevens
- Institute of Biomedical and Clinical Science, Medical School, College of Medicine and Health, University of Exeter, Exeter, United Kingdom
| | - Sebastian Oltean
- Institute of Biomedical and Clinical Science, Medical School, College of Medicine and Health, University of Exeter, Exeter, United Kingdom
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Hu S, de Vos P. Polymeric Approaches to Reduce Tissue Responses Against Devices Applied for Islet-Cell Encapsulation. Front Bioeng Biotechnol 2019; 7:134. [PMID: 31214587 PMCID: PMC6558039 DOI: 10.3389/fbioe.2019.00134] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 05/20/2019] [Indexed: 12/15/2022] Open
Abstract
Immunoisolation of pancreatic islets is a technology in which islets are encapsulated in semipermeable but immunoprotective polymeric membranes. The technology allows for successful transplantation of insulin-producing cells in the absence of immunosuppression. Different approaches of immunoisolation are currently under development. These approaches involve intravascular devices that are connected to the bloodstream and extravascular devices that can be distinguished in micro- and macrocapsules and are usually implanted in the peritoneal cavity or under the skin. The technology has been subject of intense fundamental research in the past decade. It has co-evolved with novel replenishable cell sources for cure of diseases such as Type 1 Diabetes Mellitus that need to be protected for the host immune system. Although the devices have shown significant success in animal models and even in human safety studies most technologies still suffer from undesired tissue responses in the host. Here we review the past and current approaches to modulate and reduce tissue responses against extravascular cell-containing micro- and macrocapsules with a focus on rational choices for polymer (combinations). Choices for polymers but also choices for crosslinking agents that induce more stable and biocompatible capsules are discussed. Combining beneficial properties of molecules in diblock polymers or application of these molecules or other anti-biofouling molecules have been reviewed. Emerging are also the principles of polymer brushes that prevent protein and cell-adhesion. Recently also immunomodulating biomaterials that bind to specific immune receptors have entered the field. Several natural and synthetic polymers and even combinations of these polymers have demonstrated significant improvement in outcomes of encapsulated grafts. Adequate polymeric surface properties have been shown to be essential but how the surface should be composed to avoid host responses remains to be identified. Current insight is that optimal biocompatible devices can be created which raises optimism that immunoisolating devices can be created that allows for long term survival of encapsulated replenishable insulin-producing cell sources for treatment of Type 1 Diabetes Mellitus.
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Affiliation(s)
- Shuixan Hu
- Division of Medical Biology, Department of Pathology and Medical Biology, Immunoendocrinology, University of Groningen and University Medical Center Groningen, Groningen, Netherlands
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Optimizing PLG nanoparticle-peptide delivery platforms for transplantation tolerance using an allogeneic skin transplant model. Biomaterials 2019; 210:70-82. [PMID: 31077862 DOI: 10.1016/j.biomaterials.2019.04.030] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 04/22/2019] [Accepted: 04/25/2019] [Indexed: 12/19/2022]
Abstract
A robust regimen for inducing allogeneic transplantation tolerance involves pre-emptive recipient treatment with donor splenocytes (SP) rendered apoptotic by 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide(ECDI) treatment. However, such a regimen is limited by availability of donor cells, cost of cell procurement, and regulatory hurdles associated with cell-based therapies. Nanoparticles (NP) delivering donor antigens are a promising alternative for promoting transplantation tolerance. Here, we used a B6.C-H-2bm12(bm12) to C57BL/6(B6) skin transplant model involving a defined major histocompatibility antigen mismatch to investigate design parameters of poly(lactide-co-glycolide) (PLG) NPs delivering peptides containing the donor antigen for optimizing skin allograft survival. We showed that an epitope-containing short peptide (P1) was more effective than a longer peptide (P2) at providing graft protection. Importantly, the NP and P1 complex (NP-ECDI-P1) resulted in a significant expansion of graft-infiltrating Tregs. Interestingly, in comparison to donor ECDI-SP that provided indefinite graft protection, NP-ECDI-P1 targeted different splenic phagocytes and skin allografts in these recipients harbored significantly more graft-infiltrating CD8+IFN-γ+ cells. Collectively, the current study provides initial engineering parameters for a cell-free and biocompatible NP-peptide platform for transplant immunoregulation. Moreover, it also provides guidance to future NP engineering endeavors to recapitulate the effects of donor ECDI-SP as a goal for maximizing tolerance efficacy of NP formulations.
