|
1
|
Primavera R, Wang J, Buchwald P, Ganguly A, Patel S, Bettencourt L, Chetty S, Yarani R, Regmi S, Levitte S, Kevadiya B, Guindani M, Decuzzi P, Thakor AS. Controlled Nutrient Delivery to Pancreatic Islets Using Polydopamine-Coated Mesoporous Silica Nanoparticles. NANO LETTERS 2025; 25:939-950. [PMID: 39791700 DOI: 10.1021/acs.nanolett.4c03613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/12/2025]
Abstract
In this study, we designed a nanoscale platform for sustained amino acid delivery to support transplanted pancreatic islets. The platform features mesoporous silica nanoparticles (MSNPs) loaded with glutamine (G), an essential amino acid required for islet survival and function, and coated with polydopamine (PD). We investigated various PD concentrations (0.5-2 mg/mL) and incubation times (0.5-2 h) to optimize G release, identifying that a PD concentration of 0.5 mg/mL incubated for 0.5 h yielded the best results to support islet viability and functionality ex vivo, particularly under inflammatory conditions. In syngeneic islet transplantation in STZ-diabetic mice, G alone provided only temporary benefits; however, PD-G-MSNPs significantly improved islet engraftment and function, with animals maintaining glycemic control for 30 days due to controlled G release. Our findings support the use of this nanoscale platform to provide essential nutrients like G to transplanted islets until they can establish their own blood and nutrient supply.
Collapse
Affiliation(s)
- Rosita Primavera
- Department of Radiology, Interventional Radiology Innovation at Stanford (IRIS), Stanford University School of Medicine, Palo Alto, California 94304, United States
| | - Jing Wang
- Department of Radiology, Interventional Radiology Innovation at Stanford (IRIS), Stanford University School of Medicine, Palo Alto, California 94304, United States
| | - Peter Buchwald
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, Florida 33136, United States
| | - Abantika Ganguly
- Department of Radiology, Interventional Radiology Innovation at Stanford (IRIS), Stanford University School of Medicine, Palo Alto, California 94304, United States
| | - Shaini Patel
- Department of Radiology, Interventional Radiology Innovation at Stanford (IRIS), Stanford University School of Medicine, Palo Alto, California 94304, United States
| | - Lili Bettencourt
- Department of Radiology, Interventional Radiology Innovation at Stanford (IRIS), Stanford University School of Medicine, Palo Alto, California 94304, United States
| | - Shashank Chetty
- Department of Radiology, Interventional Radiology Innovation at Stanford (IRIS), Stanford University School of Medicine, Palo Alto, California 94304, United States
| | - Reza Yarani
- Translational Type 1 Diabetes Research, Department of Clinical, Research, Steno Diabetes Center Copenhagen, Herlev 2730, Denmark
| | - Shobha Regmi
- Department of Radiology, Interventional Radiology Innovation at Stanford (IRIS), Stanford University School of Medicine, Palo Alto, California 94304, United States
| | - Steven Levitte
- Department of Radiology, Interventional Radiology Innovation at Stanford (IRIS), Stanford University School of Medicine, Palo Alto, California 94304, United States
| | - Bhavesh Kevadiya
- Department of Radiology, Interventional Radiology Innovation at Stanford (IRIS), Stanford University School of Medicine, Palo Alto, California 94304, United States
| | - Michele Guindani
- Department of Biostatistics, Jonathan and Karin Fielding School of Public Health, University of California Los Angeles, Los Angeles, California 90095, United States
| | - Paolo Decuzzi
- Laboratory of Nanotechnology for Precision Medicine, Fondazione Istituto Italiano di Tecnologia, Via Morego 30, Genoa 16163, Italy
| | - Avnesh S Thakor
- Department of Radiology, Interventional Radiology Innovation at Stanford (IRIS), Stanford University School of Medicine, Palo Alto, California 94304, United States
| |
Collapse
|
|
2
|
Félix-Martínez GJ, Osorio-Londoño D, Godínez-Fernández JR. Impact of oxygen and glucose availability on the viability and connectivity of islet cells: A computational study of reconstructed avascular human islets. PLoS Comput Biol 2024; 20:e1012357. [PMID: 39137218 PMCID: PMC11343470 DOI: 10.1371/journal.pcbi.1012357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 08/23/2024] [Accepted: 07/22/2024] [Indexed: 08/15/2024] Open
Abstract
The experimental study and transplantation of pancreatic islets requires their isolation from the surrounding tissue, and therefore, from the vasculature. Under these conditions, avascular islets rely on the diffusion of peripheral oxygen and nutrients to comply with the requirements of islet cells while responding to changes in body glucose. As a complement to the experimental work, computational models have been widely used to estimate how avascular islets would be affected by the hypoxic conditions found both in culture and transplant sites. However, previous models have been based on simplified representations of pancreatic islets which has limited the reach of the simulations performed. Aiming to contribute with a more realistic model of avascular human islets, in this work we used architectures of human islets reconstructed from experimental data to simulate the availability of oxygen for α, β and δ-cells, emulating culture and transplant conditions at different glucose concentrations. The modeling approach proposed allowed us to quantitatively estimate how the loss of cells due to severe hypoxia would impact interactions between islet cells, ultimately segregating the islet into disconnected subnetworks. According to the simulations performed, islet encapsulation, by reducing the oxygen available within the islets, could severely compromise cell viability. Moreover, our model suggests that even without encapsulation, only microislets composed of less than 100 cells would remain viable in oxygenation conditions found in transplant sites. Overall, in this article we delineate a novel modeling methodology to simulate detailed avascular islets in experimental and transplant conditions with potential applications in the field of islet encapsulation.
Collapse
Affiliation(s)
- Gerardo J. Félix-Martínez
- Investigadoras e investigadores por México, Consejo Nacional de Humanidades, Ciencias y Tecnologías, México City, México
- Department of Electrical Engineering, Universidad Autónoma Metropolitana, Iztapalapa, México City, México
| | - Diana Osorio-Londoño
- Department of Electrical Engineering, Universidad Autónoma Metropolitana, Iztapalapa, México City, México
| | | |
Collapse
|
|
3
|
Huan Z, Li J, Luo Z, Yu Y, Li L. Hydrogel-Encapsulated Pancreatic Islet Cells as a Promising Strategy for Diabetic Cell Therapy. RESEARCH (WASHINGTON, D.C.) 2024; 7:0403. [PMID: 38966749 PMCID: PMC11221926 DOI: 10.34133/research.0403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 05/16/2024] [Indexed: 07/06/2024]
Abstract
Islet transplantation has now become a promising treatment for insulin-deficient diabetes mellitus. Compared to traditional diabetes treatments, cell therapy can restore endogenous insulin supplementation, but its large-scale clinical application is impeded by donor shortages, immune rejection, and unsuitable transplantation sites. To overcome these challenges, an increasing number of studies have attempted to transplant hydrogel-encapsulated islet cells to treat diabetes. This review mainly focuses on the strategy of hydrogel-encapsulated pancreatic islet cells for diabetic cell therapy, including different cell sources encapsulated in hydrogels, encapsulation methods, hydrogel types, and a series of accessorial manners to improve transplantation outcomes. In addition, the formation and application challenges as well as prospects are also presented.
