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Mar S, Filatov E, Sasaki S, Mojibian M, Zhang D, Yang A, Nian C, Lynn FC. Tracking Insulin- and Glucagon-Expressing Cells In Vitro and In Vivo Using a Double-Reporter Human Embryonic Stem Cell Line. Diabetes 2025; 74:188-198. [PMID: 39561351 PMCID: PMC11755683 DOI: 10.2337/db24-0756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Accepted: 11/14/2024] [Indexed: 11/21/2024]
Abstract
ARTICLE HIGHLIGHTS Differentiation protocols used to generate stem cell-derived islet cells yield heterogenous cell populations. We generated a human embryonic stem cell line that reports insulin- and glucagon-expressing cells in vitro and in vivo without altering their differentiation or function. We showed some insulin- and glucagon-expressing bihormonal cells are cell-autonomously fated to become α-like cells. This reporter cell line can be used to further study and improve stem cell-derived islet differentiation and transplantation.
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Affiliation(s)
- Samantha Mar
- BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
- Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada
| | - Ekaterina Filatov
- BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
- Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada
| | - Shugo Sasaki
- BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
- Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada
| | - Majid Mojibian
- BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
- Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada
| | - Dahai Zhang
- BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
- Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada
| | - Angela Yang
- BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
- Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada
| | - Cuilan Nian
- BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
- Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada
| | - Francis C. Lynn
- BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
- Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada
- School of Biomedical Engineering, University of British Columbia, Vancouver, British Columbia, Canada
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Isenberg JS, Kandeel F. Can Islet Transplantation Possibly Reduce Mortality in Type 1 Diabetes. Cell Transplant 2025; 34:9636897241312801. [PMID: 39831598 PMCID: PMC11748148 DOI: 10.1177/09636897241312801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 11/21/2024] [Accepted: 12/22/2024] [Indexed: 01/22/2025] Open
Abstract
Islet transplantation (IT) is a successful natural cell therapy. But the benefits are known mostly to individuals with severe type 1 diabetes who undergo IT and the health care professionals that work to make the therapy available, reproducible, and safe. Data linking IT to overall survival in T1D might alter this situation and frame the therapy in a more positive light. Recent analysis of mortality in several cohorts suggests that IT has possible survival benefits when used alone or in conjunction with renal transplantation. Multi-center prospective studies with long-term follow-up of individuals that receive stand-alone IT versus individuals who qualify for but do not undergo the procedure would seem reasonable to undertake to confirm an IT survival benefit.
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Affiliation(s)
- Jeffrey S. Isenberg
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA
| | - Fouad Kandeel
- Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA
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3
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Yehya H, Wells A, Majcher M, Nakhwa D, King R, Senturk F, Padmanabhan R, Jensen J, Bukys MA. Identifying and optimizing critical process parameters for large-scale manufacturing of iPSC derived insulin-producing β-cells. Stem Cell Res Ther 2024; 15:408. [PMID: 39522051 PMCID: PMC11550522 DOI: 10.1186/s13287-024-03973-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Accepted: 10/03/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Type 1 diabetes, an autoimmune disorder leading to the destruction of pancreatic β-cells, requires lifelong insulin therapy. Islet transplantation offers a promising solution but faces challenges such as limited availability and the need for immunosuppression. Induced pluripotent stem cells (iPSCs) provide a potential alternative source of functional β-cells and have the capability for large-scale production. However, current differentiation protocols, predominantly conducted in hybrid or 2D settings, lack scalability and optimal conditions for suspension culture. METHODS We examined a range of bioreactor scaleup process parameters and quality target product profiles that might affect the differentiation process. This investigation was conducted using an optimized High Dimensional Design of Experiments (HD-DoE) protocol designed for scalability and implemented in 0.5L (PBS-0.5 Mini) vertical wheel bioreactors. RESULTS A three stage suspension manufacturing process is developed, transitioning from adherent to suspension culture, with TB2 media supporting iPSC growth during scaling. Stage-wise optimization approaches and extended differentiation times are used to enhance marker expression and maturation of iPSC-derived islet-like clusters. Continuous bioreactor runs were used to study nutrient and growth limitations and impact on differentiation. The continuous bioreactors were compared to a Control media change bioreactor showing metabolic shifts and a more β-cell-like differentiation profile. Cryopreserved aggregates harvested from the runs were recovered and showed maintenance of viability and insulin secretion capacity post-recovery, indicating their potential for storage and future transplantation therapies. CONCLUSION This study demonstrated that stage time increase and limited media replenishing with lactate accumulation can increase the differentiation capacity of insulin producing cells cultured in a large-scale suspension environment.
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Affiliation(s)
- Haneen Yehya
- Trailhead Biosystems, 23215 Commerce Park, Beachwood, OH, 44122, USA
- Cleveland State University, 2121 Euclid Ave, Cleveland, OH, 44115, USA
| | - Alexandra Wells
- Trailhead Biosystems, 23215 Commerce Park, Beachwood, OH, 44122, USA
| | - Michael Majcher
- Trailhead Biosystems, 23215 Commerce Park, Beachwood, OH, 44122, USA
| | - Dhruv Nakhwa
- Trailhead Biosystems, 23215 Commerce Park, Beachwood, OH, 44122, USA
| | - Ryan King
- Trailhead Biosystems, 23215 Commerce Park, Beachwood, OH, 44122, USA
| | - Faruk Senturk
- Trailhead Biosystems, 23215 Commerce Park, Beachwood, OH, 44122, USA
| | | | - Jan Jensen
- Trailhead Biosystems, 23215 Commerce Park, Beachwood, OH, 44122, USA
| | - Michael A Bukys
- Trailhead Biosystems, 23215 Commerce Park, Beachwood, OH, 44122, USA.
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4
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Wang Q, Huang YX, Liu L, Zhao XH, Sun Y, Mao X, Li SW. Pancreatic islet transplantation: current advances and challenges. Front Immunol 2024; 15:1391504. [PMID: 38887292 PMCID: PMC11180903 DOI: 10.3389/fimmu.2024.1391504] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Accepted: 05/20/2024] [Indexed: 06/20/2024] Open
Abstract
Diabetes is a prevalent chronic disease that traditionally requires severe reliance on medication for treatment. Oral medication and exogenous insulin can only temporarily maintain blood glucose levels and do not cure the disease. Most patients need life-long injections of exogenous insulin. In recent years, advances in islet transplantation have significantly advanced the treatment of diabetes, allowing patients to discontinue exogenous insulin and avoid complications.Long-term follow-up results from recent reports on islet transplantation suggest that they provide significant therapeutic benefit although patients still require immunotherapy, suggesting the importance of future transplantation strategies. Although organ shortage remains the primary obstacle for the development of islet transplantation, new sources of islet cells, such as stem cells and porcine islet cells, have been proposed, and are gradually being incorporated into clinical research. Further research on new transplantation sites, such as the subcutaneous space and mesenteric fat, may eventually replace the traditional portal vein intra-islet cell infusion. Additionally, the immunological rejection reaction in islet transplantation will be resolved through the combined application of immunosuppressant agents, islet encapsulation technology, and the most promising mesenchymal stem cells/regulatory T cell and islet cell combined transplantation cell therapy. This review summarizes the progress achieved in islet transplantation, and discusses the research progress and potential solutions to the challenges faced.
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Affiliation(s)
- Qi Wang
- Department of Hepatobiliary and Pancreatic Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Yu-xi Huang
- Department of Hepatobiliary and Pancreatic Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Long Liu
- Department of Hepatobiliary and Pancreatic Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiao-hong Zhao
- Department of Pharmacy, Taizhou Hospital, Zhejiang University, Taizhou, Zhejiang, China
| | - Yi Sun
- MRL Global Medical Affairs, MSD China, Shanghai, China
| | - Xinli Mao
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
- Key Laboratory of Minimally Invasive Techniques and Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Shao-wei Li
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
- Key Laboratory of Minimally Invasive Techniques and Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
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5
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De Toni T, Dal Buono T, Li CM, Gonzalez GC, Chuang ST, Buchwald P, Tomei AA, Velluto D. Drug Integrating Amphiphilic Nano-Assemblies: 2. Spatiotemporal Distribution within Inflammation Sites. Pharmaceutics 2024; 16:652. [PMID: 38794314 PMCID: PMC11124943 DOI: 10.3390/pharmaceutics16050652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Revised: 05/01/2024] [Accepted: 05/09/2024] [Indexed: 05/26/2024] Open
Abstract
The need for chronic systemic immunosuppression, which is associated with unavoidable side-effects, greatly limits the applicability of allogeneic cell transplantation for regenerative medicine applications including pancreatic islet cell transplantation to restore insulin production in type 1 diabetes (T1D). Cell transplantation in confined sites enables the localized delivery of anti-inflammatory and immunomodulatory drugs to prevent graft loss by innate and adaptive immunity, providing an opportunity to achieve local effects while minimizing unwanted systemic side effects. Nanoparticles can provide the means to achieve the needed localized and sustained drug delivery either by graft targeting or co-implantation. Here, we evaluated the potential of our versatile platform of drug-integrating amphiphilic nanomaterial assemblies (DIANAs) for targeted drug delivery to an inflamed site model relevant for islet transplantation. We tested either passive targeting of intravenous administered spherical nanomicelles (nMIC; 20-25 nm diameter) or co-implantation of elongated nanofibrils (nFIB; 5 nm diameter and >1 μm length). To assess the ability of nMIC and nFIB to target an inflamed graft site, we used a lipophilic fluorescent cargo (DiD and DiR) and evaluated the in vivo biodistribution and cellular uptake in the graft site and other organs, including draining and non-draining lymph nodes, after systemic administration (nMIC) and/or graft co-transplantation (nFIB) in mice. Localized inflammation was generated either by using an LPS injection or by using biomaterial-coated islet-like bead implantation in the subcutaneous site. A cell transplant inflammation model was used as well to test nMIC- and nFIB-targeted biodistribution. We found that nMIC can reach the inflamed site after systemic administration, while nFIB remains localized for several days after co-implantation. We confirmed that DIANAs are taken up by different immune cell populations responsible for graft inflammation. Therefore, DIANA is a useful approach for targeted and/or localized delivery of immunomodulatory drugs to decrease innate and adaptive immune responses that cause graft loss after transplantation of therapeutic cells.
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Affiliation(s)
- Teresa De Toni
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (T.D.T.); (T.D.B.); (C.M.L.); (G.C.G.); (S.-T.C.); (P.B.); (A.A.T.)
- Department of Biomedical Engineering, University of Miami, Miami, FL 33146, USA
| | - Teodora Dal Buono
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (T.D.T.); (T.D.B.); (C.M.L.); (G.C.G.); (S.-T.C.); (P.B.); (A.A.T.)
| | - Chris M. Li
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (T.D.T.); (T.D.B.); (C.M.L.); (G.C.G.); (S.-T.C.); (P.B.); (A.A.T.)
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Grisell C. Gonzalez
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (T.D.T.); (T.D.B.); (C.M.L.); (G.C.G.); (S.-T.C.); (P.B.); (A.A.T.)
| | - Sung-Ting Chuang
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (T.D.T.); (T.D.B.); (C.M.L.); (G.C.G.); (S.-T.C.); (P.B.); (A.A.T.)
| | - Peter Buchwald
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (T.D.T.); (T.D.B.); (C.M.L.); (G.C.G.); (S.-T.C.); (P.B.); (A.A.T.)
- Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Alice A. Tomei
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (T.D.T.); (T.D.B.); (C.M.L.); (G.C.G.); (S.-T.C.); (P.B.); (A.A.T.)
- Department of Biomedical Engineering, University of Miami, Miami, FL 33146, USA
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Diana Velluto
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (T.D.T.); (T.D.B.); (C.M.L.); (G.C.G.); (S.-T.C.); (P.B.); (A.A.T.)
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
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6
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Wu Y, Yano T, Enomoto T, Endo A, Okada S, Araki K, Shiraki N, Kume S. Reversal of Hyperglycemia by Subcutaneous Islet Engraftment Using an Atelocollagen Sponge as a Scaffold. Cell Transplant 2024; 33:9636897241277980. [PMID: 39344094 PMCID: PMC11450792 DOI: 10.1177/09636897241277980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 07/26/2024] [Accepted: 08/05/2024] [Indexed: 10/01/2024] Open
Abstract
Type 1 diabetes mellitus (T1DM) affects 8.4 million people worldwide, with patients primarily relying on exogenous insulin injections to maintain blood glucose levels. Islet transplantation via the portal vein has allowed for the direct internal release of insulin by glucose-sensitive islets. However, this method might not be desirable for future cell therapy transplanting pluripotent stem cell-derived β cells, facing challenges including difficulties in cell retrieval and graft loss due to the instant blood-mediated inflammatory reaction (IBMIR). Here, we established a subcutaneous transplantation protocol using an atelocollagen sponge as a scaffold. While the subcutaneous site has many advantages, the lack of a vascular bed limits its application. To address this issue, we performed angiogenesis stimulation at the transplantation site using bFGF absorbed in a gelatin sponge (Spongel), significantly improving the microvascular area. Our in vivo experiments also revealed angiogenesis stimulation is crucial for reversing hyperglycemia in streptozotocin (STZ)-induced diabetic mice. In addition to the angiogenic treatment, an atelocollagen sponge is used to carry the islets and helps avoid graft leakage. With 800 mouse islets delivered by the atelocollagen sponge, the STZ-induced diabetic mice showed a reversal of hyperglycemia and normalized glucose intolerance. Their normoglycemia was maintained until the graft was removed. Analysis of the harvested islet grafts exhibited a high vascularization and preserved morphologies, suggesting that using an atelocollagen sponge as a scaffold helps maintain the viability of the islet grafts.
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Affiliation(s)
- Yumeng Wu
- School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Japan
| | | | - Takayuki Enomoto
- School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Japan
- Biomaterials Analysis Division, Open Facility Center, Tokyo Institute of Technology, Yokohama, Japan
| | - Atena Endo
- School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Japan
| | - Seiji Okada
- Division of Hematopoiesis, Joint Research Center for Retroviral Infection, Kumamoto University, Kumamoto, Japan
| | - Kimi Araki
- Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan
- Center for Metabolic Regulation of Healthy Aging, Kumamoto University, Kumamoto, Japan
| | - Nobuaki Shiraki
- School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Japan
| | - Shoen Kume
- School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Japan
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7
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Doherty DT, Khambalia HA, van Dellen D, Jennings RE, Piper Hanley K. Unlocking the post-transplant microenvironment for successful islet function and survival. Front Endocrinol (Lausanne) 2023; 14:1250126. [PMID: 37711891 PMCID: PMC10497759 DOI: 10.3389/fendo.2023.1250126] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 08/07/2023] [Indexed: 09/16/2023] Open
Abstract
Islet transplantation (IT) offers the potential to restore euglycemia for patients with type 1 diabetes mellitus (T1DM). Despite improvements in islet isolation techniques and immunosuppressive regimes, outcomes remain suboptimal with UK five-year graft survivals (5YGS) of 55% and most patients still requiring exogenous insulin after multiple islet infusions. Native islets have a significant non-endocrine component with dense extra-cellular matrix (ECM), important for islet development, cell survival and function. Collagenase isolation necessarily disrupts this complex islet microenvironment, leaving islets devoid of a supporting framework and increasing vulnerability of transplanted islets. Following portal venous transplantation, a liver injury response is potentially induced, which typically results in inflammation and ECM deposition from liver specific myofibroblasts. The impact of this response may have important impact on islet survival and function. A fibroblast response and ECM deposition at the kidney capsule and eye chamber alongside other implantation sites have been shown to be beneficial for survival and function. Investigating the implantation site microenvironment and the interactions of transplanted islets with ECM proteins may reveal therapeutic interventions to improve IT and stem-cell derived beta-cell therapy.