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Verheyen CA, Morales L, Sussman J, Paunovska K, Manzoli V, Ziebarth NM, Tomei AA. Characterization of Polyethylene Glycol-Reinforced Alginate Microcapsules for Mechanically Stable Cell Immunoisolation. MACROMOLECULAR MATERIALS AND ENGINEERING 2019; 304:1800679. [PMID: 31929732 PMCID: PMC6953757 DOI: 10.1002/mame.201800679] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Indexed: 06/02/2023]
Abstract
Islet transplantation within mechanically stable microcapsules offers the promise of long-term diabetes reversal without chronic immunosuppression. Reinforcing the ionically gelled network of alginate (ALG) hydrogels with covalently linked polyethylene glycol (PEG) may create hybrid structures with desirable mechanical properties. This report describes the fabrication of hybrid PEG-ALG interpenetrating polymer networks and the investigation of microcapsule swelling, surface modulus, rheology, compression, and permeability. It is demonstrated that hybrid networks are more resistant to bulk swelling and compressive deformation and display improved shape recovery and long-term resilience. Interestingly, it is shown that PEG-ALG networks behave like ALG during microscale surface deformation and small amplitude shear while exhibiting similar permeability properties. The results from this report's in vitro characterization are interpreted according to viscoelastic polymer theory and provide new insight into hybrid hydrogel mechanical behavior. This new understanding of PEG-ALG mechanical performance is then linked to previous work that demonstrated the success of hybrid polymer immunoisolation devices in vivo.
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Affiliation(s)
- Connor A Verheyen
- Diabetes Research Institute, 1450 NW 10th Avenue, Miami, FL 33136, USA
| | - Laura Morales
- Diabetes Research Institute, 1450 NW 10th Avenue, Miami, FL 33136, USA
| | - Joshua Sussman
- Diabetes Research Institute, 1450 NW 10th Avenue, Miami, FL 33136, USA
| | - Kalina Paunovska
- Diabetes Research Institute, 1450 NW 10th Avenue, Miami, FL 33136, USA
| | - Vita Manzoli
- Diabetes Research Institute, 1450 NW 10th Avenue, Miami, FL 33136, USA
| | - Noel M Ziebarth
- Department of Biomedical Engineering, University of Miami, 1251 Memorial Drive, Coral Gables, FL-33146, USA
| | - Alice A Tomei
- Diabetes Research Institute, 1450 NW 10th Avenue, Miami, FL 33136, USA
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Takahashi H, Sakata N, Yoshimatsu G, Hasegawa S, Kodama S. Regenerative and Transplantation Medicine: Cellular Therapy Using Adipose Tissue-Derived Mesenchymal Stromal Cells for Type 1 Diabetes Mellitus. J Clin Med 2019; 8:249. [PMID: 30781427 PMCID: PMC6406504 DOI: 10.3390/jcm8020249] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 02/09/2019] [Accepted: 02/13/2019] [Indexed: 02/06/2023] Open
Abstract
Type 1 diabetes mellitus (T1DM) is caused by the autoimmune targeting of pancreatic β-cells, and, in the advanced stage, severe hypoinsulinemia due to islet destruction. In patients with T1DM, continuous exogenous insulin therapy cannot be avoided. However, an insufficient dose of insulin easily induces extreme hyperglycemia or diabetic ketoacidosis, and intensive insulin therapy may cause hypoglycemic symptoms including hypoglycemic shock. While these insulin therapies are efficacious in most patients, some additional therapies are warranted to support the control of blood glucose levels and reduce the risk of hypoglycemia in patients who respond poorly despite receiving appropriate treatment. There has been a recent gain in the popularity of cellular therapies using mesenchymal stromal cells (MSCs) in various clinical fields, owing to their multipotentiality, capacity for self-renewal, and regenerative and immunomodulatory potential. In particular, adipose tissue-derived MSCs (ADMSCs) have become a focus in the clinical setting due to the abundance and easy isolation of these cells. In this review, we outline the possible therapeutic benefits of ADMSC for the treatment of T1DM.