Collapse
Affiliation(s)
- Zhikun Huan
- Department of Endocrinology, Zhongda Hospital, School of Medicine,
Southeast University, Nanjing 210009, China
| | - Jingbo Li
- Department of Endocrinology, Zhongda Hospital, School of Medicine,
Southeast University, Nanjing 210009, China
| | - Zhiqiang Luo
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering,
Southeast University, Nanjing 210096, China
| | - Yunru Yu
- Pharmaceutical Sciences Laboratory,
Åbo Akademi University, Turku 20520, Finland
| | - Ling Li
- Department of Endocrinology, Zhongda Hospital, School of Medicine,
Southeast University, Nanjing 210009, China
| |
Collapse
|
|
4
|
Raoufinia R, Rahimi HR, Saburi E, Moghbeli M. Advances and challenges of the cell-based therapies among diabetic patients. J Transl Med 2024; 22:435. [PMID: 38720379 PMCID: PMC11077715 DOI: 10.1186/s12967-024-05226-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 04/22/2024] [Indexed: 05/12/2024] Open
Abstract
Diabetes mellitus is a significant global public health challenge, with a rising prevalence and associated morbidity and mortality. Cell therapy has evolved over time and holds great potential in diabetes treatment. In the present review, we discussed the recent progresses in cell-based therapies for diabetes that provides an overview of islet and stem cell transplantation technologies used in clinical settings, highlighting their strengths and limitations. We also discussed immunomodulatory strategies employed in cell therapies. Therefore, this review highlights key progresses that pave the way to design transformative treatments to improve the life quality among diabetic patients.
Collapse
Affiliation(s)
- Ramin Raoufinia
- Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamid Reza Rahimi
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ehsan Saburi
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| |
Collapse
|
|
5
|
Schubert U, Lehmann S, Schmid J, Morawietz H, Bornstein SR, Ludwig B. The Adrenal Gland and Pancreatic Islets - A Beneficial Endocrine Alliance. Horm Metab Res 2024; 56:286-293. [PMID: 38471570 DOI: 10.1055/a-2256-6344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/14/2024]
Abstract
Intraportal islet transplantation in patients with type 1 diabetes enables restoration of glucose-regulated insulin secretion. However, several factors hamper a widespread application and long-term success: chronic hypoxia, an inappropriate microenvironment and suppression of regenerative and proliferative potential by high local levels of immunosuppressive agents. Therefore, the identification of alternative and superior transplant sites is of major scientific and clinical interest. Here, we aim to evaluate the adrenal as an alternative transplantation site. The adrenal features a particular microenvironment with extensive vascularization, anti-apoptotic and pro-proliferative, anti-inflammatory and immunosuppressive effects. To validate this novel transplantation site, an in vitro co-culture system of adrenal cells and pancreatic islets was established and viability, islet survival, functional potency and antioxidative defense capacity were evaluated. For in vivo validation, an immune-deficient diabetic mouse model for intra-adrenal islet transplantation was applied. The functional capacity of intra-adrenally grafted islets to reverse diabetes was compared to a standard islet transplant model and measures of engraftment such as vascular integration were evaluated. The presence of adrenal cells positively impacted on cell metabolism and oxidative stress. Following transplantation, we could demonstrate enhanced islet function in comparison to standard models with improved engraftment and superior re-vascularization. This experimental approach allows for novel insights into the interaction of endocrine systems and may open up novel strategies for islet transplantation augmented through the bystander effect of other endocrine cells or the active factors secreted by adrenal cells modulating the microenvironment.
Collapse
Affiliation(s)
- Undine Schubert
- Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden of the Helmholtz Center Munich at the University Hospital Carl Gustav Carus and Faculty of Medicine of the Technische Universität Dresden, Dresden, Germany
| | - Susann Lehmann
- Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden of the Helmholtz Center Munich at the University Hospital Carl Gustav Carus and Faculty of Medicine of the Technische Universität Dresden, Dresden, Germany
| | - Janine Schmid
- Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden of the Helmholtz Center Munich at the University Hospital Carl Gustav Carus and Faculty of Medicine of the Technische Universität Dresden, Dresden, Germany
| | - Henning Morawietz
- Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Division of Vascular Endothelium and Microcirculation, Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Stefan R Bornstein
- Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden of the Helmholtz Center Munich at the University Hospital Carl Gustav Carus and Faculty of Medicine of the Technische Universität Dresden, Dresden, Germany
- School of Cardiovascular and Metabolic Medicine and Sciences, King's College London, Faculty of Life Sciences & Medicine, London, United Kingdom of Great Britain and Northern Ireland
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ) and University of Zurich (UZH), Zurich, Switzerland
- Center for Regenerative Therapies, Technische Universität Dresden, Dresden, Germany
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Barbara Ludwig
- Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden of the Helmholtz Center Munich at the University Hospital Carl Gustav Carus and Faculty of Medicine of the Technische Universität Dresden, Dresden, Germany
- Center for Regenerative Therapies, Technische Universität Dresden, Dresden, Germany
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| |
Collapse
|
|
6
|
Einstein SA, Steyn LV, Weegman BP, Suszynski TM, Sambanis A, O'Brien TD, Avgoustiniatos ES, Firpo MT, Graham ML, Janecek J, Eberly LE, Garwood M, Putnam CW, Papas KK. Hypoxia within subcutaneously implanted macroencapsulation devices limits the viability and functionality of densely loaded islets. FRONTIERS IN TRANSPLANTATION 2023; 2:1257029. [PMID: 38993891 PMCID: PMC11235299 DOI: 10.3389/frtra.2023.1257029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 10/20/2023] [Indexed: 07/13/2024]
Abstract
Introduction Subcutaneous macroencapsulation devices circumvent disadvantages of intraportal islet therapy. However, a curative dose of islets within reasonably sized devices requires dense cell packing. We measured internal PO2 of implanted devices, mathematically modeled oxygen availability within devices and tested the predictions with implanted devices containing densely packed human islets. Methods Partial pressure of oxygen (PO2) within implanted empty devices was measured by noninvasive 19F-MRS. A mathematical model was constructed, predicting internal PO2, viability and functionality of densely packed islets as a function of external PO2. Finally, viability was measured by oxygen consumption rate (OCR) in day 7 explants loaded at various islet densities. Results In empty devices, PO2 was 12 mmHg or lower, despite successful external vascularization. Devices loaded with human islets implanted for 7 days, then explanted and assessed by OCR confirmed trends proffered by the model but viability was substantially lower than predicted. Co-localization of insulin and caspase-3 immunostaining suggested that apoptosis contributed to loss of beta cells. Discussion Measured PO2 within empty devices declined during the first few days post-transplant then modestly increased with neovascularization around the device. Viability of islets is inversely related to islet density within devices.