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Affiliation(s)
- Daniel T. Doherty
- Faculty of Biology, Medicine & Health, University of Manchester, Manchester, United Kingdom
- Department of Renal & Pancreatic Transplantation, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Hussein A. Khambalia
- Faculty of Biology, Medicine & Health, University of Manchester, Manchester, United Kingdom
- Department of Renal & Pancreatic Transplantation, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - David van Dellen
- Faculty of Biology, Medicine & Health, University of Manchester, Manchester, United Kingdom
- Department of Renal & Pancreatic Transplantation, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Rachel E. Jennings
- Faculty of Biology, Medicine & Health, University of Manchester, Manchester, United Kingdom
- Department of Endocrinology, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Karen Piper Hanley
- Faculty of Biology, Medicine & Health, University of Manchester, Manchester, 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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9
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Du S, Li Y, Geng Z, Zhang Q, Buhler LH, Gonelle-Gispert C, Wang Y. Engineering Islets From Stem Cells: The Optimal Solution for the Treatment of Diabetes? Front Immunol 2022; 13:869514. [PMID: 35572568 PMCID: PMC9092457 DOI: 10.3389/fimmu.2022.869514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 03/25/2022] [Indexed: 11/13/2022] Open
Abstract
Diabetes is a metabolic disease characterized by insulin deficiency. Bioengineering of stem cells with the aim to restore insulin production and glucose regulation has the potential to cure diabetic patients. In this review, we focus on the recent developments for bioengineering of induced pluripotent stem cells (iPSCs), mesenchymal stem cells (MSCs), embryonic stem cells (ESCs), and pancreatic progenitor cells in view of generating insulin producing and glucose regulating cells for β-cell replacement therapies. Recent clinical trials using islet cells derived from stem cells have been initiated for the transplantation into diabetic patients, with crucial bottlenecks of tumorigenesis, post-transplant survival, genetic instability, and immunogenicity that should be further optimized. As a new approach given high expectations, bioengineered islets from stem cells occupies considerable potential for the future clinical application and addressing the treatment dilemma of diabetes.
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Affiliation(s)
- Suya Du
- Department of Clinical Pharmacy, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yanjiao Li
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Zhen Geng
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Center of Organ Transplantation, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Chengdu, China.,Institute of Organ Transplantation, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.,Chinese Academy of Sciences, Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Qi Zhang
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Leo H Buhler
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Center of Organ Transplantation, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Chengdu, China.,Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | | | - Yi Wang
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Center of Organ Transplantation, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Chengdu, China.,Institute of Organ Transplantation, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.,Chinese Academy of Sciences, Sichuan Translational Medicine Research Hospital, Chengdu, China
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10
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De Toni T, Stock AA, Devaux F, Gonzalez GC, Nunez K, Rubanich JC, Safley SA, Weber CJ, Ziebarth NM, Buchwald P, Tomei AA. Parallel Evaluation of Polyethylene Glycol Conformal Coating and Alginate Microencapsulation as Immunoisolation Strategies for Pancreatic Islet Transplantation. Front Bioeng Biotechnol 2022; 10:886483. [PMID: 35651551 PMCID: PMC9149081 DOI: 10.3389/fbioe.2022.886483] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 04/12/2022] [Indexed: 01/21/2023] Open
Abstract
Pancreatic islet transplantation improves metabolic control and prevents complications in patients with brittle type 1 diabetes (T1D). However, chronic immunosuppression is required to prevent allograft rejection and recurrence of autoimmunity. Islet encapsulation may eliminate the need for immunosuppression. Here, we analyzed in parallel two microencapsulation platforms that provided long-term diabetes reversal in preclinical T1D models, alginate single and double capsules versus polyethylene glycol conformal coating, to identify benefits and weaknesses that could inform the design of future clinical trials with microencapsulated islets. We performed in vitro and in vivo functionality assays with human islets and analyzed the explanted grafts by immunofluorescence. We quantified the size of islets and capsules, measured capsule permeability, and used these data for in silico simulations of islet functionality in COMSOL Multiphysics. We demonstrated that insulin response to glucose stimulation is dependent on capsule size, and the presence of permselective materials augments delays in insulin secretion. Non-coated and conformally coated islets could be transplanted into the fat pad of diabetic mice, resulting in comparable functionality and metabolic control. Mac-2+ cells were found in conformally coated grafts, indicating possible host reactivity. Due to their larger volume, alginate capsules were transplanted in the peritoneal cavity. Despite achieving diabetes reversal, changes in islet composition were found in retrieved capsules, and recipient mice experienced hypoglycemia indicative of hyperinsulinemia induced by glucose retention in large capsules as the in silico model predicted. We concluded that minimal capsule size is critical for physiological insulin secretion, and anti-inflammatory modulation may be beneficial for small conformal capsules.
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Affiliation(s)
- Teresa De Toni
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, United States
- Department of Biomedical Engineering, University of Miami, Miami, FL, United States
| | - Aaron A. Stock
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, United States
- Department of Biomedical Engineering, University of Miami, Miami, FL, United States
| | - Floriane Devaux
- Department of Biomedical Engineering, University of Miami, Miami, FL, United States
| | - Grisell C. Gonzalez
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Kailyn Nunez
- Department of Biomedical Engineering, University of Miami, Miami, FL, United States
| | - Jessica C. Rubanich
- Department of Biomedical Engineering, University of Miami, Miami, FL, United States
| | - Susan A. Safley
- Department of Surgery, Emory University, Atlanta, GA, United States
| | - Collin J. Weber
- Department of Surgery, Emory University, Atlanta, GA, United States
| | - Noel M. Ziebarth
- Department of Biomedical Engineering, University of Miami, Miami, FL, United States
| | - Peter Buchwald
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, United States
- Department of Molecular and Cellular Pharmacology, University of Miami, Miller School of Medicine, Miami, FL, United States
| | - Alice A. Tomei
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, United States
- Department of Biomedical Engineering, University of Miami, Miami, FL, United States
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, United States
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, United States
- *Correspondence: Alice A. Tomei,
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11
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Tan LS, Chen JT, Lim LY, Teo AKK. Manufacturing clinical-grade human induced pluripotent stem cell-derived beta cells for diabetes treatment. Cell Prolif 2022; 55:e13232. [PMID: 35474596 PMCID: PMC9357357 DOI: 10.1111/cpr.13232] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Revised: 01/26/2022] [Accepted: 03/28/2022] [Indexed: 12/25/2022] Open
Abstract
The unlimited proliferative capacity of human pluripotent stem cells (hPSCs) fortifies it as one of the most attractive sources for cell therapy application in diabetes. In the past two decades, vast research efforts have been invested in developing strategies to differentiate hPSCs into clinically suitable insulin‐producing endocrine cells or functional beta cells (β cells). With the end goal being clinical translation, it is critical for hPSCs and insulin‐producing β cells to be derived, handled, stored, maintained and expanded with clinical compliance. This review focuses on the key processes and guidelines for clinical translation of human induced pluripotent stem cell (hiPSC)‐derived β cells for diabetes cell therapy. Here, we discuss the (1) key considerations of manufacturing clinical‐grade hiPSCs, (2) scale‐up and differentiation of clinical‐grade hiPSCs into β cells in clinically compliant conditions and (3) mandatory quality control and product release criteria necessitated by various regulatory bodies to approve the use of the cell‐based products.
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Affiliation(s)
- Lay Shuen Tan
- Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology, A*STAR, Singapore, Singapore.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Precision Medicine Translational Research Programme (TRP), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Juin Ting Chen
- Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology, A*STAR, Singapore, Singapore.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Precision Medicine Translational Research Programme (TRP), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Lillian Yuxian Lim
- Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology, A*STAR, Singapore, Singapore
| | - Adrian Kee Keong Teo
- Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology, A*STAR, Singapore, Singapore.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Precision Medicine Translational Research Programme (TRP), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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12
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Nemati M, Karbalaei N, Mokarram P, Dehghani F, Dastghaib S, Aghaei Z. Cotransplant With Pancreatic Islet Homogenate Improved Survival and Long-Term Efficacy of Islet Transplant in Streptozotocin-Diabetic Rats. EXP CLIN TRANSPLANT 2022; 20:164-172. [PMID: 35282811 DOI: 10.6002/ect.2021.0385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES Pancreatic islet transplant is suggested as a promising treatment option in diabetes, but the number of viable and functional islets and the long-term efficacy of transplanted islets have not been satisfactory. Islet isolation leads to destruction of the extracellular matrix and loss of trophic support of islets, which reduces their survival and function. Reconstruction of islet microenvironment with biomaterials may preserve islet survival and graft efficacy. Accordingly, we investigated the effects of pancreatic islet homogenate on islet quality and graft outcomes in diabetic rats. MATERIALS AND METHODS Islets were isolated from the pancreas of Sprague Dawley rats and were cultured with or without pancreatic islet homogenate. Before transplant, viability, insulin content, and insulin released from cultured islets were assessed. Islets were then transplanted into subcapsular space of diabetic rat kidney. Transplant outcomes were evaluated by plasma glucose and insulin levels, glucose tolerance tests, and stress oxidative markers. RESULTS Viability and insulin release in the pancreatic islet homogenate-treated islets were significantly higher than that in the control islets. After transplant of islets, recipient rats with pancreatic islet homogenate showed significant decreases in blood glucose and malondialdehyde levels and increases in superoxide dismutase activity and plasma insulin levels. CONCLUSIONS Islet treatment with pancreatic islet homogenate could improve islet survival and transplant function and outcomes. Oxidative stress reduction might be a secondary beneficial effect of improved quality of treated islets.
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Affiliation(s)
- Marzieh Nemati
- From the Department of Physiology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.,From the Department of Endocrinology and Metabolism Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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13
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Zhang S, Yan H, Ma X, Zheng W, Wang W. Effects of different routes of heparin on instant blood-mediated inflammatory reaction after portal vein islet transplantation. ZHONG NAN DA XUE XUE BAO. YI XUE BAN = JOURNAL OF CENTRAL SOUTH UNIVERSITY. MEDICAL SCIENCES 2022; 47:1-7. [PMID: 35545357 PMCID: PMC10930478 DOI: 10.11817/j.issn.1672-7347.2022.200993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Indexed: 06/15/2023]
Abstract
OBJECTIVES Heparin is mainly used as an anticoagulant in clinic, and it also has a certain anti-inflammatory effect. At present, after portal vein islet transplantation in diabetic patients, heparin is mainly infused through the peripheral veins of the limbs to achieve the purpose of anticoagulation and protection of the graft, rather than through the portal vein. In this study, animal experiments were conducted to investigate the effect of heparin infusion via the portal vein and marginal ear vein on the instant blood-mediated inflammatory reaction (IBMIR) after portal vein islet transplantation, which is the choice of anticoagulation methods for clinical islet transplantation to provide a basis for decision-making. METHODS A total of 50 neonatal pigs (Xeno-1 type, 3-5 days) were selected. Islets were isolated and purified from the pancreas of neonatal pigs. Ten non-diabetic Landrace pigs (1.5-2.0 months) served as recipients, and 12 000 IEQ/kg neonatal porcine islets were transplanted into the liver through the portal vein. All recipients received bolus injection of 50 U/kg of heparin 10 minutes before transplantation. After the bolus injection of heparin, the experimental group received heparin via the portal vein [10 U/(kg·h), 5 recipients], and the control group received heparin via the marginal ear vein [10 U/(kg·h), 5 recipients]. The superior vena cava blood was collected from the 2 groups pre-operation at 1, 3, 24 h post-operation of the transplantation. The portal vein blood was collected from the experimental group at 1 and 3 h after the transplantation as well. The levels of complement C3a, C5a, thrombin-antithrombin complex (TAT), β-thromboglobulin (β-TG), and D-dimer as well as activated partial thromboplastin time (APTT) in superior vena cava blood from 1 and 3 h post-transplantation were detected in the 2 groups, and the levels of anti-Xa and anti-IIa in the portal vein and superior vena cava blood from 1 and 3 h post-transplantation in the experimental group were detected. Twenty four hours after the transplantation, the liver tissues in the 2 groups were collected for pathological examination to observe the inflammatory cell infiltration and peripheral thrombosis around the islets graft in liver. RESULTS Before transplantation, there was no statistically significant difference in C3a, C5a, TAT, β-TG, D-dimer levels and APTT between the 2 groups (all P>0.05). At 1 and 3 h after transplantation, the C3a, TAT, and D-dimer levels in the experimental group were significant decreased than those in the control groups (all P<0.05), and at 3 h after transplantation the C5a was significant decreased than that in the control group (P<0.05). At 1 and 3 h after transplantation, the anti-Xa and anti-IIa levels in the portal vein blood were significantly increased than those in the superior vena cava blood in the experimental group (all P<0.05). Pathological results showed the presence of islet cell clusters in the liver blood vessels. The thrombus formation and neutrophil infiltration around islet graft was not obvious in the experimental group, while massive thrombus formation and neutrophil infiltration in the control group. CONCLUSIONS Compared with marginal ear vein infusion of heparin, the direct infusion of heparin in the portal vein has a certain inhibitory effect on complement system, coagulation system activation and inflammatory cell infiltration in portal vein islet transplantation, which may attenuate the occurrence of IBMIR.
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Affiliation(s)
- Shengwang Zhang
- Department of Radiology, Third Xiangya Hospital, Central South University, Changsha 410013, China.
| | - Haixiong Yan
- Department of Radiology, Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Xiaoqian Ma
- Department of Radiology, Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Wei Zheng
- Department of Radiology, Third Xiangya Hospital, Central South University, Changsha 410013, China.
| | - Wei Wang
- Department of Radiology, Third Xiangya Hospital, Central South University, Changsha 410013, China.
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14
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Ramzy A, Thompson DM, Ward-Hartstonge KA, Ivison S, Cook L, Garcia RV, Loyal J, Kim PTW, Warnock GL, Levings MK, Kieffer TJ. Implanted pluripotent stem-cell-derived pancreatic endoderm cells secrete glucose-responsive C-peptide in patients with type 1 diabetes. Cell Stem Cell 2021; 28:2047-2061.e5. [PMID: 34861146 DOI: 10.1016/j.stem.2021.10.003] [Citation(s) in RCA: 184] [Impact Index Per Article: 46.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 04/29/2021] [Accepted: 10/08/2021] [Indexed: 12/11/2022]
Abstract
An open-label, first-in-human phase 1/2 study is being conducted to evaluate the safety and efficacy of pancreatic endoderm cells (PECs) implanted in non-immunoprotective macroencapsulation devices for the treatment of type 1 diabetes. We report an analysis on 1 year of data from the first cohort of 15 patients from a single trial site that received subcutaneous implantation of cell products combined with an immunosuppressive regimen. Implants were well tolerated with no teratoma formation or severe graft-related adverse events. After implantation, patients had increased fasting C-peptide levels and increased glucose-responsive C-peptide levels and developed mixed meal-stimulated C-peptide secretion. There were immunosuppression-related transient increases in circulating regulatory T cells, PD1high T cells, and IL17A+CD4+ T cells. Explanted grafts contained cells with a mature β cell phenotype that were immunoreactive for insulin, islet amyloid polypeptide, and MAFA. These data, and associated findings (Shapiro et al., 2021), are the first reported evidence of meal-regulated insulin secretion by differentiated stem cells in patients.