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Affiliation(s)
- Hiroyuki Takahashi
- Department of Regenerative Medicine & Transplantation, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
- Center for Regenerative Medicine, Fukuoka University Hospital, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
- Department of Gastroenterological Surgery, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
| | - Naoaki Sakata
- Department of Regenerative Medicine & Transplantation, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
- Center for Regenerative Medicine, Fukuoka University Hospital, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
| | - Gumpei Yoshimatsu
- Department of Regenerative Medicine & Transplantation, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
- Center for Regenerative Medicine, Fukuoka University Hospital, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
| | - Suguru Hasegawa
- Department of Gastroenterological Surgery, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
| | - Shohta Kodama
- Department of Regenerative Medicine & Transplantation, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
- Center for Regenerative Medicine, Fukuoka University Hospital, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
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Farina M, Alexander JF, Thekkedath U, Ferrari M, Grattoni A. Cell encapsulation: Overcoming barriers in cell transplantation in diabetes and beyond. Adv Drug Deliv Rev 2019; 139:92-115. [PMID: 29719210 DOI: 10.1016/j.addr.2018.04.018] [Citation(s) in RCA: 129] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 03/19/2018] [Accepted: 04/25/2018] [Indexed: 02/07/2023]
Abstract
Cell-based therapy is emerging as a promising strategy for treating a wide range of human diseases, such as diabetes, blood disorders, acute liver failure, spinal cord injury, and several types of cancer. Pancreatic islets, blood cells, hepatocytes, and stem cells are among the many cell types currently used for this strategy. The encapsulation of these "therapeutic" cells is under intense investigation to not only prevent immune rejection but also provide a controlled and supportive environment so they can function effectively. Some of the advanced encapsulation systems provide active agents to the cells and enable a complete retrieval of the graft in the case of an adverse body reaction. Here, we review various encapsulation strategies developed in academic and industrial settings, including the state-of-the-art technologies in advanced preclinical phases as well as those undergoing clinical trials, and assess their advantages and challenges. We also emphasize the importance of stimulus-responsive encapsulated cell systems that provide a "smart and live" therapeutic delivery to overcome barriers in cell transplantation as well as their use in patients.
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Mesenchymal stem cells in combination with low-dose rapamycin significantly prolong islet allograft survival through induction of regulatory T cells. Biochem Biophys Res Commun 2018; 506:619-625. [DOI: 10.1016/j.bbrc.2018.10.070] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Accepted: 10/11/2018] [Indexed: 12/13/2022]
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Isx9 Regulates Calbindin D28K Expression in Pancreatic β Cells and Promotes β Cell Survival and Function. Int J Mol Sci 2018; 19:ijms19092542. [PMID: 30150605 PMCID: PMC6165483 DOI: 10.3390/ijms19092542] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 08/13/2018] [Accepted: 08/19/2018] [Indexed: 11/21/2022] Open
Abstract
Pancreatic β-cell dysfunction and death contribute to the onset of diabetes, and novel strategies of β-cell function and survival under diabetogenic conditions need to be explored. We previously demonstrated that Isx9, a small molecule based on the isoxazole scaffold, drives neuroendocrine phenotypes by increasing the expression of genes required for β-cell function and improves glycemia in a model of β cell regeneration. We further investigated the role of Isx9 in β-cell survival. We find that Isx9 drives the expression of Calbindin-D28K (D28K), a key regulator of calcium homeostasis, and plays a cytoprotective role through its calcium buffering capacity in β cells. Isx9 increased the activity of the calcineurin (CN)/cytoplasmic nuclear factor of the activated T-cells (NFAT) transcription factor, a key regulator of D28K, and improved the recruitment of NFATc1, cAMP response element-binding protein (CREB), and p300 to the D28K promoter. We found that nutrient stimulation increased D28K plasma membrane enrichment and modulated calcium channel activity in order to regulate glucose-induced insulin secretion. Isx9-mediated expression of D28K protected β cells against chronic stress induced by serum withdrawal or chronic inflammation by reducing caspase 3 activity. Consequently, Isx9 improved human islet function after transplantation in NOD-SCID mice in a streptozotocin-induced diabetes model. In summary, Isx9 significantly regulates expression of genes relevant to β cell survival and function, and may be an attractive therapy to treat diabetes and improve islet function post-transplantation.