Collapse
Affiliation(s)
- Samuel A Einstein
- Center for Magnetic Resonance Research, Department of Radiology, University of Minnesota, Minneapolis, MN, United States
- Department of Radiology, The Pennsylvania State University, Hershey, PA, United States
| | - Leah V Steyn
- Department of Surgery, University of Arizona, Tucson, AZ, United States
| | - Bradley P Weegman
- Center for Magnetic Resonance Research, Department of Radiology, University of Minnesota, Minneapolis, MN, United States
- Sylvatica Biotech Inc., North Charleston, SC, United States
| | - Thomas M Suszynski
- Department of Plastic Surgery, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Athanassios Sambanis
- Department of Chemical & Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA, United States
| | - Timothy D O'Brien
- Veterinary Population Medicine Department, University of Minnesota, Saint Paul, MN, United States
- Department of Medicine, Stem Cell Institute, University of Minnesota, Minneapolis, MN, United States
| | | | - Meri T Firpo
- Department of Medicine, Stem Cell Institute, University of Minnesota, Minneapolis, MN, United States
| | - Melanie L Graham
- Veterinary Population Medicine Department, University of Minnesota, Saint Paul, MN, United States
- Department of Surgery, Preclinical Research Center, University of Minnesota, Saint Paul, MN, United States
| | - Jody Janecek
- Department of Surgery, Preclinical Research Center, University of Minnesota, Saint Paul, MN, United States
| | - Lynn E Eberly
- Division of Biostatistics, University of Minnesota, Minneapolis, MN, United States
| | - Michael Garwood
- Center for Magnetic Resonance Research, Department of Radiology, University of Minnesota, Minneapolis, MN, United States
| | - Charles W Putnam
- Department of Surgery, University of Arizona, Tucson, AZ, United States
| | - Klearchos K Papas
- Department of Surgery, University of Arizona, Tucson, AZ, United States
| |
Collapse
|
|
7
|
Liang Z, Sun D, Lu S, Lei Z, Wang S, Luo Z, Zhan J, Wu S, Jiang Y, Lu Z, Sun S, Shi Y, Long H, Wei Y, Yu W, Wang Z, Yi LS, Zhang Y, Sun W, Fang X, Li Y, Lu S, Lv J, Sui W, Shen Z, Peng X, Du Y, Deng H. Implantation underneath the abdominal anterior rectus sheath enables effective and functional engraftment of stem-cell-derived islets. Nat Metab 2023; 5:29-40. [PMID: 36624157 DOI: 10.1038/s42255-022-00713-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 11/14/2022] [Indexed: 01/11/2023]
Abstract
Human pluripotent stem cell-derived islets (hPSC islets) are a promising alternative to primary human islets for the treatment of insulin-deficient diabetes. We previously demonstrated the feasibility of this approach in nonhuman primates; however, the therapeutic effects of hPSC islets can be limited by the maladaptive processes at the transplantation site. Here, we demonstrate successful implantation of hPSC-derived islets in a new transplantation site in the abdomen, the subanterior rectus sheath, in eight nonhuman primates (five male and three female). In this proof-of-principle study, we find that hPSC islets survive and gradually mature after transplantation, leading to improved glycemic control in diabetic primates. Notably, C-peptide secretion responds to meal challenge from 6 weeks post-transplantation (wpt), with stimulation indices comparable to those of native islets. The average post-prandial C-peptide level reaches approximately 2.0 ng ml-1 from 8 wpt, which is five times higher than the peak value we previously obtained after portal vein infusion of hPSC islets and was associated with a decrease of glycated hemoglobin levels by 44% at 12 wpt. Although additional studies in larger cohorts involving long-term follow-up of transplants are needed, our results indicate that the subanterior rectus sheath supports functional maturation and maintenance of hPSC islets, suggesting that it warrants further exploration as a transplantation target site in the context of for hPSC-based cell-replacement therapies.
Collapse
Affiliation(s)
- Zhen Liang
- MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
- Hangzhou Reprogenix Bioscience, Hangzhou, China
| | - Dong Sun
- MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | - Shuaiyao Lu
- State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Medical Primate Research Center, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | | | - Shusen Wang
- Organ Transplant Center, NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Nankai University, Tianjin, China
| | - Zhifeng Luo
- The Second Department of Urology, Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Jinqin Zhan
- Ultrasonic Department, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | | | - Yong Jiang
- Hangzhou Reprogenix Bioscience, Hangzhou, China
| | - Zhi Lu
- Hangzhou Reprogenix Bioscience, Hangzhou, China
| | - Shicheng Sun
- MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | | | - Haiting Long
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Yunnan, China
| | - Yanling Wei
- Hangzhou Reprogenix Bioscience, Hangzhou, China
| | - Wenhai Yu
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Yunnan, China
| | - Zhihui Wang
- Hangzhou Reprogenix Bioscience, Hangzhou, China
| | - Liew Soon Yi
- MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | - Yun Zhang
- Hangzhou Reprogenix Bioscience, Hangzhou, China
| | - Wenyong Sun
- Hangzhou Repugene Technology, Hangzhou, China
| | | | - Yanyan Li
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Yunnan, China
| | - Sufang Lu
- Hangzhou Reprogenix Bioscience, Hangzhou, China
| | - Jiayun Lv
- Hangzhou Repugene Technology, Hangzhou, China
| | - Weiguo Sui
- The Second Department of Urology, Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Zhongyang Shen
- Organ Transplant Center, NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Nankai University, Tianjin, China
| | - Xiaozhong Peng
- State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Medical Primate Research Center, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Yunnan, China.
| | - Yuanyuan Du
- MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
- Hangzhou Reprogenix Bioscience, Hangzhou, China.
| | - Hongkui Deng
- MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
| |
Collapse
|
|
8
|
Berney T, Wassmer CH, Lebreton F, Bellofatto K, Fonseca LM, Bignard J, Hanna R, Peloso A, Berishvili E. From islet of Langerhans transplantation to the bioartificial pancreas. Presse Med 2022; 51:104139. [PMID: 36202182 DOI: 10.1016/j.lpm.2022.104139] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Accepted: 09/29/2022] [Indexed: 11/09/2022] Open
Abstract
Type 1 diabetes is a disease resulting from autoimmune destruction of the insulin-producing beta cells in the pancreas. When type 1 diabetes develops into severe secondary complications, in particular end-stage nephropathy, or life-threatening severe hypoglycemia, the best therapeutic approach is pancreas transplantation, or more recently transplantation of the pancreatic islets of Langerhans. Islet transplantation is a cell therapy procedure, that is minimally invasive and has a low morbidity, but does not display the same rate of functional success as the more invasive pancreas transplantation because of suboptimal engraftment and survival. Another issue is that pancreas or islet transplantation (collectively known as beta cell replacement therapy) is limited by the shortage of organ donors and by the need for lifelong immunosuppression to prevent immune rejection and recurrence of autoimmunity. A bioartificial pancreas is a construct made of functional, insulin-producing tissue, embedded in an anti-inflammatory, immunomodulatory microenvironment and encapsulated in a perm-selective membrane allowing glucose sensing and insulin release, but isolating from attacks by cells of the immune system. A successful bioartificial pancreas would address the issues of engraftment, survival and rejection. Inclusion of unlimited sources of insulin-producing cells, such as xenogeneic porcine islets or stem cell-derived beta cells would further solve the problem of organ shortage. This article reviews the current status of clinical islet transplantation, the strategies aiming at developing a bioartificial pancreas, the clinical trials conducted in the field and the perspectives for further progress.