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Affiliation(s)
- Adam Ramzy
- Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - David M Thompson
- Division of Endocrinology, Department of Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Kirsten A Ward-Hartstonge
- Department of Surgery, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; BC Children's Hospital Research Institute (BCCHRI), Vancouver, BC V5Z 4H4, Canada
| | - Sabine Ivison
- Department of Surgery, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; BC Children's Hospital Research Institute (BCCHRI), Vancouver, BC V5Z 4H4, Canada
| | - Laura Cook
- Department of Surgery, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; BC Children's Hospital Research Institute (BCCHRI), Vancouver, BC V5Z 4H4, Canada
| | - Rosa V Garcia
- Department of Surgery, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; BC Children's Hospital Research Institute (BCCHRI), Vancouver, BC V5Z 4H4, Canada
| | - Jackson Loyal
- Division of Endocrinology, Department of Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Peter T W Kim
- Department of Surgery, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Garth L Warnock
- Department of Surgery, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Megan K Levings
- Department of Surgery, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; BC Children's Hospital Research Institute (BCCHRI), Vancouver, BC V5Z 4H4, Canada; School of Biomedical Engineering, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Timothy J Kieffer
- Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; Department of Surgery, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; School of Biomedical Engineering, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
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15
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McDermott B, Robinson S, Holcombe S, Levey RE, Dockery P, Johnson P, Wang S, Dolan EB, Duffy GP. Developing a morphomics framework to optimize implant site-specific design parameters for islet macroencapsulation devices. J R Soc Interface 2021; 18:20210673. [PMID: 34932928 PMCID: PMC8692035 DOI: 10.1098/rsif.2021.0673] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 11/22/2021] [Indexed: 12/22/2022] Open
Abstract
Delivering a clinically impactful cell number is a major design challenge for cell macroencapsulation devices for Type 1 diabetes. It is important to understand the transplant site anatomy to design a device that is practical and that can achieve a sufficient cell dose. We identify the posterior rectus sheath plane as a potential implant site as it is easily accessible, can facilitate longitudinal monitoring of transplants, and can provide nutritive support for cell survival. We have investigated this space using morphomics across a representative patient cohort (642 participants) and have analysed the data in terms of gender, age and BMI. We used a shape optimization process to maximize the volume and identified that elliptical devices achieve a clinically impactful cell dose while meeting device manufacture and delivery requirements. This morphomics framework has the potential to significantly influence the design of future macroencapsulation devices to better suit the needs of patients.
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Affiliation(s)
- Barry McDermott
- Translational Medical Device Lab, College of Medicine Nursing and Health Sciences, National University of Ireland (NUI) Galway, Galway, Ireland
| | - Scott Robinson
- Anatomy and Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine Nursing and Health Sciences, National University of Ireland (NUI) Galway, Galway, Ireland
- Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI, USA
- Advanced Materials and BioEngineering Research Centre (AMBER), Royal College of Surgeons in Ireland and Trinity College Dublin, Dublin, Ireland
| | - Sven Holcombe
- Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Ruth E. Levey
- Anatomy and Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine Nursing and Health Sciences, National University of Ireland (NUI) Galway, Galway, Ireland
| | - Peter Dockery
- Anatomy and Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine Nursing and Health Sciences, National University of Ireland (NUI) Galway, Galway, Ireland
| | - Paul Johnson
- Nuffield Department of Surgical Sciences and NIHR Biomedical Research Centre, Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK
| | - Stewart Wang
- Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Eimear B. Dolan
- Biomedical Engineering, School of Engineering, College of Science and Engineering, National University of Ireland (NUI) Galway, Galway, Ireland
- CURAM, Centre for Research in Medical Devices, National University of Ireland (NUI) Galway, Galway, Ireland
| | - Garry P. Duffy
- Anatomy and Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine Nursing and Health Sciences, National University of Ireland (NUI) Galway, Galway, Ireland
- CURAM, Centre for Research in Medical Devices, National University of Ireland (NUI) Galway, Galway, Ireland
- Advanced Materials and BioEngineering Research Centre (AMBER), Royal College of Surgeons in Ireland and Trinity College Dublin, Dublin, Ireland
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16
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Parsons RF, Baquerizo A, Kirchner VA, Malek S, Desai CS, Schenk A, Finger EB, Brennan TV, Parekh KR, MacConmara M, Brayman K, Fair J, Wertheim JA. Challenges, highlights, and opportunities in cellular transplantation: A white paper of the current landscape. Am J Transplant 2021; 21:3225-3238. [PMID: 34212485 DOI: 10.1111/ajt.16740] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 06/22/2021] [Accepted: 06/22/2021] [Indexed: 02/05/2023]
Abstract
Although cellular transplantation remains a relatively small field compared to solid organ transplantation, the prospects for advancement in basic science and clinical care remain bountiful. In this review, notable historical events and the current landscape of the field of cellular transplantation are reviewed with an emphasis on islets (allo- and xeno-), hepatocytes (including bioartificial liver), adoptive regulatory immunotherapy, and stem cells (SCs, specifically endogenous organ-specific and mesenchymal). Also, the nascent but rapidly evolving field of three-dimensional bioprinting is highlighted, including its major processing steps and latest achievements. To reach its full potential where cellular transplants are a more viable alternative than solid organ transplants, fundamental change in how the field is regulated and advanced is needed. Greater public and private investment in the development of cellular transplantation is required. Furthermore, consistent with the call of multiple national transplant societies for allo-islet transplants, the oversight of cellular transplants should mirror that of solid organ transplants and not be classified under the unsustainable, outdated model that requires licensing as a drug with the Food and Drug Administration. Cellular transplantation has the potential to bring profound benefit through progress in bioengineering and regenerative medicine, limiting immunosuppression-related toxicity, and providing markedly reduced surgical morbidity.
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Affiliation(s)
- Ronald F Parsons
- Department of Surgery, Emory Transplant Center, Emory University School of Medicine, Atlanta, Georgia
| | - Angeles Baquerizo
- Scripps Center for Cell and Organ Transplantation, La Jolla, California
| | - Varvara A Kirchner
- Division of Transplantation, Department of Surgery, University of Minnesota, Minneapolis, Minnesota
| | - Sayeed Malek
- Division of Transplant Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Chirag S Desai
- Division of Transplantation, Department of Surgery, University of North Carolina, Chapel Hill, North Carolina
| | - Austin Schenk
- Division of Transplantation, Department of Surgery, Ohio State University, Columbus, Ohio
| | - Erik B Finger
- Division of Transplantation, Department of Surgery, University of Minnesota, Minneapolis, Minnesota
| | - Todd V Brennan
- Department of Surgery, Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California
| | - Kalpaj R Parekh
- Division of Cardiothoracic Surgery, Department of Surgery, Carver College of Medicine, University of Iowa, Iowa City, Iowa
| | - Malcolm MacConmara
- Division of Surgical Transplantation, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Kenneth Brayman
- Division of Transplantation, Department of Surgery, University of Virginia, Charlottesville, Virginia
| | - Jeffrey Fair
- Division of Transplant Surgery, Department of Surgery, University of Texas Medical Branch, Galveston, Texas
| | - Jason A Wertheim
- Departments of Surgery and Biomedical Engineering, University of Arizona Health Sciences, Tucson, Arizona
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17
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Goswami D, Domingo‐Lopez DA, Ward NA, Millman JR, Duffy GP, Dolan EB, Roche ET. Design Considerations for Macroencapsulation Devices for Stem Cell Derived Islets for the Treatment of Type 1 Diabetes. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:e2100820. [PMID: 34155834 PMCID: PMC8373111 DOI: 10.1002/advs.202100820] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 04/24/2021] [Indexed: 05/08/2023]
Abstract
Stem cell derived insulin producing cells or islets have shown promise in reversing Type 1 Diabetes (T1D), yet successful transplantation currently necessitates long-term modulation with immunosuppressant drugs. An alternative approach to avoiding this immune response is to utilize an islet macroencapsulation device, where islets are incorporated into a selectively permeable membrane that can protect the transplanted cells from acute host response, whilst enabling delivery of insulin. These macroencapsulation systems have to meet a number of stringent and challenging design criteria in order to achieve the ultimate goal of reversing T1D. In this progress report, the design considerations and functional requirements of macroencapsulation systems are reviewed, specifically for stem-cell derived islets (SC-islets), highlighting distinct design parameters. Additionally, a perspective on the future for macroencapsulation systems is given, and how incorporating continuous sensing and closed-loop feedback can be transformative in advancing toward an autonomous biohybrid artificial pancreas.
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Affiliation(s)
- Debkalpa Goswami
- Institute for Medical Engineering and ScienceMassachusetts Institute of TechnologyCambridgeMA02139USA
| | - Daniel A. Domingo‐Lopez
- Department of AnatomyCollege of Medicine, Nursing, and Health SciencesNational University of Ireland GalwayGalwayH91 TK33Ireland
| | - Niamh A. Ward
- Department of Biomedical EngineeringSchool of EngineeringCollege of Science and EngineeringNational University of Ireland GalwayGalwayH91 TK33Ireland
| | - Jeffrey R. Millman
- Division of Endocrinology, Metabolism & Lipid ResearchWashington University School of MedicineSt. LouisMO63110USA
- Department of Biomedical EngineeringWashington University in St. LouisSt. LouisMO63110USA
| | - Garry P. Duffy
- Department of AnatomyCollege of Medicine, Nursing, and Health SciencesNational University of Ireland GalwayGalwayH91 TK33Ireland
- Advanced Materials and BioEngineering Research Centre (AMBER)Trinity College DublinDublinD02 PN40Ireland
- CÚRAM, Centre for Research in Medical DevicesNational University of Ireland GalwayGalwayH91 TK33Ireland
| | - Eimear B. Dolan
- Department of Biomedical EngineeringSchool of EngineeringCollege of Science and EngineeringNational University of Ireland GalwayGalwayH91 TK33Ireland
| | - Ellen T. Roche
- Institute for Medical Engineering and ScienceMassachusetts Institute of TechnologyCambridgeMA02139USA
- Department of Mechanical EngineeringMassachusetts Institute of TechnologyCambridgeMA02139USA
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18
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Kochar IS, Jain R. Pancreas transplant in type 1 diabetes mellitus: the emerging role of islet cell transplant. Ann Pediatr Endocrinol Metab 2021; 26:86-91. [PMID: 34218630 PMCID: PMC8255858 DOI: 10.6065/apem.2142012.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 05/12/2021] [Indexed: 11/28/2022] Open
Abstract
Pancreas transplant, both whole pancreas and islet cell, is a known therapeutic option for treatment of type 1 diabetes mellitus. Islet cell transplant began as an experimental therapy but is emerging to be quite beneficial due to less surgical risk and fewer complications. It is also considered a promising option in pediatric patients. In this review the authors discuss the indications, procedure, and benefits of islet cell transplant along with newer strategies for improving outcomes.
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Affiliation(s)
- Inderpal Singh Kochar
- Department of Pediatric and Adolescent Endocrinology, Indraprastha Apollo Hospital, New Delhi, India
| | - Rakhi Jain
- Department of Pediatric and Adolescent Endocrinology, Indraprastha Apollo Hospital, New Delhi, India,Address for correspondence: Rakhi Jain Department of Pediatric and Adolescent Endocrinology, Indraprastha Apollo Hospital, Sarita Vihar, New Delhi 110076, India
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19
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Washburn RL, Hibler T, Thompson LA, Kaur G, Dufour JM. Therapeutic application of Sertoli cells for treatment of various diseases. Semin Cell Dev Biol 2021; 121:10-23. [PMID: 33910764 DOI: 10.1016/j.semcdb.2021.04.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 04/07/2021] [Indexed: 12/11/2022]
Abstract
Sertoli cells (SCs) are immune privileged cells found in the testis that function to immunologically protect maturing germ cells from immune destruction. This immune protection is due to the blood-testis-barrier, which prevents infiltration of cytotoxic immune cells and antibodies, and SC production of immunomodulatory factors, that favor a tolerogenic environment. The ability of SCs to create an immune privileged environment has led to the exploration of their potential use in the treatment of various diseases. SCs have been utilized to create a tolerogenic ectopic microenvironment, to protect co-grafted cells, and to deliver therapeutic proteins through gene therapy. To date, numerous studies have reported the potential use of SCs for the treatment of diabetes, neurodegenerative disorders, and restoration of spermatogenesis. Additionally, SCs have been investigated as a delivery vehicle for therapeutic products to treat other diseases like Laron syndrome, muscular dystrophy, and infections. This review will provide an overview of these therapeutic applications.
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Affiliation(s)
- Rachel L Washburn
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Taylor Hibler
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Lea Ann Thompson
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Gurvinder Kaur
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Medical Education, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
| | - Jannette M Dufour
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Medical Education, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
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20
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Witkowski P, Philipson LH, Kaufman DB, Ratner LE, Abouljoud MS, Bellin MD, Buse JB, Kandeel F, Stock PG, Mulligan DC, Markmann JF, Kozlowski T, Andreoni KA, Alejandro R, Baidal DA, Hardy MA, Wickrema A, Mirmira RG, Fung J, Becker YT, Josephson MA, Bachul PJ, Pyda JS, Charlton M, Millis JM, Gaglia JL, Stratta RJ, Fridell JA, Niederhaus SV, Forbes RC, Jayant K, Robertson RP, Odorico JS, Levy MF, Harland RC, Abrams PL, Olaitan OK, Kandaswamy R, Wellen JR, Japour AJ, Desai CS, Naziruddin B, Balamurugan AN, Barth RN, Ricordi C, for The “Islets for US” Collaborative. The demise of islet allotransplantation in the United States: A call for an urgent regulatory update. Am J Transplant 2021; 21:1365-1375. [PMID: 33251712 PMCID: PMC8016716 DOI: 10.1111/ajt.16397] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 10/14/2020] [Accepted: 11/02/2020] [Indexed: 02/06/2023]
Abstract
Islet allotransplantation in the United States (US) is facing an imminent demise. Despite nearly three decades of progress in the field, an archaic regulatory framework has stymied US clinical practice. Current regulations do not reflect the state-of-the-art in clinical or technical practices. In the US, islets are considered biologic drugs and "more than minimally manipulated" human cell and tissue products (HCT/Ps). In contrast, across the world, human islets are appropriately defined as "minimally manipulated tissue" and not regulated as a drug, which has led to islet allotransplantation (allo-ITx) becoming a standard-of-care procedure for selected patients with type 1 diabetes mellitus. This regulatory distinction impedes patient access to islets for transplantation in the US. As a result only 11 patients underwent allo-ITx in the US between 2016 and 2019, and all as investigational procedures in the settings of a clinical trials. Herein, we describe the current regulations pertaining to islet transplantation in the United States. We explore the progress which has been made in the field and demonstrate why the regulatory framework must be updated to both better reflect our current clinical practice and to deal with upcoming challenges. We propose specific updates to current regulations which are required for the renaissance of ethical, safe, effective, and affordable allo-ITx in the United States.