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Brandhorst D, Parnaud G, Friberg A, Lavallard V, Demuylder-Mischler S, Hughes S, Saphörster J, Kurfürst M, Korsgren O, Berney T, Johnson PRV. Multicenter Assessment of Animal-free Collagenase AF-1 for Human Islet Isolation. Cell Transplant 2018; 26:1688-1693. [PMID: 29251107 PMCID: PMC5753983 DOI: 10.1177/0963689717731574] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Animal-free (AF) SERVA Collagenase AF-1 and Neutral Protease (NP) AF GMP Grade have recently become available for human islet isolation. This report describes the initial experiences of 3 different islet transplant centers. Thirty-four human pancreases were digested using 1 vial of the 6 different lots of Collagenase AF-1 (2,000–2,583 PZ-U/vial) supplemented with 4 different lots of NP AF in a range of 50 to 160 DMC-U per pancreas. Isolation, culture, and quality assessment were performed using standard techniques as previously described. All data are presented as mean ± standard error of the mean (SEM). Variability of pancreas weight was associated with a wide range of collagenase and NP activities, ranging from 12.7 to 46.6 PZ-U/g (26.0 ± 1.5 PZ-U/g) and 0.4 to 3.0 DMC-U/g (1.5 ± 0.1 DMC-U/g), respectively. Postpurification islet yield was 296,494 ± 33,620 islet equivalents (IEQ) equivalent to 3,274 ± 450 IEQ/g with a purity of 55.9% ± 3.2%. Quality assessment performed after 2 to 4 d of culture demonstrated a viability of 88.1% ± 1.5% and a stimulation index of 3.7 ± 0.7. Eighteen of the 34 preparations were transplanted into type 1 diabetic patients equivalent to a transplantation rate of 52.9%. Six preparations, which were infused into patients as first transplant, could be analyzed and increased the fasting C-peptide level from 0.11 ± 0.08 pretransplant to 1.23 ± 0.24 and 2.27 ± 0.31 ng/mL 3 and 6 mo posttransplant (P < 0.05), respectively. Insulin requirements were simultaneously reduced at the same time from 39.2 ± 3.8 IU/d before transplantation to 10.8 ± 4.1 and 4.0 ± 2.3 IU/d, after 3 and 6 mo posttransplant (P < 0.05), respectively. This study demonstrates the efficiency of AF SERVA Collagenase AF-1 and NP AF for clinical islet isolation and transplantation. The new plant-based production process makes these products a safe new option for the islet field.