Collapse
Affiliation(s)
- Thierry Berney
- Cell Isolation and Transplantation Center, Department of Surgery, University of Geneva School of Medicine, Geneva, Switzerland; Division of Transplantation, Department of Surgery, University of Geneva Hospitals, Geneva, Switzerland; Faculty Diabetes Center, University of Geneva School of Medicine, Geneva, Switzerland; Department of Surgery, School of Medicine and Natural Sciences, Ilia State University, Tbilisi, Georgia
| | - Charles H Wassmer
- Cell Isolation and Transplantation Center, Department of Surgery, University of Geneva School of Medicine, Geneva, Switzerland; Division of Transplantation, Department of Surgery, University of Geneva Hospitals, Geneva, Switzerland
| | - Fanny Lebreton
- Cell Isolation and Transplantation Center, Department of Surgery, University of Geneva School of Medicine, Geneva, Switzerland
| | - Kevin Bellofatto
- Cell Isolation and Transplantation Center, Department of Surgery, University of Geneva School of Medicine, Geneva, Switzerland
| | - Laura Mar Fonseca
- Cell Isolation and Transplantation Center, Department of Surgery, University of Geneva School of Medicine, Geneva, Switzerland; Division of Transplantation, Department of Surgery, University of Geneva Hospitals, Geneva, Switzerland
| | - Juliette Bignard
- Cell Isolation and Transplantation Center, Department of Surgery, University of Geneva School of Medicine, Geneva, Switzerland
| | - Reine Hanna
- Cell Isolation and Transplantation Center, Department of Surgery, University of Geneva School of Medicine, Geneva, Switzerland
| | - Andrea Peloso
- Division of Transplantation, Department of Surgery, University of Geneva Hospitals, Geneva, Switzerland
| | - Ekaterine Berishvili
- Cell Isolation and Transplantation Center, Department of Surgery, University of Geneva School of Medicine, Geneva, Switzerland; Faculty Diabetes Center, University of Geneva School of Medicine, Geneva, Switzerland; Institute of Medical and Public Health Research, Ilia State University, Tbilisi, Georgia.
| |
Collapse
|
|
9
|
Verhoeff K, Marfil-Garza BA, Sandha G, Cooper D, Dajani K, Bigam DL, Anderson B, Kin T, Lam A, O'Gorman D, Senior PA, Ricordi C, Shapiro AMJ. Outcomes Following Extrahepatic and Intraportal Pancreatic Islet Transplantation: A Comparative Cohort Study. Transplantation 2022; 106:2224-2231. [PMID: 35676866 DOI: 10.1097/tp.0000000000004180] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
BACKGROUND Preliminary studies show promise for extrahepatic islet transplantation (ITx). However, clinical comparisons with intraportal ITx outcomes remain limited. METHODS This single-center cohort study evaluates patients receiving extrahepatic or intraportal ITx between 1999 and 2018. Primary outcome was stimulated C-peptide level. Secondary outcomes were fasting plasma glucose, BETA-2 scores, and fasting C-peptide level. Multivariable logistic modeling evaluated factors independently associated with a composite variable of early graft failure and primary nonfunction within 60 d of ITx. RESULTS Of 264 patients, 9 (3.5%) received extrahepatic ITx (gastric submucosal = 2, subcutaneous = 3, omental = 4). Group demographics were similar at baseline (age, body mass index, diabetes duration, and glycemic control). At 1-3 mo post-first infusion, patients receiving extrahepatic ITx had significantly lower stimulated C-peptide (0.05 nmol/L versus 1.2 nmol/L, P < 0.001), higher fasting plasma glucose (9.3 mmol/L versus 7.3 mmol/L, P < 0.001), and lower BETA-2 scores (0 versus 11.6, P < 0.001) and SUITO indices (1.5 versus 39.6, P < 0.001) compared with those receiving intraportal ITx. Subjects receiving extrahepatic grafts failed to produce median C-peptide ≥0.2 nmol/L within the first 60 d after transplant. Subsequent intraportal infusion following extrahepatic transplants achieved equivalent outcomes compared with patients receiving intraportal transplant alone. Extrahepatic ITx was independently associated with early graft failure/primary non-function (odds ratio 1.709, confidence interval 73.8-39 616.0, P < 0.001), whereas no other factors were independently predictive. CONCLUSIONS Using current techniques, intraportal islet infusion remains the gold standard for clinical ITx, with superior engraftment, graft function, and glycemic outcomes compared with extrahepatic transplantation of human islets.
Collapse
Affiliation(s)
- Kevin Verhoeff
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
| | - Braulio A Marfil-Garza
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
- National Institute of Medical Sciences and Nutrition Salvador Zubiran, Mexico City, Mexico
- CHRISTUS-LatAm Hub - Excellence and Innovation Center, Monterrey, Mexico
| | - Gurpal Sandha
- Department of Medicine, Division of Gastroenterology, University of Alberta, Edmonton, AB, Canada
| | | | - Khaled Dajani
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
| | - David L Bigam
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
| | - Blaire Anderson
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
| | - Tatsuya Kin
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
| | - Anna Lam
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
- Department of Medicine, Division of Endocrinology, University of Alberta, Edmonton, AB, Canada
| | - Doug O'Gorman
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
| | - Peter A Senior
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
- Department of Medicine, Division of Endocrinology, University of Alberta, Edmonton, AB, Canada
| | - Camillo Ricordi
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL
| | - A M James Shapiro
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
| |
Collapse
|
|
10
|
Jeyagaran A, Lu CE, Zbinden A, Birkenfeld AL, Brucker SY, Layland SL. Type 1 diabetes and engineering enhanced islet transplantation. Adv Drug Deliv Rev 2022; 189:114481. [PMID: 36002043 PMCID: PMC9531713 DOI: 10.1016/j.addr.2022.114481] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 08/01/2022] [Accepted: 08/02/2022] [Indexed: 01/24/2023]
Abstract
The development of new therapeutic approaches to treat type 1 diabetes mellitus (T1D) relies on the precise understanding and deciphering of insulin-secreting β-cell biology, as well as the mechanisms responsible for their autoimmune destruction. β-cell or islet transplantation is viewed as a potential long-term therapy for the millions of patients with diabetes. To advance the field of insulin-secreting cell transplantation, two main research areas are currently investigated by the scientific community: (1) the identification of the developmental pathways that drive the differentiation of stem cells into insulin-producing cells, providing an inexhaustible source of cells; and (2) transplantation strategies and engineered transplants to provide protection and enhance the functionality of transplanted cells. In this review, we discuss the biology of pancreatic β-cells, pathology of T1D and current state of β-cell differentiation. We give a comprehensive view and discuss the different possibilities to engineer enhanced insulin-secreting cell/islet transplantation from a translational perspective.