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Affiliation(s)
- Piotr Witkowski
- Department of Surgery, Transplantation Institute, University of Chicago, Chicago, Illinois, USA
| | | | - Dixon B. Kaufman
- Division of Transplantation, Department of Surgery, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, USA
| | - Lloyd E. Ratner
- Department of Surgery, Columbia University College of Physicians and Surgeons, New York, New York, USA
| | - Marwan S. Abouljoud
- Transplant and Hepatobiliary Surgery, Henry Ford Hospital, Detroit, Michigan, USA
| | - Melena D. Bellin
- Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA
| | - John B. Buse
- Division of Endocrinology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
| | - Fouad Kandeel
- Department of Translational Research and Cellular Therapeutics, Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, California, USA
| | - Peter G. Stock
- Division of Transplant Surgery, Department of Surgery, University of California, San Francisco, California, USA
| | - David C. Mulligan
- Department of Surgery, Transplantation and Immunology, Yale University, New Haven, Connecticut, USA
| | - James F. Markmann
- Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Tomasz Kozlowski
- Division of Transplantation, Department of Surgery, The University of Oklahoma College of Medicine, Oklahoma City, Oklahoma, USA
| | - Kenneth A. Andreoni
- Department of Surgery, University of Florida, College of Medicine, Gainesville, Florida, USA
| | - Rodolfo Alejandro
- Diabetes Research Institute and Cell Transplant Center, University of Miami, Miami, Florida, USA
| | - David A. Baidal
- Diabetes Research Institute and Cell Transplant Center, University of Miami, Miami, Florida, USA
| | - Mark A. Hardy
- Department of Surgery, Columbia University College of Physicians and Surgeons, New York, New York, USA
| | - Amittha Wickrema
- Department of Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, Illinois, USA
| | - Raghavendra G. Mirmira
- Department of Medicine, Translational Research Center, University of Chicago, Chicago, Illinois, USA
| | - John Fung
- Department of Surgery, Transplantation Institute, University of Chicago, Chicago, Illinois, USA
| | - Yolanda T. Becker
- Department of Surgery, Transplantation Institute, University of Chicago, Chicago, Illinois, USA
| | - Michelle A. Josephson
- Department of Surgery, Transplantation Institute, University of Chicago, Chicago, Illinois, USA
| | - Piotr J. Bachul
- Department of Surgery, Transplantation Institute, University of Chicago, Chicago, Illinois, USA
| | - Jordan S. Pyda
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Michael Charlton
- Department of Surgery, Transplantation Institute, University of Chicago, Chicago, Illinois, USA
| | - J. Michael Millis
- Department of Surgery, Transplantation Institute, University of Chicago, Chicago, Illinois, USA
| | - Jason L. Gaglia
- Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Robert J. Stratta
- Department of Surgery, Section of Transplantation, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Jonathan A. Fridell
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Silke V. Niederhaus
- Department of Surgery, University of Maryland Medical Center, Baltimore, Maryland, USA
| | - Rachael C. Forbes
- Division of Kidney and Pancreas Transplantation, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Kumar Jayant
- Department of Surgery, Transplantation Institute, University of Chicago, Chicago, Illinois, USA
| | - R. Paul Robertson
- Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Washington, Seattle, Washington, USA
| | - Jon S. Odorico
- Division of Transplantation, Department of Surgery, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, USA
| | - Marlon F. Levy
- Division of Transplantation, Hume-Lee Transplant Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | | | - Peter L. Abrams
- MedStar Georgetown Transplant Institute, Washington, District of Columbia, USA
| | | | - Raja Kandaswamy
- Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA
| | - Jason R. Wellen
- Department of Surgery, Washington University, St Louis, Missouri, USA
| | - Anthony J. Japour
- Anthony Japour and Associates, Medical and Scientific Consulting Inc, Miami, FL, USA
| | - Chirag S. Desai
- Department of Surgery, Section of Transplantation, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Bashoo Naziruddin
- Transplantation Institute, Baylor University Medical Center, Dallas, Texas, USA
| | - Appakalai N. Balamurugan
- Division of Pediatric General and Thoracic Surgery, Department of Surgery, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA
| | - Rolf N. Barth
- Department of Surgery, Transplantation Institute, University of Chicago, Chicago, Illinois, USA
| | - Camillo Ricordi
- Diabetes Research Institute and Cell Transplant Center, University of Miami, Miami, Florida, USA
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21
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C-Peptide as a Therapy for Type 1 Diabetes Mellitus. Biomedicines 2021; 9:biomedicines9030270. [PMID: 33800470 PMCID: PMC8000702 DOI: 10.3390/biomedicines9030270] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 03/02/2021] [Accepted: 03/03/2021] [Indexed: 12/13/2022] Open
Abstract
Diabetes mellitus (DM) is a complex metabolic disease affecting one-third of the United States population. It is characterized by hyperglycemia, where the hormone insulin is either not produced sufficiently or where there is a resistance to insulin. Patients with Type 1 DM (T1DM), in which the insulin-producing beta cells are destroyed by autoimmune mechanisms, have a significantly increased risk of developing life-threatening cardiovascular complications, even when exogenous insulin is administered. In fact, due to various factors such as limited blood glucose measurements and timing of insulin administration, only 37% of T1DM adults achieve normoglycemia. Furthermore, T1DM patients do not produce C-peptide, a cleavage product from insulin processing. C-peptide has potential therapeutic effects in vitro and in vivo on many complications of T1DM, such as peripheral neuropathy, atherosclerosis, and inflammation. Thus, delivery of C-peptide in conjunction with insulin through a pump, pancreatic islet transplantation, or genetically engineered Sertoli cells (an immune privileged cell type) may ameliorate many of the cardiovascular and vascular complications afflicting T1DM patients.
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22
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Verhoeff K, Henschke SJ, Marfil-Garza BA, Dadheech N, Shapiro AMJ. Inducible Pluripotent Stem Cells as a Potential Cure for Diabetes. Cells 2021; 10:cells10020278. [PMID: 33573247 PMCID: PMC7911560 DOI: 10.3390/cells10020278] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2021] [Revised: 01/22/2021] [Accepted: 01/24/2021] [Indexed: 02/07/2023] Open
Abstract
Over the last century, diabetes has been treated with subcutaneous insulin, a discovery that enabled patients to forego death from hyperglycemia. Despite novel insulin formulations, patients with diabetes continue to suffer morbidity and mortality with unsustainable costs to the health care system. Continuous glucose monitoring, wearable insulin pumps, and closed-loop artificial pancreas systems represent an advance, but still fail to recreate physiologic euglycemia and are not universally available. Islet cell transplantation has evolved into a successful modality for treating a subset of patients with ‘brittle’ diabetes but is limited by organ donor supply and immunosuppression requirements. A novel approach involves generating autologous or immune-protected islet cells for transplant from inducible pluripotent stem cells to eliminate detrimental immune responses and organ supply limitations. In this review, we briefly discuss novel mechanisms for subcutaneous insulin delivery and define their shortfalls. We describe embryological development and physiology of islets to better understand their role in glycemic control and, finally, discuss cell-based therapies for diabetes and barriers to widespread use. In response to these barriers, we present the promise of stem cell therapy, and review the current gaps requiring solutions to enable widespread use of stem cells as a potential cure for diabetes.
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Affiliation(s)
- Kevin Verhoeff
- Department of Surgery, University of Alberta, Edmonton, AB T6G 2B7, Canada;
- Correspondence: ; Tel.: +1-780-984-1836
| | - Sarah J. Henschke
- Department of Emergency Medicine, University of Saskatchewan, Saskatoon, SK S7N 0W8, Canada;
| | | | - Nidheesh Dadheech
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB T6G 2B7, Canada;
| | - Andrew Mark James Shapiro
- FRCS (Eng) FRCSC MSM FCAHS, Clinical Islet Transplant Program, Alberta Diabetes Institute, Department of Surgery, Canadian National Transplant Research Program, Edmonton, AB T6G 2B7, Canada;
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23
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Bachul PJ, Golab K, Basto L, Zangan S, Pyda JS, Perez-Gutierrez A, Borek P, Wang LJ, Tibudan M, Tran DK, Anteby R, Generette GS, Chrzanowski J, Fendler W, Perea L, Jayant K, Lucander A, Thomas C, Philipson L, Millis JM, Fung J, Witkowski P. Post-Hoc Analysis of a Randomized, Double Blind, Prospective Study at the University of Chicago: Additional Standardizations of Trial Protocol are Needed to Evaluate the Effect of a CXCR1/2 Inhibitor in Islet Allotransplantation. Cell Transplant 2021; 30:9636897211001774. [PMID: 33908301 PMCID: PMC8085379 DOI: 10.1177/09636897211001774] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 01/14/2021] [Accepted: 02/22/2021] [Indexed: 12/11/2022] Open
Abstract
A recent randomized, multicenter trial did not show benefit of a CXCR1/2 receptor inhibitor (Reparixin) when analysis included marginal islet mass (>3,000 IEQ/kg) for allotransplantation and when immunosuppression regimens were not standardized among participating centers. We present a post-hoc analysis of trial patients from our center at the University of Chicago who received an islet mass of over 5,000 IEQ/kg and a standardized immunosuppression regimen of anti-thymocyte globulin (ATG) for induction. Twelve islet allotransplantation (ITx) recipients were randomized (2:1) to receive Reparixin (N = 8) or placebo (N = 4) in accordance with the multicenter trial protocol. Pancreas and donor characteristics did not differ between Reparixin and placebo groups. Five (62.5%) patients who received Reparixin, compared to none in the placebo group, achieved insulin independence after only one islet infusion and remained insulin-free for over 2 years (P = 0.08). Following the first ITx with ATG induction, distinct cytokine, chemokine, and miR-375 release profiles were observed for both the Reparixin and placebo groups. After excluding procedures with complications, islet engraftment on post-operative day 75 after a single transplant was higher in the Reparixin group (n = 7) than in the placebo (n = 3) group (P = 0.03) when islet graft function was measured by the ratio of the area under the curve (AUC) for c-peptide to glucose in mixed meal tolerance test (MMTT). Additionally, the rate of engraftment was higher when determined via BETA-2 score instead of MMTT (P = 0.01). Our analysis suggests that Reparixin may have improved outcomes compared to placebo when sufficient islet mass is transplanted and when standardized immunosuppression with ATG is used for induction. However, further studies are warranted. Investigation of Reparixin and other novel agents under more standardized and optimized conditions would help exclude confounding factors and allow for a more definitive evaluation of their role in improving outcomes in islet transplantation. Clinical trial reg. no. NCT01817959, clinicaltrials.gov.
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Affiliation(s)
- Piotr J. Bachul
- Department of Surgery, The Transplantation Institute, University of Chicago, Chicago, IL, USA
| | - Karolina Golab
- Department of Surgery, The Transplantation Institute, University of Chicago, Chicago, IL, USA
| | - Lindsay Basto
- Department of Surgery, The Transplantation Institute, University of Chicago, Chicago, IL, USA
| | - Steven Zangan
- Department of Radiology, University of Chicago, Chicago, IL, USA
| | - Jordan S. Pyda
- Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | | | - Peter Borek
- Department of Surgery, The Transplantation Institute, University of Chicago, Chicago, IL, USA
| | - Ling-Jia Wang
- Department of Surgery, The Transplantation Institute, University of Chicago, Chicago, IL, USA
| | - Martin Tibudan
- Department of Surgery, The Transplantation Institute, University of Chicago, Chicago, IL, USA
| | - Dong-Kha Tran
- Department of Surgery, The Transplantation Institute, University of Chicago, Chicago, IL, USA
| | - Roi Anteby
- Department of Surgery, The Transplantation Institute, University of Chicago, Chicago, IL, USA
| | - Gabriela S. Generette
- Department of Surgery, The Transplantation Institute, University of Chicago, Chicago, IL, USA
| | - Jędrzej Chrzanowski
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, Lodz, Poland
| | - Wojciech Fendler
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, Lodz, Poland
| | - Laurencia Perea
- Department of Surgery, The Transplantation Institute, University of Chicago, Chicago, IL, USA
| | - Kumar Jayant
- Department of Surgery, The Transplantation Institute, University of Chicago, Chicago, IL, USA
| | - Aaron Lucander
- Department of Surgery, The Transplantation Institute, University of Chicago, Chicago, IL, USA
| | - Celeste Thomas
- Department of Medicine, University of Chicago, Chicago, IL, USA
| | - Louis Philipson
- Department of Medicine, University of Chicago, Chicago, IL, USA
| | - J. Michael Millis
- Department of Surgery, The Transplantation Institute, University of Chicago, Chicago, IL, USA
| | - John Fung
- Department of Surgery, The Transplantation Institute, University of Chicago, Chicago, IL, USA
| | - Piotr Witkowski
- Department of Surgery, The Transplantation Institute, University of Chicago, Chicago, IL, USA
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24
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Kimura A, Toyoda T, Iwasaki M, Hirama R, Osafune K. Combined Omics Approaches Reveal the Roles of Non-canonical WNT7B Signaling and YY1 in the Proliferation of Human Pancreatic Progenitor Cells. Cell Chem Biol 2020; 27:1561-1572.e7. [PMID: 33125912 DOI: 10.1016/j.chembiol.2020.08.018] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Revised: 08/18/2020] [Accepted: 08/27/2020] [Indexed: 02/07/2023]
Abstract
The proliferation of human pancreatic progenitor cells (PPCs) is critical for developing cell therapies for diabetes. Here, using transcriptome analysis combined with small interfering RNA (siRNA) screening, we revealed that WNT7B is a downstream growth factor of AT7867, a compound known to promote the proliferation of PPCs generated from human pluripotent stem cells. Feeder cell lines stably expressing mouse Wnt7a or Wnt7b, but not other Wnts, enhanced PPC proliferation in the absence of AT7867. Importantly, Wnt7a/b ligands did not activate the canonical Wnt pathway, and PPC proliferation depended on the non-canonical Wnt/PKC pathway. A comparison of the phosphoproteome in response to AT7867 or a newly synthesized AT7867 derivative uncovered the function of YY1 as a transcriptional regulator of WNT7B. Overall, our data highlight unknown roles of non-canonical WNT7B/PKC signaling and YY1 in human PPC proliferation and will contribute to the stable supply of a cell source for pancreatic disease modeling and therapeutic applications.
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Affiliation(s)
- Azuma Kimura
- Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan
| | - Taro Toyoda
- Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan
| | - Mio Iwasaki
- Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan
| | - Ryusuke Hirama
- Research Institute for Bioscience Products and Fine Chemicals, Ajinomoto Co., Inc., Kawasaki, Kanagawa 210-8681, Japan
| | - Kenji Osafune
- Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
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25
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Matsumoto S, Shimoda M. Current situation of clinical islet transplantation from allogeneic toward xenogeneic. J Diabetes 2020; 12:733-741. [PMID: 32246528 DOI: 10.1111/1753-0407.13041] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 03/25/2020] [Indexed: 12/30/2022] Open
Abstract
Currently, type 1 diabetes requires lifelong insulin injection and careful blood glucose control to prevent secondary complications, but islet transplantation could make a type 1 diabetic patient insulin independent. On the other hand, islet transplantation needs human donors and donor shortage is the most serious issue. To alleviate the donor shortage, non-heart-beating and living donors were used; in addition, the efficacy of islet isolation and transplantation has been improved. However, the donor shortage issue will not be solved as long as human donors are the only source. To solve the donor shortage issue, islet xenotransplantation using porcine islets was initiated in 1994. Islet xenotransplantation has a potential to cure many type 1 diabetic patients, although there is the risk of developing serious or novel infection. Therefore, the World Health Organization has been interested in xenotransplantation, and the International Xenotransplantation Association (IXA) has published consensus statements to initiate xenogeneic islet transplantation. Clinical islet xenotransplantation was conducted under the official regulation, and safety and efficacy data have been accumulated. Currently an efficient method to overcome xenorejection is an important research target. In addition to traditional immunosuppressive drugs and immune isolation methods, the gene modification with CRISPR and blastocyst complementation have been investigated with promising outcomes. Once the xenorejection issue is overcome, islet xenotransplantation should become a curative treatment for type 1 diabetic patients.