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Affiliation(s)
- Daniel Brandhorst
- 1 Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom.,2 Oxford Centre for Diabetes, Endocrinology, and Metabolism (OCDEM), Churchill Hospital, Oxford, United Kingdom
| | - Géraldine Parnaud
- 3 Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospital, Geneva, Switzerland
| | - Andrew Friberg
- 4 Department of Immunology, Genetics and Pathology, University of Uppsala, Uppsala, Sweden
| | - Vanessa Lavallard
- 3 Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospital, Geneva, Switzerland
| | - Sandrine Demuylder-Mischler
- 3 Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospital, Geneva, Switzerland
| | - Stephen Hughes
- 1 Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom.,2 Oxford Centre for Diabetes, Endocrinology, and Metabolism (OCDEM), Churchill Hospital, Oxford, United Kingdom
| | | | | | - Olle Korsgren
- 4 Department of Immunology, Genetics and Pathology, University of Uppsala, Uppsala, Sweden
| | - Thierry Berney
- 3 Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospital, Geneva, Switzerland
| | - Paul R V Johnson
- 1 Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom.,2 Oxford Centre for Diabetes, Endocrinology, and Metabolism (OCDEM), Churchill Hospital, Oxford, United Kingdom
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The Spleen as an Optimal Site for Islet Transplantation and a Source of Mesenchymal Stem Cells. Int J Mol Sci 2018; 19:ijms19051391. [PMID: 29735923 PMCID: PMC5983746 DOI: 10.3390/ijms19051391] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Revised: 05/04/2018] [Accepted: 05/04/2018] [Indexed: 01/09/2023] Open
Abstract
This review demonstrates the unique potential of the spleen as an optimal site for islet transplantation and as a source of mesenchymal stem cells. Islet transplantation is a cellular replacement therapy used to treat severe diabetes mellitus; however, its clinical outcome is currently unsatisfactory. Selection of the most appropriate transplantation site is a major factor affecting the clinical success of this therapy. The spleen has long been studied as a candidate site for islet transplantation. Its advantages include physiological insulin drainage and regulation of immunity, and it has recently also been shown to contribute to the regeneration of transplanted islets. However, the efficacy of transplantation in the spleen is lower than that of intraportal transplantation, which is the current representative method of clinical islet transplantation. Safer and more effective methods of islet transplantation need to be established to allow the spleen to be used for clinical transplantation. The spleen is also of interest as a mesenchymal stem cell reservoir. Splenic mesenchymal stem cells contribute to the repair of damaged tissue, and their infusion may thus be a promising therapy for autoimmune diseases, including type 1 diabetes mellitus and Sjogren’s syndrome.
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Weaver JD, Headen DM, Hunckler MD, Coronel MM, Stabler CL, García AJ. Design of a vascularized synthetic poly(ethylene glycol) macroencapsulation device for islet transplantation. Biomaterials 2018; 172:54-65. [PMID: 29715595 DOI: 10.1016/j.biomaterials.2018.04.047] [Citation(s) in RCA: 93] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Revised: 04/19/2018] [Accepted: 04/23/2018] [Indexed: 10/25/2022]
Abstract
The use of immunoisolating macrodevices in islet transplantation confers the benefit of safety and translatability by containing transplanted cells within a single retrievable device. To date, there has been limited development and characterization of synthetic poly(ethylene glycol) (PEG)-based hydrogel macrodevices for islet encapsulation and transplantation. Herein, we describe a two-component synthetic PEG hydrogel macrodevice system, designed for islet delivery to an extrahepatic islet transplant site, consisting of a hydrogel core cross-linked with a non-degradable PEG dithiol and a vasculogenic outer layer cross-linked with a proteolytically sensitive peptide to promote degradation and enhance localized vascularization. Synthetic PEG macrodevices exhibited equivalent passive molecular transport to traditional microencapsulation materials (e.g., alginate) and long-term stability in the presence of proteases in vitro and in vivo, out to 14 weeks in rats. Encapsulated islets demonstrated high viability within the device in vitro and the incorporation of RGD adhesive peptides within the islet encapsulating PEG hydrogel improved insulin responsiveness to a glucose challenge. In vivo, the implementation of a vasculogenic, degradable hydrogel layer at the outer interface of the macrodevice enhanced vascular density within the rat omentum transplant site, resulting in improved encapsulated islet viability in a syngeneic diabetic rat model. These results highlight the benefits of the facile PEG platform to provide controlled presentation of islet-supportive ligands, as well as degradable interfaces for the promotion of engraftment and overall graft efficacy.