Collapse
Affiliation(s)
- Abiramy Jeyagaran
- Institute of Biomedical Engineering, Department for Medical Technologies and Regenerative Medicine, Eberhard Karls University Tübingen, 72076 Tübingen, Germany; NMI Natural and Medical Sciences Institute at the University Tübingen, 72770 Reutlingen, Germany
| | - Chuan-En Lu
- Institute of Biomedical Engineering, Department for Medical Technologies and Regenerative Medicine, Eberhard Karls University Tübingen, 72076 Tübingen, Germany
| | - Aline Zbinden
- Department of Immunology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Andreas L Birkenfeld
- Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, German Center for Diabetes Research (DZD e.V.), Munich, Germany
| | - Sara Y Brucker
- Department of Women's Health, Eberhard Karls University, 72076 Tübingen, Germany
| | - Shannon L Layland
- Institute of Biomedical Engineering, Department for Medical Technologies and Regenerative Medicine, Eberhard Karls University Tübingen, 72076 Tübingen, Germany; Department of Women's Health, Eberhard Karls University, 72076 Tübingen, Germany.
| |
Collapse
|
|
11
|
Sordi V, Monaco L, Piemonti L. Cell Therapy for Type 1 Diabetes: From Islet Transplantation to Stem Cells. Horm Res Paediatr 2022; 96:658-669. [PMID: 36041412 DOI: 10.1159/000526618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 08/08/2022] [Indexed: 11/19/2022] Open
Abstract
The field of cell therapy of type 1 diabetes is a particularly interesting example in the scenario of regenerative medicine. In fact, β-cell replacement has its roots in the experience of islet transplantation, which began 40 years ago and is currently a rapidly accelerating field, with several ongoing clinical trials using β cells derived from stem cells. Type 1 diabetes is particularly suitable for cell therapy as it is a disease due to the deficiency of only one cell type, the insulin-producing β cell, and this endocrine cell does not need to be positioned inside the pancreas to perform its function. On the other hand, the presence of a double immunological barrier, the allogeneic one and the autoimmune one, makes the protection of β cells from rejection a major challenge. Until today, islet transplantation has taught us a lot, pioneering immunosuppressive therapies, graft encapsulation, tissue engineering, and test of different implant sites and has stimulated a great variety of studies on β-cell function. This review starts from islet transplantation, presenting its current indications and the latest published trials, to arrive at the prospects of stem cell therapy, presenting the latest innovations in the field.
Collapse
Affiliation(s)
- Valeria Sordi
- Diabetes Research Institute, San Raffaele Hospital, Milan, Italy,
| | - Laura Monaco
- Diabetes Research Institute, San Raffaele Hospital, Milan, Italy
| | - Lorenzo Piemonti
- Diabetes Research Institute, San Raffaele Hospital, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| |
Collapse
|
|
12
|
Viability and Functionality of Neonatal Porcine Islet-like Cell Clusters Bioprinted in Alginate-Based Bioinks. Biomedicines 2022; 10:biomedicines10061420. [PMID: 35740440 PMCID: PMC9220255 DOI: 10.3390/biomedicines10061420] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 06/09/2022] [Accepted: 06/13/2022] [Indexed: 11/17/2022] Open
Abstract
The transplantation of pancreatic islets can prevent severe long-term complications in diabetes mellitus type 1 patients. With respect to a shortage of donor organs, the transplantation of xenogeneic islets is highly attractive. To avoid rejection, islets can be encapsulated in immuno-protective hydrogel-macrocapsules, whereby 3D bioprinted structures with macropores allow for a high surface-to-volume ratio and reduced diffusion distances. In the present study, we applied 3D bioprinting to encapsulate the potentially clinically applicable neonatal porcine islet-like cell clusters (NICC) in alginate-methylcellulose. The material was additionally supplemented with bovine serum albumin or the human blood plasma derivatives platelet lysate and fresh frozen plasma. NICC were analysed for viability, proliferation, the presence of hormones, and the release of insulin in reaction to glucose stimulation. Bioprinted NICC are homogeneously distributed, remain morphologically intact, and show a comparable viability and proliferation to control NICC. The number of insulin-positive cells is comparable between the groups and over time. The amount of insulin release increases over time and is released in response to glucose stimulation over 4 weeks. In summary, we show the successful bioprinting of NICC and could demonstrate functionality over the long-term in vitro. Supplementation resulted in a trend for higher viability, but no additional benefit on functionality was observed.
Collapse
|
|
13
|
Nathan JD, Ellery K, Balakrishnan K, Bhatt H, Ganoza A, Husain SZ, Kumar R, Morinville VD, Quiros JA, Schwarzenberg SJ, Sellers ZM, Uc A, Abu-El-Haija M. The Role of Surgical Management in Chronic Pancreatitis in Children: A Position Paper From the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Pancreas Committee. J Pediatr Gastroenterol Nutr 2022; 74:706-719. [PMID: 35258494 PMCID: PMC10286947 DOI: 10.1097/mpg.0000000000003439] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVES Chronic pancreatitis (CP) is rare in childhood but impactful because of its high disease burden. There is limited literature regarding the management of CP in children, specifically about the various surgical approaches. Herein, we summarize the current pediatric and adult literature and provide recommendations for the surgical management of CP in children. METHODS The literature review was performed to include the scope of the problem, indications for operation, conventional surgical options as well as total pancreatectomy with islet autotransplantation, and outcomes following operations for CP. RESULTS Surgery is indicated for children with debilitating CP who have failed maximal medical and endoscopic interventions. Surgical management must be tailored to the patient's unique needs, considering the anatomy and morphology of their disease. A conventional surgical approach (eg, drainage operation, partial resection, combination drainage-resection) may be considered in the presence of significant and uniform pancreatic duct dilation or an inflammatory head mass. Total pancreatectomy with islet autotransplantation is the best surgical option in patients with small duct disease. The presence of genetic risk factors often portends a suboptimal outcome following a conventional operation. CONCLUSIONS The morphology of disease and the presence of genetic risk factors must be considered while determining the optimal surgical approach for children with CP. Surgical outcomes for CP are variable and depend on the type of intervention. A multidisciplinary team approach is needed to assure that the best possible operation is selected for each patient, their recovery is optimized, and their immediate and long-term postoperative needs are well-met.