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Affiliation(s)
- Shinichi Matsumoto
- Islet Transplantation Project, National Institute for Global Health and Medicine, Tokyo, Japan
| | - Masayuki Shimoda
- Islet Transplantation Project, National Institute for Global Health and Medicine, Tokyo, Japan
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26
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Nicolas CT, Kaiser RA, Hickey RD, Allen KL, Du Z, VanLith CJ, Guthman RM, Amiot B, Suksanpaisan L, Han B, Francipane MG, Cheikhi A, Jiang H, Bansal A, Pandey MK, Garg I, Lowe V, Bhagwate A, O’Brien D, Kocher JPA, DeGrado TR, Nyberg SL, Lagasse E, Lillegard JB. Ex Vivo Cell Therapy by Ectopic Hepatocyte Transplantation Treats the Porcine Tyrosinemia Model of Acute Liver Failure. Mol Ther Methods Clin Dev 2020; 18:738-750. [PMID: 32913881 PMCID: PMC7452193 DOI: 10.1016/j.omtm.2020.07.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 07/07/2020] [Indexed: 11/19/2022]
Abstract
The effectiveness of cell-based therapies to treat liver failure is often limited by the diseased liver environment. Here, we provide preclinical proof of concept for hepatocyte transplantation into lymph nodes as a cure for liver failure in a large-animal model with hereditary tyrosinemia type 1 (HT1), a metabolic liver disease caused by deficiency of fumarylacetoacetate hydrolase (FAH) enzyme. Autologous porcine hepatocytes were transduced ex vivo with a lentiviral vector carrying the pig Fah gene and transplanted into mesenteric lymph nodes. Hepatocytes showed early (6 h) and durable (8 months) engraftment in lymph nodes, with reproduction of vascular and hepatic microarchitecture. Subsequently, hepatocytes migrated to and repopulated the native diseased liver. The corrected cells generated sufficient liver mass to clinically ameliorate the acute liver failure and HT1 disease as early as 97 days post-transplantation. Integration site analysis defined the corrected hepatocytes in the liver as a subpopulation of hepatocytes from lymph nodes, indicating that the lymph nodes served as a source for healthy hepatocytes to repopulate a diseased liver. Therefore, ectopic transplantation of healthy hepatocytes cures this pig model of liver failure and presents a promising approach for the development of cures for liver disease in patients.
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Affiliation(s)
- Clara T. Nicolas
- Department of Surgery, Mayo Clinic, Rochester, MN 55905, USA
- Faculty of Medicine, University of Barcelona, Barcelona, Spain
- Department of Surgery, University of Alabama Birmingham, Birmingham, AL, USA
| | - Robert A. Kaiser
- Department of Surgery, Mayo Clinic, Rochester, MN 55905, USA
- Children’s Hospitals and Clinics of Minnesota, Midwest Fetal Care Center, Minneapolis, MN, USA
| | | | - Kari L. Allen
- Department of Surgery, Mayo Clinic, Rochester, MN 55905, USA
| | - Zeji Du
- Department of Surgery, Mayo Clinic, Rochester, MN 55905, USA
| | | | - Rebekah M. Guthman
- Department of Surgery, Mayo Clinic, Rochester, MN 55905, USA
- Medical College of Wisconsin, Wausau, WI, USA
| | - Bruce Amiot
- Department of Surgery, Mayo Clinic, Rochester, MN 55905, USA
| | | | - Bing Han
- McGowan Institute for Regenerative Medicine and Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Maria Giovanna Francipane
- McGowan Institute for Regenerative Medicine and Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA
- Ri.MED Foundation, Palermo, Italy
| | - Amin Cheikhi
- Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, PA, USA
| | - Huailei Jiang
- Department of Radiology, Mayo Clinic, Rochester, MN, USA
| | - Aditya Bansal
- Department of Radiology, Mayo Clinic, Rochester, MN, USA
| | | | - Ishan Garg
- Department of Radiology, Mayo Clinic, Rochester, MN, USA
| | - Val Lowe
- Department of Radiology, Mayo Clinic, Rochester, MN, USA
| | - Aditya Bhagwate
- Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - Daniel O’Brien
- Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - Jean-Pierre A. Kocher
- Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | | | - Scott L. Nyberg
- Department of Surgery, Mayo Clinic, Rochester, MN 55905, USA
| | - Eric Lagasse
- McGowan Institute for Regenerative Medicine and Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Joseph B. Lillegard
- Department of Surgery, Mayo Clinic, Rochester, MN 55905, USA
- Children’s Hospitals and Clinics of Minnesota, Midwest Fetal Care Center, Minneapolis, MN, USA
- Pediatric Surgical Associates, Minneapolis, MN, USA
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27
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Marfil‐Garza BA, Polishevska K, Pepper AR, Korbutt GS. Current State and Evidence of Cellular Encapsulation Strategies in Type 1 Diabetes. Compr Physiol 2020; 10:839-878. [DOI: 10.1002/cphy.c190033] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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28
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Nemati M, Karbalaei N, Mokarram P, Dehghani F. Effects of platelet-rich plasma on the pancreatic islet survival and function, islet transplantation outcome and pancreatic pdx 1 and insulin gene expression in streptozotocin-induced diabetic rats. Growth Factors 2020; 38:137-151. [PMID: 33569978 DOI: 10.1080/08977194.2021.1881502] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Platelet-rich plasma (PRP) is a therapeutic option in different fields based on its growth factors. We investigated influence of PRP on islet survival, function, transplantation outcomes, and pancreatic genes expression in diabetic rats. In vitro: pancreatic isolated islets were incubated with/without PRP then viability, insulin secretion, and content were assessed. In vivo: Series 1 were designed to determine whether islet treatment with PRP improves transplantation outcome in diabetic rats by evaluating plasma glucose and insulin concentrations and oxidative parameters. Series 2, effects of PRP subcutaneous injection were evaluated on pancreatic genes expression and glucose tolerance test in diabetic rats. PRP enhanced viability and secretary function of islet. Reduced glucose and malondialdehyde levels as well as increased insulin levels, superoxide dismutase activity, and expressions of pdx1 and insulin were observed in diabetic rats. PRP treatment has positive effects on islet viability, function, transplantation outcome, and pancreatic genes expression in diabetic rats.
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Affiliation(s)
- Marzieh Nemati
- Department of Physiology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Narges Karbalaei
- Department of Physiology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
- Histomorphometry and Stereology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Pooneh Mokarram
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Farzaneh Dehghani
- Histomorphometry and Stereology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Anatomy, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
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29
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Alcazar O, Hernandez LF, Nakayasu ES, Piehowski PD, Ansong C, Abdulreda MH, Buchwald P. Longitudinal proteomics analysis in the immediate microenvironment of islet allografts during progression of rejection. J Proteomics 2020; 223:103826. [PMID: 32442648 DOI: 10.1016/j.jprot.2020.103826] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Revised: 05/08/2020] [Accepted: 05/12/2020] [Indexed: 12/12/2022]
Abstract
The applicability and benefits of pancreatic islet transplantation are limited due to various issues including the need to avoid immune-mediated rejection. Here, we used our experimental platform of allogeneic islet transplant in the anterior chamber of the eye (ACE-platform) to longitudinally monitor the progress of rejection in mice and obtain aqueous humor samples representative of the microenvironment of the graft for accurately-timed proteomic analyses. LC-MS/MS-based proteomics performed on such mass-limited samples (~5 μL) identified a total of 1296 proteins. Various analyses revealed distinct protein patterns associated with the mounting of the inflammatory and immune responses and their evolution with the progression of the rejection. Pathway analyses indicated predominant changes in cytotoxic functions, cell movement, and innate and adaptive immune responses. Network prediction analyses revealed transition from humoral to cellular immune response and exacerbation of pro-inflammatory signaling. One of the proteins identified by this localized proteomics as a candidate biomarker of islet rejection, Cystatin 3, was further validated by ELISA in the aqueous humor. This study provides (1) experimental evidence demonstrating the feasibility of longitudinal localized proteomics using small aqueous humor samples and (2) proof-of-concept for the discovery of biomarkers of impending immune attack from the immediate local microenvironment of ACE-transplanted islets. SIGNIFICANCE: The combination of the ACE-platform and longitudinal localized proteomics offers a powerful approach to biomarker discovery during the various stages of immune reactions mounted against transplanted tissues including pancreatic islets. It also supports proteomics-assisted drug discovery and development efforts aimed at preventing rejection through efficacy assessment of new agents by noninvasive and longitudinal graft monitoring.
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Affiliation(s)
- Oscar Alcazar
- University of Miami Miller School of Medicine, Diabetes Research Institute, Miami, FL, USA
| | - Luis F Hernandez
- University of Miami Miller School of Medicine, Diabetes Research Institute, Miami, FL, USA
| | - Ernesto S Nakayasu
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Paul D Piehowski
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Charles Ansong
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Midhat H Abdulreda
- University of Miami Miller School of Medicine, Diabetes Research Institute, Miami, FL, USA; University of Miami Miller School of Medicine, Department of Surgery, Miami, FL, USA; University of Miami Miller School of Medicine, Department of Microbiology and Immunology, Miami, FL, USA; University of Miami Miller School of Medicine, Department of Ophthalmology, Miami, FL, USA.
| | - Peter Buchwald
- University of Miami Miller School of Medicine, Diabetes Research Institute, Miami, FL, USA; University of Miami Miller School of Medicine, Department of Molecular and Cellular Pharmacology, Miami, FL, USA.
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Vishwakarma SK, Jaiswal J, Park K, Lakkireddy C, Raju N, Bardia A, Habeeb MA, Paspala SAB, Khan AA, Dhayal M. TiO
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Nanoflowers on Conducting Substrates Ameliorate Effective Transdifferentiation of Human Hepatic Progenitor Cells for Long‐Term Hyperglycemia Reversal in Diabetic Mice. ADVANCED THERAPEUTICS 2020. [DOI: 10.1002/adtp.201900205] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Sandeep Kumar Vishwakarma
- Clinical Research FacilityCSIR‐Centre for Cellular and Molecular Biology Hyderabad Telangana 500007 India
- Central Laboratory for Stem Cell Research and Translational MedicineCentre for Liver Research and Diagnostics, Deccan College of Medical Sciences Kanchanbagh Hyderabad Telangana 500058 India
- Dr. Habeebullah Life Sciences Limited Attapur Hyderabad Telangana 500048 India
| | - Juhi Jaiswal
- Nano‐Cellular Medicine and Biophysics Laboratory, School of Biomedical EngineeringIndian Institute of Technology (Banaras Hindu University) Varanasi Uttar Pradesh 221005 India
| | - Kyung‐Hee Park
- Department of Dental Materials and Hard‐tissue Biointerface Research Center, School of DentistryChonnam National University Gwangju 61186 Republic of Korea
| | - Chandrakala Lakkireddy
- Central Laboratory for Stem Cell Research and Translational MedicineCentre for Liver Research and Diagnostics, Deccan College of Medical Sciences Kanchanbagh Hyderabad Telangana 500058 India
| | - Nagarapu Raju
- Central Laboratory for Stem Cell Research and Translational MedicineCentre for Liver Research and Diagnostics, Deccan College of Medical Sciences Kanchanbagh Hyderabad Telangana 500058 India
- Dr. Habeebullah Life Sciences Limited Attapur Hyderabad Telangana 500048 India
| | - Avinash Bardia
- Central Laboratory for Stem Cell Research and Translational MedicineCentre for Liver Research and Diagnostics, Deccan College of Medical Sciences Kanchanbagh Hyderabad Telangana 500058 India
- Dr. Habeebullah Life Sciences Limited Attapur Hyderabad Telangana 500048 India
| | - Md. Aejaz Habeeb
- Central Laboratory for Stem Cell Research and Translational MedicineCentre for Liver Research and Diagnostics, Deccan College of Medical Sciences Kanchanbagh Hyderabad Telangana 500058 India
- Dr. Habeebullah Life Sciences Limited Attapur Hyderabad Telangana 500048 India
| | - Syed Ameer Basha Paspala
- Central Laboratory for Stem Cell Research and Translational MedicineCentre for Liver Research and Diagnostics, Deccan College of Medical Sciences Kanchanbagh Hyderabad Telangana 500058 India
- Dr. Habeebullah Life Sciences Limited Attapur Hyderabad Telangana 500048 India
| | - Aleem Ahmed Khan
- Central Laboratory for Stem Cell Research and Translational MedicineCentre for Liver Research and Diagnostics, Deccan College of Medical Sciences Kanchanbagh Hyderabad Telangana 500058 India
- Dr. Habeebullah Life Sciences Limited Attapur Hyderabad Telangana 500048 India
| | - Marshal Dhayal
- Clinical Research FacilityCSIR‐Centre for Cellular and Molecular Biology Hyderabad Telangana 500007 India
- Nano‐Cellular Medicine and Biophysics Laboratory, School of Biomedical EngineeringIndian Institute of Technology (Banaras Hindu University) Varanasi Uttar Pradesh 221005 India
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Role of bone marrow-derived mesenchymal stem cells on the parotid glands of streptozotocin induced diabetes rats. J Oral Biol Craniofac Res 2020; 10:33-37. [PMID: 32099770 DOI: 10.1016/j.jobcr.2020.02.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 02/03/2020] [Accepted: 02/04/2020] [Indexed: 01/04/2023] Open
Abstract
The functional insufficiency of salivary glands constitute the common oral complaints in both type 1 and type 2 diabetes mellitus. The treatment with stem cell could decrease diabetic-induced hyposalivation and improve the quality of life for patients. OBJECTIVE The current study designed to assess the biological outcome of systemic injection of stem cells on the parotid salivary gland in streptozotocin induced diabetic. METHODS Twenty-four albino rats received intra-peritoneal injection of 50 mg/kg streptozotocin for induction of diabetes and were divided into two groups (n = 12): Group I (control) were kept without any manipulation, Group II received intravenous injection of 1×106 of mesenchymal stem cells of bone marrow derived for two days. All rats were sacrificed at 1, 3 weeks, then the parotid glands were isolated, fixed and processed for Heamatoxylin and Eosin examination, immunohistochemical staining for aquaporin-5. RESULTS group I groups showed intracellular cytoplasmic vacuoles and focal loss of salivary architecture, while group II showed maintenance of gland architecture. Immunohistochemical examination of aquaporin-5 showed significant difference between the two groups. CONCLUSION bone marrow derived stem cell treatment considers as an improved methods in prevention and treatment of diabeticinduced hyposalivation.