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Affiliation(s)
- Jessica D Weaver
- Woodruff School of Mechanical Engineering and Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA
| | - Devon M Headen
- Woodruff School of Mechanical Engineering and Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA
| | - Michael D Hunckler
- Woodruff School of Mechanical Engineering and Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA
| | - Maria M Coronel
- Woodruff School of Mechanical Engineering and Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA
| | - Cherie L Stabler
- Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA
| | - Andrés J García
- Woodruff School of Mechanical Engineering and Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA.
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Abstract
The role of arsenic trioxide (As2O3) in inhibiting immune rejection and prolonging islet allograft survival has been identified in islet allotransplantation. This study aims to explore the role of As2O3 in islet xenotransplantation and the action mechanism. The streptozotocin (STZ) was used in C57BL/6 mice to induce the type 1 diabetes mellitus (T1DM) for xenotransplantation models establishment. Donor islets were isolated by digesting. The flow cytometry (FCM) was used to analyze lymphocyte types. The blood sugar level was detected by using intraperitoneal glucose tolerance test (IPGTT). The serum level of cytokines was determined by the enzyme-linked immunosorbent assay (ELIZA). The cell proliferation was measured by MTT assay. The mRNA levels were quantified with qRT-PCR. As2O3 prolonged the survival of the recipient mice but had no influence on body weight. As2O3 protected the function of xenograft in insulin secretion and suppressed immune rejection of recipient. As2O3 inhibited proliferation of T lymphocyte and increased the proportion of Foxp3+ regulatory T cells in recipient mice. As2O3 inhibited activation and promoted clonal anergy of T lymphocyte. As2O3 decreased total number of B cells and reduced partial antibody levels in recipient mice. As2O3 and leflunomide showed a synergistic effect in suppressing islet xenotransplant rejection. As2O3 prolongs islet xenograft survival by inhibiting cellular immune response, and increasing Foxp3+ regulatory T cells, while decreasing partial antibody levels in serum.
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Inoo K, Bando H, Tabata Y. Enhanced survival and insulin secretion of insulinoma cell aggregates by incorporating gelatin hydrogel microspheres. Regen Ther 2018; 8:29-37. [PMID: 30271863 PMCID: PMC6149185 DOI: 10.1016/j.reth.2017.12.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Revised: 12/27/2017] [Accepted: 12/30/2017] [Indexed: 11/19/2022] Open
Abstract
Introduction The objective of this study is to evaluate the survival and glucose-induced insulin secretion of rat-derived insulinoma cells (INS-1) from their aggregates incorporating different size of gelatin hydrogel microspheres comparing with microspheres-free cell aggregates. Methods The gelatin hydrogel microspheres were prepared by the conventional w/o emulsion method. The INS-1 cells were cultured in a V-bottomed well, combining with or without the gelatin hydrogel microspheres to form their aggregates with or without microspheres. Results When the cell viability, the live cell number, the reductase activity, and the insulin secretion of cell aggregates were evaluated 7 or 14 days after incubation, the cell aggregates incorporating gelatin hydrogel microspheres showed higher cell viability, reductase activity and a larger number of live cells. The cell aggregates incorporating larger size and number of gelatin hydrogel microspheres secreted a larger amount of insulin, compared with those incorporating smaller size and number of microspheres or without microspheres. Conclusion It is conceivable that the incorporation of gelatin hydrogel microspheres in cell aggregates is promising to improve their survival and insulin secretion function.
INS-1 cell aggregates incorporating gelatin hydrogel microspheres are prepared. Gelatin hydrogel microspheres incorporation improves cell viability and glucose-induced insulin secretion of cell aggregates. The size and number of gelatin hydrogel microspheres affected the cell condition and function.