Collapse
Affiliation(s)
- Jaimie D. Nathan
- Nationwide Children’s Hospital, Department of Abdominal Transplant and Hepatopancreatobiliary Surgery, The Ohio State University College of Medicine, Department of Surgery, Columbus, Ohio, United States
| | - Kate Ellery
- University of Pittsburgh Medical Center, Division of Gastroenterology, Hepatology and Nutrition, Pittsburgh, Pennsylvania, United States
| | - Keshawadhana Balakrishnan
- Texas Children’s Hospital, Section of Pediatric Gastroenterology, Baylor College of Medicine, Department of Pediatrics, Houston, Texas, United States
| | - Heli Bhatt
- University of Minnesota, Masonic Children’s Hospital, Minneapolis, Minnesota, United States
| | - Armando Ganoza
- University of Pittsburgh Medical Center, Children’s Hospital of Pittsburgh, Hillman Center for Pediatric Transplantation, Pittsburgh, Pennsylvania, United States
| | - Sohail Z. Husain
- Lucile Packard Children’s Hospital at Stanford, Pediatric Gastroenterology, Hepatology and Nutrition and Department of Pediatrics, Stanford University, Palo Alto, California, United States
| | - Rakesh Kumar
- Promedica Russell J. Ebeid Children’s Hospital, Toledo, Ohio, United States
| | - Veronique D. Morinville
- McGill University Health Center, Montreal Children’s Hospital, Division of Pediatric Gastroenterology and Nutrition, Montreal, Quebec, Canada
| | - J. Antonio Quiros
- Icahn School of Medicine, Mount Sinai Kravis Children’s Hospital, New York, New York, United States
| | - Sarah J. Schwarzenberg
- University of Minnesota, Masonic Children’s Hospital, Minneapolis, Minnesota, United States
| | - Zachary M. Sellers
- Lucile Packard Children’s Hospital at Stanford, Pediatric Gastroenterology, Hepatology and Nutrition and Department of Pediatrics, Stanford University, Palo Alto, California, United States
| | - Aliye Uc
- University of Iowa, Carver College of Medicine, Stead Family Department of Pediatrics, Iowa City, Iowa, United States
| | - Maisam Abu-El-Haija
- Cincinnati Children’s Hospital Medical Center, Division of Gastroenterology, Hepatology and Nutrition, University of Cincinnati College of Medicine, Department of Pediatrics, Cincinnati, Ohio, United States
| |
Collapse
|
|
14
|
Quizon MJ, García AJ. Engineering β Cell Replacement Therapies for Type 1 Diabetes: Biomaterial Advances and Considerations for Macroscale Constructs. ANNUAL REVIEW OF PATHOLOGY 2022; 17:485-513. [PMID: 34813353 DOI: 10.1146/annurev-pathol-042320-094846] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
While significant progress has been made in treatments for type 1 diabetes (T1D) based on exogenous insulin, transplantation of insulin-producing cells (islets or stem cell-derived β cells) remains a promising curative strategy. The current paradigm for T1D cell therapy is clinical islet transplantation (CIT)-the infusion of islets into the liver-although this therapeutic modality comes with its own limitations that deteriorate islet health. Biomaterials can be leveraged to actively address the limitations of CIT, including undesired host inflammatory and immune responses, lack of vascularization, hypoxia, and the absence of native islet extracellular matrix cues. Moreover, in efforts toward a clinically translatable T1D cell therapy, much research now focuses on developing biomaterial platforms at the macroscale, at which implanted platforms can be easily retrieved and monitored. In this review, we discuss how biomaterials have recently been harnessed for macroscale T1D β cell replacement therapies.
Collapse
Affiliation(s)
- Michelle J Quizon
- George W. Woodruff School of Mechanical Engineering and Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332, USA; ,
| | - Andrés J García
- George W. Woodruff School of Mechanical Engineering and Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332, USA; ,
| |
Collapse
|
|
15
|
Kepple JD, Barra JM, Young ME, Hunter CS, Tse HM. Islet transplantation into brown adipose tissue can delay immune rejection. JCI Insight 2022; 7:152800. [PMID: 35015736 PMCID: PMC8876467 DOI: 10.1172/jci.insight.152800] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 01/05/2022] [Indexed: 11/17/2022] Open
Abstract
Type 1 diabetes is an autoimmune disease characterized by insulin-producing β cell destruction. Although islet transplantation restores euglycemia and improves patient outcomes, an ideal transplant site remains elusive. Brown adipose tissue (BAT) has a highly vascularized and antiinflammatory microenvironment. Because these tissue features can promote islet graft survival, we hypothesized that islets transplanted into BAT will maintain islet graft and BAT function while delaying immune-mediated rejection. We transplanted syngeneic and allogeneic islets into BAT or under the kidney capsule of streptozotocin-induced diabetic NOD.Rag and NOD mice to investigate islet graft function, BAT function, metabolism, and immune-mediated rejection. Islet grafts within BAT restored euglycemia similarly to kidney capsule controls. Islets transplanted in BAT maintained expression of islet hormones and transcription factors and were vascularized. Compared with those in kidney capsule and euglycemic mock-surgery controls, no differences in glucose or insulin tolerance, thermogenic regulation, or energy expenditure were observed with islet grafts in BAT. Immune profiling of BAT revealed enriched antiinflammatory macrophages and T cells. Compared with the kidney capsule control, there were significant delays in autoimmune and allograft rejection of islets transplanted in BAT, possibly due to increased antiinflammatory immune populations. Our data support BAT as an alternative islet transplant site that may improve graft survival.
Collapse
Affiliation(s)
- Jessica D Kepple
- Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America
| | - Jessie M Barra
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, United States of America
| | - Martin E Young
- Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America
| | - Chad S Hunter
- Department of Medicine, University of Alabama at Birmingham, Birmingham, United States of America
| | - Hubert M Tse
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, United States of America
| |
Collapse
|
|
16
|
Memon B, Abdelalim EM. OUP accepted manuscript. Stem Cells Transl Med 2022; 11:704-714. [PMID: 35640144 PMCID: PMC9299517 DOI: 10.1093/stcltm/szac030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Accepted: 04/09/2022] [Indexed: 11/14/2022] Open
Abstract
Although genome profiling provides important genetic and phenotypic details for applying precision medicine to diabetes, it is imperative to integrate in vitro human cell models, accurately recapitulating the genetic alterations associated with diabetes. The absence of the appropriate preclinical human models and the unavailability of genetically relevant cells substantially limit the progress in developing personalized treatment for diabetes. Human pluripotent stem cells (hPSCs) provide a scalable source for generating diabetes-relevant cells carrying the genetic signatures of the patients. Remarkably, allogenic hPSC-derived pancreatic progenitors and β cells are being used in clinical trials with promising preliminary results. Autologous hiPSC therapy options exist for those with monogenic and type 2 diabetes; however, encapsulation or immunosuppression must be accompanied with in the case of type 1 diabetes. Furthermore, genome-wide association studies-identified candidate variants can be introduced in hPSCs for deciphering the associated molecular defects. The hPSC-based disease models serve as excellent resources for drug development facilitating personalized treatment. Indeed, hPSC-based diabetes models have successfully provided valuable knowledge by modeling different types of diabetes, which are discussed in this review. Herein, we also evaluate their strengths and shortcomings in dissecting the underlying pathogenic molecular mechanisms and discuss strategies for improving hPSC-based disease modeling investigations.