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Schaschkow A, Sigrist S, Mura C, Barthes J, Vrana NE, Czuba E, Lemaire F, Neidl R, Dissaux C, Lejay A, Lavalle P, Bruant-Rodier C, Bouzakri K, Pinget M, Maillard E. Glycaemic control in diabetic rats treated with islet transplantation using plasma combined with hydroxypropylmethyl cellulose hydrogel. Acta Biomater 2020; 102:259-272. [PMID: 31811957 DOI: 10.1016/j.actbio.2019.11.047] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 11/15/2019] [Accepted: 11/22/2019] [Indexed: 12/18/2022]
Abstract
Islet transplantation is one of the most efficient cell therapies used in clinics and could treat a large proportion of patients with diabetes. However, it is limited by the high requirement of pancreas necessary to provide the sufficient surviving islet mass in the hepatic tissue and restore normoglycaemia. Reduction in organ procurement requirements could be achieved by extrahepatic transplantation using a biomaterial that enhances islet survival and function. We report a plasma-supplemented hydroxypropyl methylcellulose (HPMC) hydrogel, engineered specifically using a newly developed technique for intra-omental islet infusion, known as hOMING (h-Omental Matrix Islet filliNG). The HPMC hydrogel delivered islets with better performance than that of the classical intrahepatic infusion. After the validation of the HPMC suitability for islets in vivo and in vitro, plasma supplementation modified the rheological properties of HPMC without affecting its applicability with hOMING. The biomaterial association was proven to be more efficient both in vitro and in vivo, with better islet viability and function than that of the current clinical intrahepatic delivery technique. Indeed, when the islet mass was decreased by 25% or 35%, glycaemia control was observed in the group of plasma-supplemented hydrogels, whereas no regulation was observed in the hepatic group. Plasma gelation, observed immediately post infusion, decreased anoïkis and promoted vascularisation. To conclude, the threshold mass for islet transplantation could be decreased using HPMC-Plasma combined with the hOMING technique. The simplicity of the hOMING technique and the already validated use of its components could facilitate its transfer to clinics. STATEMENT OF SIGNIFICANCE: One of the major limitations for the broad deployment of current cell therapy for brittle type 1 diabetes is the islets' destruction during the transplantation process. Retrieved from their natural environment, the islets are grafted into a foreign tissue, which triggers massive cell loss. It is mandatory to provide the islets with an 3D environment specifically designed for promoting isletimplantation to improve cell therapy outcomes. For this aim, we combined HPMC and plasma. HPMC provides suitable rheological properties to the plasma to be injectable and be maintained in the omentum. Afterwards, the plasma polymerises around the graft in vivo, thereby allowing their optimal integration into their transplantation site. As a result, the islet mass required to obtain glycaemic control was reduced by 35%.
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Chen YJ, Yamazoe T, Leavens KF, Cardenas-Diaz FL, Georgescu A, Huh D, Gadue P, Stanger BZ. iPreP is a three-dimensional nanofibrillar cellulose hydrogel platform for long-term ex vivo preservation of human islets. JCI Insight 2019; 4:124644. [PMID: 31672937 DOI: 10.1172/jci.insight.124644] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Accepted: 09/20/2019] [Indexed: 01/12/2023] Open
Abstract
Islet transplantation is an effective therapy for achieving and maintaining normoglycemia in patients with type 1 diabetes mellitus. However, the supply of transplantable human islets is limited. Upon removal from the pancreas, islets rapidly disintegrate and lose function, resulting in a short interval for studies of islet biology and pretransplantation assessment. Here, we developed a biomimetic platform that can sustain human islet physiology for a prolonged period ex vivo. Our approach involved the creation of a multichannel perifusion system to monitor dynamic insulin secretion and intracellular calcium flux simultaneously, enabling the systematic evaluation of glucose-stimulated insulin secretion under multiple conditions. Using this tool, we developed a nanofibrillar cellulose hydrogel-based islet-preserving platform (iPreP) that can preserve islet viability, morphology, and function for nearly 12 weeks ex vivo, and with the ability to ameliorate glucose levels upon transplantation into diabetic hosts. Our platform has potential applications in the prolonged maintenance of human islets, providing an expanded time window for pretransplantation assessment and islet studies.
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Affiliation(s)
- Yi-Ju Chen
- Gastroenterology Division, Department of Medicine.,Department of Cell and Developmental Biology, and.,Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.,Genetic Resource Science, The Jackson Laboratory, Bar Harbor, Maine, USA
| | | | - Karla F Leavens
- Center for Cellular and Molecular Therapeutics, Department of Pathology and Laboratory Medicine.,Division of Endocrinology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Fabian L Cardenas-Diaz
- Center for Cellular and Molecular Therapeutics, Department of Pathology and Laboratory Medicine
| | - Andrei Georgescu
- Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Dongeun Huh
- Department of Bioengineering, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Paul Gadue
- Center for Cellular and Molecular Therapeutics, Department of Pathology and Laboratory Medicine
| | - Ben Z Stanger
- Gastroenterology Division, Department of Medicine.,Department of Cell and Developmental Biology, and.,Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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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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Open Randomized Multicenter Study to Evaluate Safety and Efficacy of Low Molecular Weight Sulfated Dextran in Islet Transplantation. Transplantation 2019; 103:630-637. [PMID: 30211831 DOI: 10.1097/tp.0000000000002425] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND When transplanted human pancreatic islets are exposed to blood during intraportal infusion, an innate immune response is triggered. This instant blood-mediated inflammatory reaction (IBMIR) activates the coagulation and complement cascades and leads to the destruction of 25% of all transplanted islets within minutes, contributing to the need, in most patients, for islets from more than 1 donor. Low molecular dextran sulfate (LMW-DS) has been shown in experimental settings to inhibit IBMIR. METHODS The Clinical Islet Transplantation consortium 01 study was a phase II, multicenter, open label, active control, randomized study. Twenty-four subjects were randomized to peritransplant intraportal and systemic treatment with either LMW-DS or heparin, targeting an activated partial thromboplastin time of 150 ± 10 seconds and 50 ± 5 seconds, respectively. C-peptide response was measured with a mixed meal tolerance test at 75 and 365 days after transplant. RESULTS Low molecular dextran sulfate was safe and well tolerated with similar observed adverse events (mostly attributed to immunosuppression) as in the heparin arm. There was no difference in the primary endpoint (stimulated C-peptide 75 ± 5 days after the first transplant) between the 2 arms (1.33 ± 1.10 versus 1.56 ± 1.36 ng/mL, P = 0.66). Insulin requirement, metabolic parameters, Clarke and HYPO score, quality of life, and safety were similar between the 2 treatments groups. CONCLUSIONS Even with low dosing, LMW-DS showed similar efficacy in preventing IBMIR to promote islet engraftment when compared to "state-of-the art" treatment with heparin. Furthermore, no substantial differences in the efficacy and safety endpoints were detected, providing important information for future studies with more optimal dosing of LMW-DS for the prevention of IBMIR in islet transplantation.
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Abdulreda MH, Berman DM, Shishido A, Martin C, Hossameldin M, Tschiggfrie A, Hernandez LF, Hernandez A, Ricordi C, Parel JM, Jankowska-Gan E, Burlingham WJ, Arrieta-Quintero EA, Perez VL, Kenyon NS, Berggren PO. Operational immune tolerance towards transplanted allogeneic pancreatic islets in mice and a non-human primate. Diabetologia 2019; 62:811-821. [PMID: 30701283 PMCID: PMC6451664 DOI: 10.1007/s00125-019-4814-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Accepted: 12/14/2018] [Indexed: 12/31/2022]
Abstract
AIMS/HYPOTHESIS Patients with autoimmune type 1 diabetes transplanted with pancreatic islets to their liver experience significant improvement in quality of life through better control of blood sugar and enhanced awareness of hypoglycaemia. However, long-term survival and efficacy of the intrahepatic islet transplant are limited owing to liver-specific complications, such as immediate blood-mediated immune reaction, hypoxia, a highly enzymatic and inflammatory environment and locally elevated levels of drugs including immunosuppressive agents, all of which are injurious to islets. This has spurred a search for new islet transplant sites and for innovative ways to achieve long-term graft survival and efficacy without life-long systemic immunosuppression and its complications. METHODS We used our previously established approach of islet transplant in the anterior chamber of the eye in allogeneic recipient mouse models and a baboon model of diabetes, which were treated transiently with anti-CD154/CD40L blocking antibody in the peri-transplant period. Survival of the intraocular islet allografts was assessed by direct visualisation in the eye and metabolic variables (blood glucose and C-peptide measurements). We evaluated longitudinally the cytokine profile in the local microenvironment of the intraocular islet allografts, represented in aqueous humour, under conditions of immune rejection vs tolerance. We also evaluated the recall response in the periphery of the baboon recipient using delayed-type hypersensitivity (DTH) assay, and in mice after repeat transplant in the kidney following initial transplant with allogeneic islets in the eye or kidney. RESULTS Results in mice showed >300 days immunosuppression-free survival of allogeneic islets transplanted in the eye or kidney. Notably, >70% of tolerant mice, initially transplanted in the eye, exhibited >400 days of graft survival after re-transplant in the kidney without immunosuppression compared with ~30% in mice that were initially transplanted in the kidney. Cytokine and DTH data provided evidence of T helper 2-driven local and peripheral immune regulatory mechanisms in support of operational immune tolerance towards the islet allografts in both models. CONCLUSIONS/INTERPRETATION We are currently evaluating the safety and efficacy of intraocular islet transplantation in a phase 1 clinical trial. In this study, we demonstrate immunosuppression-free long-term survival of intraocular islet allografts in mice and in a baboon using transient peri-transplant immune intervention. These results highlight the potential for inducing islet transplant immune tolerance through the intraocular route. Therefore, the current findings are conceptually significant and may impact markedly on clinical islet transplantation in the treatment of diabetes.
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Affiliation(s)
- Midhat H Abdulreda
- Diabetes Research Institute and Cell Transplant Center, University of Miami Miller School of Medicine, 1450 NW 10th Ave, Miami, FL, 33136, USA.
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA.
- Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA.
| | - Dora M Berman
- Diabetes Research Institute and Cell Transplant Center, University of Miami Miller School of Medicine, 1450 NW 10th Ave, Miami, FL, 33136, USA
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Alexander Shishido
- Diabetes Research Institute and Cell Transplant Center, University of Miami Miller School of Medicine, 1450 NW 10th Ave, Miami, FL, 33136, USA
| | - Christopher Martin
- Diabetes Research Institute and Cell Transplant Center, University of Miami Miller School of Medicine, 1450 NW 10th Ave, Miami, FL, 33136, USA
| | - Maged Hossameldin
- Diabetes Research Institute and Cell Transplant Center, University of Miami Miller School of Medicine, 1450 NW 10th Ave, Miami, FL, 33136, USA
| | - Ashley Tschiggfrie
- Diabetes Research Institute and Cell Transplant Center, University of Miami Miller School of Medicine, 1450 NW 10th Ave, Miami, FL, 33136, USA
| | - Luis F Hernandez
- Diabetes Research Institute and Cell Transplant Center, University of Miami Miller School of Medicine, 1450 NW 10th Ave, Miami, FL, 33136, USA
| | - Ana Hernandez
- Diabetes Research Institute and Cell Transplant Center, University of Miami Miller School of Medicine, 1450 NW 10th Ave, Miami, FL, 33136, USA
| | - Camillo Ricordi
- Diabetes Research Institute and Cell Transplant Center, University of Miami Miller School of Medicine, 1450 NW 10th Ave, Miami, FL, 33136, USA
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
- Diabetes Research Institute Federation, Hollywood, FL, USA
| | - Jean-Marie Parel
- Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Ewa Jankowska-Gan
- Department of Surgery, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
| | - William J Burlingham
- Department of Surgery, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
| | | | - Victor L Perez
- Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Duke Ophthalmology, Duke University, Durham, NC, USA
| | - Norma S Kenyon
- Diabetes Research Institute and Cell Transplant Center, University of Miami Miller School of Medicine, 1450 NW 10th Ave, Miami, FL, 33136, USA
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Per-Olof Berggren
- Diabetes Research Institute and Cell Transplant Center, University of Miami Miller School of Medicine, 1450 NW 10th Ave, Miami, FL, 33136, USA.
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital L1, SE-17176, Stockholm, Sweden.
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Kelly AC, Smith KE, Purvis WG, Min CG, Weber CS, Cooksey AM, Hasilo C, Paraskevas S, Suszynski TM, Weegman BP, Anderson MJ, Camacho LE, Harland RC, Loudovaris T, Jandova J, Molano DS, Price ND, Georgiev IG, Scott WE, Manas D, Shaw J, O’Gorman D, Kin T, McCarthy FM, Szot GL, Posselt AM, Stock PG, Karatzas T, Shapiro WJ, Lynch RM, Limesand SW, Papas KK. Oxygen Perfusion (Persufflation) of Human Pancreata Enhances Insulin Secretion and Attenuates Islet Proinflammatory Signaling. Transplantation 2019; 103:160-167. [PMID: 30095738 PMCID: PMC6371803 DOI: 10.1097/tp.0000000000002400] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND All human islets used in research and for the clinical treatment of diabetes are subject to ischemic damage during pancreas procurement, preservation, and islet isolation. A major factor influencing islet function is exposure of pancreata to cold ischemia during unavoidable windows of preservation by static cold storage (SCS). Improved preservation methods may prevent this functional deterioration. In the present study, we investigated whether pancreas preservation by gaseous oxygen perfusion (persufflation) better preserved islet function versus SCS. METHODS Human pancreata were preserved by SCS or by persufflation in combination with SCS. Islets were subsequently isolated, and preparations in each group matched for SCS or total preservation time were compared using dynamic glucose-stimulated insulin secretion as a measure of β-cell function and RNA sequencing to elucidate transcriptomic changes. RESULTS Persufflated pancreata had reduced SCS time, which resulted in islets with higher glucose-stimulated insulin secretion compared to islets from SCS only pancreata. RNA sequencing of islets from persufflated pancreata identified reduced inflammatory and greater metabolic gene expression, consistent with expectations of reducing cold ischemic exposure. Portions of these transcriptional responses were not associated with time spent in SCS and were attributable to pancreatic reoxygenation. Furthermore, persufflation extended the total preservation time by 50% without any detectable decline in islet function or viability. CONCLUSIONS These data demonstrate that pancreas preservation by persufflation rather than SCS before islet isolation reduces inflammatory responses and promotes metabolic pathways in human islets, which results in improved β cell function.