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Affiliation(s)
- Kanako Inoo
- Laboratory of Biomaterials, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Hiroto Bando
- Regenerative Medicine Unit, Takeda Pharmaceutical Company Limited, Cambridge, MA, USA
| | - Yasuhiko Tabata
- Laboratory of Biomaterials, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
- Corresponding author. Institute for Life and Frontier Medical Sciences, Kyoto University, 53 Kawara-cho Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan. Fax: +81 75 751 4646.
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Inoo K, Bando H, Tabata Y. Insulin secretion of mixed insulinoma aggregates-gelatin hydrogel microspheres after subcutaneous transplantation. Regen Ther 2018; 8:38-45. [PMID: 30271864 PMCID: PMC6147372 DOI: 10.1016/j.reth.2018.01.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Revised: 12/31/2017] [Accepted: 01/09/2018] [Indexed: 12/31/2022] Open
Abstract
Introduction The objective of this study is to evaluate the insulin secretion of mixed aggregates of insulinoma cells (INS-1) and gelatin hydrogel microspheres after their subcutaneous transplantation. Methods Gelatin hydrogel microspheres were prepared by the conventional w/o emulsion method. Cell aggregates mixed with or without the hydrogel microspheres were encapsulated into a pouched-device of polytetrafluoroethylene membrane. An agarose hydrogel or MedGel™ incorporating basic fibroblast growth factor (bFGF) was subcutaneously implanted to induce vascularization. After the vascularization induction, cell aggregates encapsulated in the pouched-device was transplanted. Results The vascularization had the potential to enable transplanted cell aggregates to enhance the level of insulin secretion compared with those of no vascularization induction. In addition, the insulin secretion of cell aggregates was significantly promoted by the mixing of gelatin hydrogel microspheres even in the pouched-device encapsulated state. Conclusion It is possible that the microspheres mixing gives cells in aggregates better survival condition, resulting in promoted insulin secretion.
INS-1 cell aggregates incorporating gelatin hydrogel microspheres are prepared. The ratio and number of cells and gelatin hydrogel microspheres affected the formation of cell aggregates. Gelatin hydrogel microspheres incorporation improves glucose-induced insulin secretion of cell aggregates in vitro. Gelatin hydrogel microspheres incorporation has the tendency to improve glucose-induced insulin secretion of cell aggregates in vivo. Vascularization has the potential to improve cell function.
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Affiliation(s)
- Kanako Inoo
- Laboratory of Biomaterials, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Hiroto Bando
- Regenerative Medicine Unit, Takeda Pharmaceutical Company Limited, Cambridge, MA, USA
| | - Yasuhiko Tabata
- Laboratory of Biomaterials, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
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Abstract
PURPOSE OF REVIEW Transplantation of allogenic pancreatic islets is a minimally invasive treatment option to control severe hypoglycemia and dependence on exogenous insulin among type 1 diabetes (T1D) patients. This overview summarizes the current issues and progress in islet transplantation outcomes and research. RECENT FINDINGS Several clinical trials from North America and other countries have documented the safety and efficacy of clinical islet transplantation for T1D patients with impaired hypoglycemia awareness. A recently completed phase 3 clinical trial allows centres in the United States to apply for a Food and Drug Administration Biologics License for the procedure. Introduction of anti-inflammatory drugs along with T-cell depleting induction therapy has significantly improved long-term function of transplanted islets. Research into islet biomarkers, immunosuppression, extrahepatic transplant sites and potential alternative beta cell sources is driving further progress. SUMMARY Allogeneic islet transplantation has vastly improved over the past two decades. Success in restoration of glycemic control and hypoglycemic awareness after islet transplantation has been further highlighted by clinical trials. However, lack of effective strategies to maintain long-term islet function and insufficient sources of donor tissue still impose limitations to the widespread use of islet transplantation. In the United States, wide adoption of this technology still awaits regulatory approval and, importantly, a financial mechanism to support the use of this technology.
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