Collapse
Affiliation(s)
- Bushra Memon
- College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Education City, Doha, Qatar
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
| | - Essam M Abdelalim
- Corresponding author: Essam M. Abdelalim, Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa, University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar. Tel: +974 445 46432; Fax: +974 445 41770;
| |
Collapse
|
|
17
|
Hashemi J, Barati G, Bibak B. Decellularized Matrix Bioscaffolds: Implementation of Native Microenvironment in Pancreatic Tissue Engineering. Pancreas 2021; 50:942-951. [PMID: 34643609 DOI: 10.1097/mpa.0000000000001868] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
ABSTRACT Type 1 diabetes is an autoimmune disease, and its incidence is usually estimated in the range of 5% to 10%. Currently, the administration of exogenous insulin is the standard of care therapy. However, this therapy is not effective in some patients who may develop some chronic complications. Islet transplantation into the liver is another therapy with promising outcomes; however, the long-term efficacy of this therapeutic option is limited to a small number of patients. Because native extracellular matrix (ECM) components provide a suitable microenvironment for islet functions, engineering a 3-dimensional construct that recapitulates the native pancreatic environment could address these obstacles. Many attempts have been conducted to mimic an in vivo microenvironment to increase the survival of islets or islet-like clusters. With the advent of decellularization technology, it is possible to use a native ECM in organ engineering. Pancreatic decellularized bioscaffold provides proper cell-cell and cell-ECM interactions and retains growth factors that are critical in the determination of cell fate within a native organ. This review summarizes the current knowledge of decellularized matrix technology and addresses its possible limitations before use in the clinic.
Collapse
Affiliation(s)
- Javad Hashemi
- From the Department of Pathobiology and Laboratory Sciences, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd
| | | | | |
Collapse
|
|
18
|
Total pancreatectomy sequelae and quality of life: results of islet autotransplantation as a possible mitigation strategy. Updates Surg 2021; 73:1237-1246. [PMID: 34319573 DOI: 10.1007/s13304-021-01129-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 07/12/2021] [Indexed: 12/17/2022]
Abstract
Total pancreatectomy (TP) is a procedure weighed down not only by postoperative morbidity and mortality but also by long-term effects as a consequence of endocrine and exocrine pancreatic insufficiency. While the latter is now managed quite effectively with pancreatic enzyme replacement therapy, the former remains a challenge. The diabetes resulting after TP, with the complete loss of endogenous insulin and contraregulatory hormones, is characterized by important glycemic variations and is, therefore, frequently referred to as "brittle diabetes". One method to reduce the impact of brittle diabetes in patients undergoing TP is the re-infusion of autologous pancreatic islets isolated from the resected pancreas. Indications to islet autotransplantation (IAT), originally described for patients undergoing TP for chronic pancreatitis, have since been extended to selected patients with other benign and malignant diseases of pancreas. This review recaps on the literature regarding long-term postoperative complications, their impact on quality of life after TP and the role of IAT.
Collapse
|
|
19
|
Nagaya M, Hasegawa K, Uchikura A, Nakano K, Watanabe M, Umeyama K, Matsunari H, Osafune K, Kobayashi E, Nakauchi H, Nagashima H. Feasibility of large experimental animal models in testing novel therapeutic strategies for diabetes. World J Diabetes 2021; 12:306-330. [PMID: 33889282 PMCID: PMC8040081 DOI: 10.4239/wjd.v12.i4.306] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 01/30/2021] [Accepted: 03/11/2021] [Indexed: 02/06/2023] Open
Abstract
Diabetes is among the top 10 causes of death in adults and caused approximately four million deaths worldwide in 2017. The incidence and prevalence of diabetes is predicted to increase. To alleviate this potentially severe situation, safer and more effective therapeutics are urgently required. Mice have long been the mainstay as preclinical models for basic research on diabetes, although they are not ideally suited for translating basic knowledge into clinical applications. To validate and optimize novel therapeutics for safe application in humans, an appropriate large animal model is needed. Large animals, especially pigs, are well suited for biomedical research and share many similarities with humans, including body size, anatomical features, physiology, and pathophysiology. Moreover, pigs already play an important role in translational studies, including clinical trials for xenotransplantation. Progress in genetic engineering over the past few decades has facilitated the development of transgenic animals, including porcine models of diabetes. This article discusses features that attest to the attractiveness of genetically modified porcine models of diabetes for testing novel treatment strategies using recent technical advances.
Collapse
Affiliation(s)
- Masaki Nagaya
- Meiji University International Institute for Bio-Resource Research, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Department of Immunology, St. Marianna University School of Medicine, Kawasaki 261-8511, Kanagawa, Japan
| | - Koki Hasegawa
- Laboratory of Medical Bioengineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
| | - Ayuko Uchikura
- Laboratory of Medical Bioengineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
| | - Kazuaki Nakano
- Meiji University International Institute for Bio-Resource Research, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Laboratory of Medical Bioengineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Research and Development, PorMedTec Co. Ltd, Kawasaki 214-0034, Kanagawa, Japan
| | - Masahito Watanabe
- Meiji University International Institute for Bio-Resource Research, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Laboratory of Medical Bioengineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Research and Development, PorMedTec Co. Ltd, Kawasaki 214-0034, Kanagawa, Japan
| | - Kazuhiro Umeyama
- Meiji University International Institute for Bio-Resource Research, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Laboratory of Medical Bioengineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Research and Development, PorMedTec Co. Ltd, Kawasaki 214-0034, Kanagawa, Japan
| | - Hitomi Matsunari
- Meiji University International Institute for Bio-Resource Research, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Laboratory of Medical Bioengineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
| | - Kenji Osafune
- Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Kyoto, Japan
| | - Eiji Kobayashi
- Department of Organ Fabrication, Keio University School of Medicine, Shinjuku 160-8582, Tokyo, Japan
| | - Hiromitsu Nakauchi
- Institute for Stem Cell Biology and Regenerative Medicine, Department of Genetics, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, United States
- Division of Stem Cell Therapy, Institute of Medical Science, The University of Tokyo, Minato 108-8639, Tokyo, Japan
| | - Hiroshi Nagashima
- Meiji University International Institute for Bio-Resource Research, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Laboratory of Medical Bioengineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
| |
Collapse
|
|
20
|
Hladíková Z, Voglová B, Pátíková A, Berková Z, Kříž J, Vojtíšková A, Leontovyč I, Jirák D, Saudek F. Bioluminescence Imaging In Vivo Confirms the Viability of Pancreatic Islets Transplanted into the Greater Omentum. Mol Imaging Biol 2021; 23:639-649. [PMID: 33599904 DOI: 10.1007/s11307-021-01588-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Revised: 02/01/2021] [Accepted: 02/02/2021] [Indexed: 01/28/2023]
Abstract
PURPOSE The liver is the most widely used site for pancreatic islet transplantation. However, several site-specific limitations impair functional success, with instant blood-mediated inflammatory reaction being the most important. The aim of this study was to develop a preclinical model for placement of the islet graft into a highly vascularized omental flap using a fibrin gel. For this purpose, we tested islet viability by bioluminescence imaging (BLI). PROCEDURES Pancreatic islets were isolated from luciferase-positive and luciferase-negative rats, mixed at a 1:1 ratio, placed into a plasma-thrombin bioscaffold, and transplanted in standard (10 pancreatic islets/g wt; n = 10) and marginal (4 pancreatic islets/g wt; n = 7) numbers into the omentums of syngeneic diabetic animals. For the control, 4 pancreatic islets/g were transplanted into the liver using the standard procedure (n = 7). Graft viability was tested by bioluminescence at days 14, 30, 60, and 90 post transplant. Glucose levels, intravenous glucose tolerance, and serum C-peptide were assessed regularly. RESULTS Nonfasting glucose levels < 10 mmol/l were restored in all animals. While islet viability in the omentum was clearly detected by stable luminescence signals throughout the whole study period, no signals were detected from islets transplanted into the liver. The bioluminescence signals were highly correlated with stimulated C-peptide levels detected at 80 days post transplant. Glucose tolerance did not differ among the 3 groups. CONCLUSIONS We successfully tested a preclinical model of islet transplantation into the greater omentum using a biocompatible scaffold made from autologous plasma and human thrombin. Both standard and marginal pancreatic islet numbers in a gel-form bioscaffold placed in the omentum restored glucose homeostasis in recipients with diabetes. Bioluminescence was shown promising as a direct proof of islet viability.