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Affiliation(s)
- Amy C. Kelly
- School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson AZ
| | - Kate E. Smith
- Physiological Sciences, University of Arizona, Tucson AZ
| | - William G. Purvis
- Department of Surgery, Institute for Cellular Transplantation, University of Arizona, Tucson AZ
| | | | - Craig S. Weber
- Physiological Sciences, University of Arizona, Tucson AZ
| | - Amanda M. Cooksey
- School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson AZ
| | - Craig Hasilo
- Human Islet Transplant Laboratory, McGill University Health Centre, Montreal, Quebec, CA
| | - Steven Paraskevas
- Human Islet Transplant Laboratory, McGill University Health Centre, Montreal, Quebec, CA
| | - Thomas M. Suszynski
- Department of Surgery, Institute for Cellular Transplantation, University of Arizona, Tucson AZ
| | - Bradley P. Weegman
- Department of Surgery, Institute for Cellular Transplantation, University of Arizona, Tucson AZ
| | - Miranda J. Anderson
- School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson AZ
| | - Leticia E. Camacho
- School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson AZ
| | - Robert C. Harland
- Department of Surgery, Institute for Cellular Transplantation, University of Arizona, Tucson AZ
| | - Tom Loudovaris
- Department of Surgery, Institute for Cellular Transplantation, University of Arizona, Tucson AZ
| | - Jana Jandova
- Department of Surgery, Institute for Cellular Transplantation, University of Arizona, Tucson AZ
| | - Diana S. Molano
- Department of Surgery, Institute for Cellular Transplantation, University of Arizona, Tucson AZ
| | - Nicholas D. Price
- Department of Surgery, Institute for Cellular Transplantation, University of Arizona, Tucson AZ
| | - Ivan G. Georgiev
- Department of Surgery, Institute for Cellular Transplantation, University of Arizona, Tucson AZ
| | - William E. Scott
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - Derek Manas
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - James Shaw
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - Doug O’Gorman
- Clinical Islet Transplant Program, Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, CA
| | - Tatsuya Kin
- Clinical Islet Transplant Program, Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, CA
| | - Fiona M. McCarthy
- School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson AZ
| | - Gregory L. Szot
- Department of Surgery, University of California San Francisco, San Francisco, CA
| | - Andrew M. Posselt
- Department of Surgery, University of California San Francisco, San Francisco, CA
| | - Peter G. Stock
- Department of Surgery, University of California San Francisco, San Francisco, CA
| | | | - William J. Shapiro
- Clinical Islet Transplant Program, Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, CA
| | | | - Sean W. Limesand
- School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson AZ
| | - Klearchos K. Papas
- Department of Surgery, Institute for Cellular Transplantation, University of Arizona, Tucson AZ
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Black CK, Termanini KM, Aguirre O, Hawksworth JS, Sosin M. Solid organ transplantation in the 21 st century. ANNALS OF TRANSLATIONAL MEDICINE 2018; 6:409. [PMID: 30498736 PMCID: PMC6230860 DOI: 10.21037/atm.2018.09.68] [Citation(s) in RCA: 195] [Impact Index Per Article: 27.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Accepted: 09/29/2018] [Indexed: 12/20/2022]
Abstract
Solid organ transplantation (SOT) has emerged from an experimental approach in the 20th century to now being an established and practical definitive treatment option for patients with end-organ dysfunction. The evolution of SOT has seen the field progress rapidly over the past few decades with incorporation of a variety of solid organs-liver, kidney, pancreas, heart, and lung-into the donor pool. New advancements in surgical technique have allowed for more efficient and refined multi-organ procurements with minimal complications and decreased ischemic injury events. Additionally, immunosuppression therapy has also seen advancements with the expansion of immunosuppressive protocols to dampen the host immune response and improve short and long-term graft survival. However, the field of SOT faces new barriers, most importantly the expanding demand for SOT that is outpacing the current supply. Allocation protocols have been developed in an attempt to address these concerns. Other avenues for SOT are also being explored to increase the donor pool, including split-liver donor transplants, islet cell implantation for pancreas transplants, and xenotransplantation. The future of SOT is bright with exciting new research being explored to overcome current obstacles.
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Affiliation(s)
- Cara K. Black
- Georgetown University School of Medicine, Washington, DC, USA
| | | | - Oswaldo Aguirre
- MedStar Georgetown University Hospital, MedStar Georgetown Transplant Institute, Washington, DC, USA
| | - Jason S. Hawksworth
- MedStar Georgetown University Hospital, MedStar Georgetown Transplant Institute, Washington, DC, USA
| | - Michael Sosin
- Hansjörg Wyss Department of Plastic Surgery, NYU Langone Health, New York, NY, USA
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40
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Nicolas CT, Hickey RD, Allen KL, Du Z, Guthman RM, Kaiser RA, Amiot B, Bansal A, Pandey MK, Suksanpaisan L, DeGrado TR, Nyberg SL, Lillegard JB. Hepatocyte spheroids as an alternative to single cells for transplantation after ex vivo gene therapy in mice and pig models. Surgery 2018; 164:473-481. [PMID: 29884476 PMCID: PMC6573031 DOI: 10.1016/j.surg.2018.04.012] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Revised: 03/31/2018] [Accepted: 04/12/2018] [Indexed: 11/20/2022]
Abstract
BACKGROUND Autologous hepatocyte transplantation after ex vivo gene therapy is an alternative to liver transplantation for metabolic liver disease. Here we evaluate ex vivo gene therapy followed by transplantation of single-cell or spheroid hepatocytes. METHODS Pig and mouse hepatocytes were isolated, labeled with zirconium-89 and returned to the liver as single cells or spheroids. Biodistribution was evaluated through positron emission tomography-computed tomography. Fumarylacetoacetate hydrolase-deficient pig hepatocytes were isolated and transduced with a lentiviral vector containing the Fah gene. Animals received portal vein infusion of single-cell or spheroid autologous hepatocytes after ex vivo gene delivery. Portal pressures were measured and ultrasound was used to evaluate for thrombus. Differences in engraftment and expansion of ex vivo corrected single-cell or spheroid hepatocytes were followed through histologic analysis and animals' ability to thrive off 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione. RESULTS Positron emission tomography-computed tomography imaging showed spheroid hepatocytes with increased heterogeneity in biodistribution as compared with single cells, which spread more uniformly throughout the liver. Animals receiving spheroids experienced higher mean changes in portal pressure than animals receiving single cells (P < .01). Additionally, two animals from the spheroid group developed portal vein thrombi that required systemic anticoagulation. Immunohistochemical analysis of spheroid- and single-cell-transplanted animals showed similar engraftment and expansion rates of fumarylacetoacetate hydrolase-positive hepatocytes in the liver, correlating with similar weight stabilization curves. CONCLUSION Ex vivo gene correction of autologous hepatocytes in fumarylacetoacetate hydrolase-deficient pigs can be performed using hepatocyte spheroids or single-cell hepatocytes, with spheroids showing a more heterogeneous distribution within the liver and higher risks for portal vein thrombosis and increased portal pressures.
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Affiliation(s)
- Clara T Nicolas
- Department of Surgery, Mayo Clinic, Rochester, MN; Faculty of Medicine, University of Barcelona, Spain
| | - Raymond D Hickey
- Department of Surgery, Mayo Clinic, Rochester, MN; Department of Molecular Medicine, Mayo Clinic, Rochester, MN
| | - Kari L Allen
- Department of Surgery, Mayo Clinic, Rochester, MN
| | - Zeji Du
- Department of Surgery, Mayo Clinic, Rochester, MN
| | | | - Robert A Kaiser
- Department of Surgery, Mayo Clinic, Rochester, MN; Midwest Fetal Care Center, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN
| | - Bruce Amiot
- Department of Surgery, Mayo Clinic, Rochester, MN
| | - Aditya Bansal
- Department of Nuclear Medicine, Mayo Clinic, Rochester, MN
| | | | | | | | | | - Joseph B Lillegard
- Department of Surgery, Mayo Clinic, Rochester, MN; Midwest Fetal Care Center, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN; Pediatric Surgical Associates, Minneapolis, MN.
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Garcia Ribeiro RS, Gysemans C, da Cunha JPMCM, Manshian BB, Jirak D, Kriz J, Gallo J, Bañobre-López M, Struys T, De Cuyper M, Mathieu C, Soenen SJ, Gsell W, Himmelreich U. Magnetoliposomes as Contrast Agents for Longitudinal in vivo Assessment of Transplanted Pancreatic Islets in a Diabetic Rat Model. Sci Rep 2018; 8:11487. [PMID: 30065302 PMCID: PMC6068133 DOI: 10.1038/s41598-018-29136-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Accepted: 06/12/2018] [Indexed: 01/07/2023] Open
Abstract
Magnetoliposomes (MLs) were synthesized and tested for longitudinal monitoring of transplanted pancreatic islets using magnetic resonance imaging (MRI) in rat models. The rat insulinoma cell line INS-1E and isolated pancreatic islets from outbred and inbred rats were used to optimize labeling conditions in vitro. Strong MRI contrast was generated by islets exposed to 50 µg Fe/ml for 24 hours without any increased cell death, loss of function or other signs of toxicity. In vivo experiments showed that pancreatic islets (50-1000 units) labeled with MLs were detectable for up to 6 weeks post-transplantation in the kidney subcapsular space. Islets were also monitored for two weeks following transplantation through the portal vein of the liver. Hereby, islets labeled with MLs and transplanted under the left kidney capsule were able to correct hyperglycemia and had stable MRI signals until nephrectomy. Interestingly, in vivo MRI of streptozotocin induced diabetic rats transplanted with allogeneic islets demonstrated loss of MRI contrast between 7-16 days, indicative of loss of islet structure. MLs used in this study were not only beneficial for monitoring the location of transplanted islets in vivo with high sensitivity but also reported on islet integrity and hereby indirectly on islet function and rejection.
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Affiliation(s)
- Rita Sofia Garcia Ribeiro
- Biomedical MRI/MoSAIC, Department of Imaging and Pathology, Biomedical Sciences Group, KU LEUVEN, Herestraat 49, 3000, Leuven, Belgium
| | - Conny Gysemans
- Clinical and Experimental Endocrinology, Department of Chronic Diseases, Metabolism and Ageing, KU LEUVEN, Herestraat 49, 3000, Leuven, Belgium
| | | | - Bella B Manshian
- Biomedical MRI/MoSAIC, Department of Imaging and Pathology, Biomedical Sciences Group, KU LEUVEN, Herestraat 49, 3000, Leuven, Belgium
| | - Daniel Jirak
- MR Spectroscopy Unit, Institute for Clinical and Experimental Medicine (IKEM), Videnska 1958/9, 140 21, Prague, Czech Republic
- Department of Biophysics, Institute of Biophysics and Informatics, First Faculty of Medicine, Charles University, Salmovska 1, 120 00, Prague 2, Czech Republic
| | - Jan Kriz
- Diabetes Center, Institute for Clinical and Experimental Medicine (IKEM), Videnska 1958/9, 140 21, Prague, Czech Republic
| | - Juan Gallo
- Diagnostic Tools & Methods/Advanced (magnetic) Theranostic Nanostructures Lab, International Iberian Nanotechnology Laboratory (INL), Av. Mestre José Veiga s/n, 4715-330, Braga, Portugal
| | - Manuel Bañobre-López
- Diagnostic Tools & Methods/Advanced (magnetic) Theranostic Nanostructures Lab, International Iberian Nanotechnology Laboratory (INL), Av. Mestre José Veiga s/n, 4715-330, Braga, Portugal
| | - Tom Struys
- Lab of Histology, Biomedical Research Institute, Hasselt University, Campus Diepenbeek, Agoralaan, B3590, Diepenbeek, Belgium
| | - Marcel De Cuyper
- Laboratory of BioNanoColloids, Interdisciplinary Research Centre, KULAK/KU LEUVEN, Etienne Sabbelaan 53, 8500, Kortrijk, Belgium
| | - Chantal Mathieu
- Clinical and Experimental Endocrinology, Department of Chronic Diseases, Metabolism and Ageing, KU LEUVEN, Herestraat 49, 3000, Leuven, Belgium
| | - Stefaan J Soenen
- Biomedical MRI/MoSAIC, Department of Imaging and Pathology, Biomedical Sciences Group, KU LEUVEN, Herestraat 49, 3000, Leuven, Belgium
| | - Willy Gsell
- Biomedical MRI/MoSAIC, Department of Imaging and Pathology, Biomedical Sciences Group, KU LEUVEN, Herestraat 49, 3000, Leuven, Belgium
| | - Uwe Himmelreich
- Biomedical MRI/MoSAIC, Department of Imaging and Pathology, Biomedical Sciences Group, KU LEUVEN, Herestraat 49, 3000, Leuven, Belgium.
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Nie W, Ma X, Yang C, Chen Z, Rong P, Wu M, Jiang J, Tan M, Yi S, Wang W. Human mesenchymal-stem-cells-derived exosomes are important in enhancing porcine islet resistance to hypoxia. Xenotransplantation 2018; 25:e12405. [PMID: 29932262 DOI: 10.1111/xen.12405] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Revised: 03/25/2018] [Accepted: 04/16/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Hypoxia-induced damage is one of the key factors associated with islet graft dysfunction. Mesenchymal stem cells (MSCs) could be used to enhance the therapeutic effect of islet transplantation due to their paracrine potential such as exosomes. In this study, we investigated whether exosomes from human umbilical cord-derived MSC-conditioned medium (hu-MSC-CM) could increase the survival and function of neonatal porcine islet cell clusters (NICCs) exposed to hypoxia. METHODS Neonatal porcine islet cell clusters were cultured with hu-MSC-CM, with or without exosomes, and native medium RPMI-1640 (Control) under hypoxic conditions (1% O2 ). The effects of exosomes on NICCs viability and function in vitro were examined by FACS, the Loops system, and the Extracellular Flux assay, respectively. RESULTS Compared with NICCs cultured in RPMI-1640 medium and hu-MSC-CM without exosomes, the survival ratio, viability, and function increased in NICCs cultured in hu-MSC-CM with exosomes. CONCLUSIONS This study found that hu-MSC-CM could protect NICCs from hypoxia-induced dysfunction, and exosomes played an important role in hypoxic resistance, suggesting a potential strategy to improve islet transplantation outcomes.
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Affiliation(s)
- Wei Nie
- Cell Transplantation and Gene Therapy Institute, The Third Xiang Ya Hospital, Central South University, Changsha, Hunan, China.,Engineering and Technology Research Center for Xenotransplantation of Hunan Province, Changsha, China
| | - Xiaoqian Ma
- Cell Transplantation and Gene Therapy Institute, The Third Xiang Ya Hospital, Central South University, Changsha, Hunan, China.,Engineering and Technology Research Center for Xenotransplantation of Hunan Province, Changsha, China
| | - Cejun Yang
- Cell Transplantation and Gene Therapy Institute, The Third Xiang Ya Hospital, Central South University, Changsha, Hunan, China.,Engineering and Technology Research Center for Xenotransplantation of Hunan Province, Changsha, China
| | - Zeyi Chen
- Engineering and Technology Research Center for Xenotransplantation of Hunan Province, Changsha, China
| | - Pengfei Rong
- Cell Transplantation and Gene Therapy Institute, The Third Xiang Ya Hospital, Central South University, Changsha, Hunan, China
| | - Minghua Wu
- Cell Transplantation and Gene Therapy Institute, The Third Xiang Ya Hospital, Central South University, Changsha, Hunan, China
| | - Jianhui Jiang
- State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, China
| | - Mengqun Tan
- Engineering and Technology Research Center for Xenotransplantation of Hunan Province, Changsha, China
| | - Shounan Yi
- Engineering and Technology Research Center for Xenotransplantation of Hunan Province, Changsha, China.,Center for Transplant and Renal Research, Westmead Institute for Medical Research, University of Sydney, Westmead, NSW, Australia
| | - Wei Wang
- Cell Transplantation and Gene Therapy Institute, The Third Xiang Ya Hospital, Central South University, Changsha, Hunan, China.,Engineering and Technology Research Center for Xenotransplantation of Hunan Province, Changsha, China
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Aijaz A, Li M, Smith D, Khong D, LeBlon C, Fenton OS, Olabisi RM, Libutti S, Tischfield J, Maus MV, Deans R, Barcia RN, Anderson DG, Ritz J, Preti R, Parekkadan B. Biomanufacturing for clinically advanced cell therapies. Nat Biomed Eng 2018; 2:362-376. [PMID: 31011198 PMCID: PMC6594100 DOI: 10.1038/s41551-018-0246-6] [Citation(s) in RCA: 123] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Accepted: 05/08/2018] [Indexed: 02/07/2023]
Abstract
The achievements of cell-based therapeutics have galvanized efforts to bring cell therapies to the market. To address the demands of the clinical and eventual commercial-scale production of cells, and with the increasing generation of large clinical datasets from chimeric antigen receptor T-cell immunotherapy, from transplants of engineered haematopoietic stem cells and from other promising cell therapies, an emphasis on biomanufacturing requirements becomes necessary. Robust infrastructure should address current limitations in cell harvesting, expansion, manipulation, purification, preservation and formulation, ultimately leading to successful therapy administration to patients at an acceptable cost. In this Review, we highlight case examples of cutting-edge bioprocessing technologies that improve biomanufacturing efficiency for cell therapies approaching clinical use.
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Affiliation(s)
- Ayesha Aijaz
- Department of Biomedical Engineering, Rutgers University, Piscataway, NJ, USA
| | - Matthew Li
- Department of Surgery, Center for Surgery, Innovation, and Bioengineering, Massachusetts General Hospital, Harvard Medical School and Shriners Hospitals for Children, Boston, MA, USA
| | - David Smith
- Hitachi Chemical Advanced Therapeutics Solutions, Allendale, NJ, USA
| | - Danika Khong
- Department of Surgery, Center for Surgery, Innovation, and Bioengineering, Massachusetts General Hospital, Harvard Medical School and Shriners Hospitals for Children, Boston, MA, USA
| | - Courtney LeBlon
- Hitachi Chemical Advanced Therapeutics Solutions, Allendale, NJ, USA
| | - Owen S Fenton
- Department of Chemical Engineering, Institute for Medical Engineering and Science, Division of Health Science and Technology, and the David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Ronke M Olabisi
- Department of Biomedical Engineering, Rutgers University, Piscataway, NJ, USA
| | | | - Jay Tischfield
- Human Genetics Institute of New Jersey, RUCDR, Piscataway, NJ, USA
| | - Marcela V Maus
- Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA
| | | | | | - Daniel G Anderson
- Department of Chemical Engineering, Institute for Medical Engineering and Science, Division of Health Science and Technology, and the David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Jerome Ritz
- Cell Manipulation Core Facility, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Harvard Stem Cell Institute, Cambridge, MA, USA
| | - Robert Preti
- Hitachi Chemical Advanced Therapeutics Solutions, Allendale, NJ, USA
| | - Biju Parekkadan
- Department of Biomedical Engineering, Rutgers University, Piscataway, NJ, USA.
- Department of Surgery, Center for Surgery, Innovation, and Bioengineering, Massachusetts General Hospital, Harvard Medical School and Shriners Hospitals for Children, Boston, MA, USA.
- Sentien Biotechnologies, Inc, Lexington, MA, USA.
- Harvard Stem Cell Institute, Cambridge, MA, USA.
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Fujita I, Utoh R, Yamamoto M, Okano T, Yamato M. The liver surface as a favorable site for islet cell sheet transplantation in type 1 diabetes model mice. Regen Ther 2018; 8:65-72. [PMID: 30271868 PMCID: PMC6147207 DOI: 10.1016/j.reth.2018.04.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 03/19/2018] [Accepted: 04/12/2018] [Indexed: 01/21/2023] Open
Abstract
INTRODUCTION Islet transplantation is one of the most promising therapeutic approaches for patients with severe type 1 diabetes mellitus (T1DM). Transplantation of engineered islet cell sheets holds great potential for treating T1DM as it enables the creation of stable neo-islet tissues. However, a large mass of islet cell sheets is required for the subcutaneous transplantation to reverse hyperglycemia in diabetic mice. Here, we investigated whether the liver surface could serve as an alternative site for islet cell sheet transplantation. METHODS Dispersed rat islet cells (0.8 × 106 cells) were cultured on laminin-332-coated thermoresponsive culture dishes. After 2 days of cultivation, we harvested the islet cell sheets by lowering the culture temperature using a support membrane with a gelatin gel. We transplanted two recovered islet cell sheets into the subcutaneous space or onto the liver surface of severe combined immunodeficiency (SCID) mice with streptozocin-induced diabetes. RESULTS In the liver surface group, the non-fasting blood glucose level decreased rapidly within several days after transplantation. In marked contrast, the hyperglycemia state was maintained in the subcutaneous space transplantation group. The levels of rat C-peptide and insulin in the liver surface group were significantly higher than those in the subcutaneous space group. An immunohistological analysis confirmed that most of the islet cells engrafted on the liver surface were insulin-positive. The CD31-positive endothelial cells formed vascular networks within the neo-islets and in the surrounding tissues. In contrast, viable islet cells were not found in the subcutaneous space group. CONCLUSIONS Compared with the subcutaneous space, a relatively small mass of islet cell sheets was enough to achieve normoglycemia in diabetic mice when the liver surface was selected as the transplantation site. Our results demonstrate that the optimization of the transplantation site for islet cell sheets leads to significant improvements in the therapeutic efficiency for T1DM.
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Affiliation(s)
- Izumi Fujita
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Rie Utoh
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
- Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
| | - Masakazu Yamamoto
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Teruo Okano
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Masayuki Yamato
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
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Fukuda Y, Akagi T, Asaoka T, Eguchi H, Sasaki K, Iwagami Y, Yamada D, Noda T, Kawamoto K, Gotoh K, Kobayashi S, Mori M, Doki Y, Akashi M. Layer-by-layer cell coating technique using extracellular matrix facilitates rapid fabrication and function of pancreatic β-cell spheroids. Biomaterials 2018; 160:82-91. [DOI: 10.1016/j.biomaterials.2018.01.020] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 01/11/2018] [Accepted: 01/13/2018] [Indexed: 12/13/2022]
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Lee EM, Park I, Lee YJ, You YH, Kim JW, Kim MJ, Ahn YB, Kim P, Ko SH. Effect of resveratrol treatment on graft revascularization after islet transplantation in streptozotocin-induced diabetic mice. Islets 2018; 10:25-39. [PMID: 29333922 PMCID: PMC5800387 DOI: 10.1080/19382014.2017.1414764] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Revised: 11/22/2017] [Accepted: 12/03/2017] [Indexed: 01/07/2023] Open
Abstract
We evaluated the effect of resveratrol (RSV) on graft survival after islet transplantation (ITx) in diabetic mice. Isolated islets from Balb/c mice (200 IEQ) were transplanted under the kidney capsule of diabetic Balb/c mice. Vehicle or RSV (200 mg/kg/day, orally) was given for 14 days after ITx. Two more control groups [STZ-treated (No-ITx-Control) and STZ+RSV-treated (No-ITx-RSV) mice without ITx] were added. Glucose tolerance tests (GTT) was performed at 14 days after ITx. In vitro, isolated islets pretreated with vehicle or RSV (1 μM) were incubated in a hypoxic chamber (O2 1%, 1hr). Some of the ITx was performed in mouse insulin 1 gene promoter-green fluorescent protein (MIP-GFP) transgenic mice and analyzed using an in vivo imaging system. After 14 days of ITx, 2-hr glucose levels on GTT in the RSV-treated group were significantly lower than those of other control groups. But the glucose status was not improved in No-ITx mice with RSV. At day 3, the percentage of Ki-67/insulin co-stained cells in islet graft was significantly increased in the RSV-ITx group. Immunostaining with anti-insulin and anti-BS-1 antibodies revealed significantly higher insulin-stained area and vascular density in RSV-treated islet grafts. The mean vessel volume per islet graft measured by in vivo imaging was significantly higher in the RSV-treated group at day 3. In isolated islets cultured in hypoxic conditions, the cell death rate and oxidative stress were significantly attenuated with RSV pretreatment. Hypoxic treatment for isolated islets decreased the expression of SIRT-1 mRNA, and this attenuation was recovered by RSV pretreatment. Our data suggest that RSV treatment improved glycemic control, beta-cell proliferation, reduced oxidative stress, and enhanced islet revascularization and the outcome of ITx in diabetic mice.
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Affiliation(s)
- Eun-Mi Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Inwon Park
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | - Ye-Jee Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Young-Hye You
- Division of Endocrinology and Metabolism, Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Ji-Won Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Myung-Jun Kim
- Department of Physiology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Yu-Bae Ahn
- Division of Endocrinology and Metabolism, Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Pilhan Kim
- Graduate School of Nanoscience and Technology, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | - Seung-Hyun Ko
- Division of Endocrinology and Metabolism, Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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Oxygen environment and islet size are the primary limiting factors of isolated pancreatic islet survival. PLoS One 2017; 12:e0183780. [PMID: 28832685 PMCID: PMC5568442 DOI: 10.1371/journal.pone.0183780] [Citation(s) in RCA: 93] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Accepted: 08/10/2017] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Type 1 diabetes is an autoimmune disease that destroys insulin-producing beta cells in the pancreas. Pancreatic islet transplantation could be an effective treatment option for type 1 diabetes once several issues are resolved, including donor shortage, prevention of islet necrosis and loss in pre- and post-transplantation, and optimization of immunosuppression. This study seeks to determine the cause of necrotic loss of isolated islets to improve transplant efficiency. METHODOLOGY The oxygen tension inside isolated human islets of different sizes was simulated under varying oxygen environments using a computational in silico model. In vitro human islet viability was also assessed after culturing in different oxygen conditions. Correlation between simulation data and experimentally measured islet viability was examined. Using these in vitro viability data of human islets, the effect of islet diameter and oxygen tension of the culture environment on islet viability was also analyzed using a logistic regression model. PRINCIPAL FINDINGS Computational simulation clearly revealed the oxygen gradient inside the islet structure. We found that oxygen tension in the islet core was greatly lower (hypoxic) than that on the islet surface due to the oxygen consumption by the cells. The hypoxic core was expanded in the larger islets or in lower oxygen cultures. These findings were consistent with results from in vitro islet viability assays that measured central necrosis in the islet core, indicating that hypoxia is one of the major causes of central necrosis. The logistic regression analysis revealed a negative effect of large islet and low oxygen culture on islet survival. CONCLUSIONS/SIGNIFICANCE Hypoxic core conditions, induced by the oxygen gradient inside islets, contribute to the development of central necrosis of human isolated islets. Supplying sufficient oxygen during culture could be an effective and reasonable method to maintain isolated islets viable.
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Liu W, Son DO, Lau HK, Zhou Y, Prud'homme GJ, Jin T, Wang Q. Combined Oral Administration of GABA and DPP-4 Inhibitor Prevents Beta Cell Damage and Promotes Beta Cell Regeneration in Mice. Front Pharmacol 2017; 8:362. [PMID: 28676760 PMCID: PMC5476705 DOI: 10.3389/fphar.2017.00362] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2017] [Accepted: 05/26/2017] [Indexed: 12/12/2022] Open
Abstract
γ-aminobutyric acid (GABA) or glucagon-like peptide-1 based drugs, such as sitagliptin (a dipeptidyl peptidase-4 inhibitor), were shown to induce beta cell regenerative effects in various diabetic mouse models. We propose that their combined administration can bring forth an additive therapeutic effect. We tested this hypothesis in a multiple low-dose streptozotocin (STZ)-induced beta cell injury mouse model (MDSD). Male C57BL/6J mice were assigned randomly into four groups: non-treatment diabetic control, GABA, sitagliptin, or GABA plus sitagliptin. Oral drug administration was initiated 1 week before STZ injection and maintained for 6 weeks. GABA or sitagliptin administration decreased ambient blood glucose levels and improved the glucose excursion rate. This was associated with elevated plasma insulin and reduced plasma glucagon levels. Importantly, combined use of GABA and sitagliptin significantly enhanced these effects as compared with each of the monotherapies. An additive effect on reducing water consumption was also observed. Immunohistochemical analyses revealed that combined GABA and sitagliptin therapy was superior in increasing beta cell mass, associated with increased small-size islet numbers, Ki67+ and PDX-1+ beta cell counts; and reduced Tunel+ beta cell counts. Thus, beta cell proliferation was increased, whereas apoptosis was reduced. We also noticed a suppressive effect of GABA or sitagliptin on alpha cell mass, which was not significantly altered by combining the two agents. Although either GABA or sitagliptin administration delays the onset of MDSD, our study indicates that combined use of them produces superior therapeutic outcomes. This is likely due to an amelioration of beta cell proliferation and a decrease of beta cell apoptosis.
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Affiliation(s)
- Wenjuan Liu
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan UniversityShanghai, China.,Division of Endocrinology and Metabolism, The Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, TorontoON, Canada
| | - Dong Ok Son
- Division of Endocrinology and Metabolism, The Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, TorontoON, Canada
| | - Harry K Lau
- Division of Endocrinology and Metabolism, The Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, TorontoON, Canada
| | - Yinghui Zhou
- Division of Endocrinology and Metabolism, The Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, TorontoON, Canada
| | - Gerald J Prud'homme
- Department of Laboratory Medicine and Pathobiology, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, TorontoON, Canada
| | - Tianru Jin
- Division of Advanced Diagnostics, Toronto General Research Institutes, University Health Network, TorontoON, Canada.,Institute of Medical Science, University of Toronto, TorontoON, Canada.,Department of Physiology, University of Toronto, TorontoON, Canada.,Department of Medicine, University of Toronto, TorontoON, Canada
| | - Qinghua Wang
- Department of Endocrinology and Metabolism, Huashan Hospital, Fudan UniversityShanghai, China.,Division of Endocrinology and Metabolism, The Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, TorontoON, Canada.,Department of Physiology, University of Toronto, TorontoON, Canada.,Department of Medicine, University of Toronto, TorontoON, Canada
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Abstract
Clinical pancreatic islet transplantation can be considered one of the safest and least invasive transplant procedures. Remarkable progress has occurred in both the technical aspects of islet cell processing and the outcomes of clinical islet transplantation. With >1,500 patients treated since 2000, this therapeutic strategy has moved from a curiosity to a realistic treatment option for selected patients with type 1 diabetes mellitus (that is, those with hypoglycaemia unawareness, severe hypoglycaemic episodes and glycaemic lability). This Review outlines the techniques required for human islet isolation, in vitro culture before the transplant and clinical islet transplantation, and discusses indications, optimization of recipient immunosuppression and management of adjunctive immunomodulatory and anti-inflammatory strategies. The potential risks, long-term outcomes and advances in treatment after the transplant are also discussed to further move this treatment towards becoming a more widely available option for patients with type 1 diabetes mellitus and eventually a potential cure.
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Affiliation(s)
- A M James Shapiro
- Clinical Islet Transplant Program, University of Alberta, 2000 College Plaza, 8215 112th Street, Edmonton, Alberta T6G 2C8, Canada
- The Diabetes Research Institute Federation, 1450 NW 10 Avenue, Miami, Florida 33136, USA
- The Cure Alliance, 550 Bay Point Road, Miami, Florida 33137, USA
| | - Marta Pokrywczynska
- The Diabetes Research Institute Federation, 1450 NW 10 Avenue, Miami, Florida 33136, USA
- The Cure Alliance, 550 Bay Point Road, Miami, Florida 33137, USA
- Department of Regenerative Medicine, Nicolaus Copernicus University in Torun, Ludwik Rydygier Medical College in Bydgoszcz, Karlowicza 24 Street, 85-092 Bydgoszcz, Poland
| | - Camillo Ricordi
- The Diabetes Research Institute Federation, 1450 NW 10 Avenue, Miami, Florida 33136, USA
- The Cure Alliance, 550 Bay Point Road, Miami, Florida 33137, USA
- Diabetes Research Institute and Cell Transplant Program, University of Miami Miller School of Medicine, 1450 NW 10th Avenue, Miami, Florida 33136, USA
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