Collapse
Affiliation(s)
- Zuzana Hladíková
- Diabetes Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.,First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Barbora Voglová
- Diabetes Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.,First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Alžběta Pátíková
- First Faculty of Medicine, Charles University, Prague, Czech Republic.,Laboratory of Pancreatic Islets, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Zuzana Berková
- Laboratory of Pancreatic Islets, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Jan Kříž
- Diabetes Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.,First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Alžběta Vojtíšková
- First Faculty of Medicine, Charles University, Prague, Czech Republic.,Laboratory of Pancreatic Islets, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Ivan Leontovyč
- Laboratory of Pancreatic Islets, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Daniel Jirák
- MR Unit, Department of Radiodiagnostic and Interventional Radiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - František Saudek
- Diabetes Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic. .,First Faculty of Medicine, Charles University, Prague, Czech Republic.
| |
Collapse
|
|
21
|
Liu Y, Yang M, Cui Y, Yao Y, Liao M, Yuan H, Gong G, Deng S, Zhao G. A novel prevascularized tissue-engineered chamber as a site for allogeneic and xenogeneic islet transplantation to establish a bioartificial pancreas. PLoS One 2020; 15:e0234670. [PMID: 33270650 PMCID: PMC7714105 DOI: 10.1371/journal.pone.0234670] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 11/18/2020] [Indexed: 12/16/2022] Open
Abstract
Although sites for clinical or experimental islet transplantation are well established, pancreatic islet survival and function in these locations remain unsatisfactory. A possible factor that might account for this outcome is local hypoxia caused by the limited blood supply. Here, we modified a prevascularized tissue-engineered chamber (TEC) that facilitated the viability and function of the seeded islets in vivo by providing a microvascular network prior to transplantation. TECs were created, filled with Growth Factor-Matrigel™ (Matrigel™) and then implanted into the groins of mice with streptozotocin-induced diabetes. The degree of microvascularization in each TECs was analyzed by histology, real-time PCR, and Western blotting. Three hundred syngeneic islets were seeded into each chamber on days 0, 14, and 28 post-chamber implantation, and 300, 200, or 100 syngeneic islets were seeded into additional chambers on day 28 post-implantation, respectively. Furthermore, allogeneic or xenogeneic islet transplantation is a potential solution for organ shortage. The feasibility of TECs as transplantation sites for islet allografts or xenografts and treatment with anti-CD45RB and/or anti-CD40L (MR-1) was therefore explored. A highly developed microvascularized network was established in each TEC on day 28 post-implantation. Normalization of blood glucose levels in diabetic mice was negatively correlated with the duration of prevascularization and the number of seeded syngeneic islets. Combined treatment with anti-CD45RB and MR-1 resulted in long-term survival of the grafts following allotransplantation (5/5, 100%) and xenotransplantation (16/20, 80%). Flow cytometry demonstrated that the frequency of CD4+Foxp3-Treg and CD4+IL-4+-Th2 cells increased significantly after tolerogenic xenograft transplantation, while the number of CD4+IFN-γ-Th1 cells decreased. These findings demonstrate that highly developed microvascularized constructs can facilitate the survival of transplanted islets in a TECs, implying its potential application as artificial pancreas in the future.
Collapse
Affiliation(s)
- Yanzhuo Liu
- Department of Gastrointestinal, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan Province, China
| | - Maozhu Yang
- Organ Transplantation Translational Medicine Key Laboratory of Sichuan Province, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, Sichuan Province, China
| | - Yuanyuan Cui
- Department of Gastrointestinal, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan Province, China
| | - Yuanyuan Yao
- Department of Gastrointestinal, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan Province, China
| | - Minxue Liao
- Department of Gastrointestinal, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan Province, China
| | - Hao Yuan
- Department of Gastrointestinal, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan Province, China
| | - Guojin Gong
- Department of Gastrointestinal Surgery, Xi Chang People’s Hospital, Xi Chang, Sichuan Province, China
| | - Shaoping Deng
- Organ Transplantation Translational Medicine Key Laboratory of Sichuan Province, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, Sichuan Province, China
| | - Gaoping Zhao
- Department of Gastrointestinal, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan Province, China
- Organ Transplantation Translational Medicine Key Laboratory of Sichuan Province, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, Sichuan Province, China
- * E-mail:
| |
Collapse
|
|
22
|
Ghoneim MA, Refaie AF, Elbassiouny BL, Gabr MM, Zakaria MM. From Mesenchymal Stromal/Stem Cells to Insulin-Producing Cells: Progress and Challenges. Stem Cell Rev Rep 2020; 16:1156-1172. [PMID: 32880857 PMCID: PMC7667138 DOI: 10.1007/s12015-020-10036-3] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Mesenchymal stromal cells (MSCs) are an attractive option for cell therapy for type 1 diabetes mellitus (DM). These cells can be obtained from many sources, but bone marrow and adipose tissue are the most studied. MSCs have distinct advantages since they are nonteratogenic, nonimmunogenic and have immunomodulatory functions. Insulin-producing cells (IPCs) can be generated from MSCs by gene transfection, gene editing or directed differentiation. For directed differentiation, MSCs are usually cultured in a glucose-rich medium with various growth and activation factors. The resulting IPCs can control chemically-induced diabetes in immune-deficient mice. These findings are comparable to those obtained from pluripotent cells. PD-L1 and PD-L2 expression by MSCs is upregulated under inflammatory conditions. Immunomodulation occurs due to the interaction between these ligands and PD-1 receptors on T lymphocytes. If this function is maintained after differentiation, life-long immunosuppression or encapsulation could be avoided. In the clinical setting, two sites can be used for transplantation of IPCs: the subcutaneous tissue and the omentum. A 2-stage procedure is required for the former and a laparoscopic procedure for the latter. For either site, cells should be transplanted within a scaffold, preferably one from fibrin. Several questions remain unanswered. Will the transplanted cells be affected by the antibodies involved in the pathogenesis of type 1 DM? What is the functional longevity of these cells following their transplantation? These issues have to be addressed before clinical translation is attempted. Graphical Abstract Bone marrow MSCs are isolated from the long bone of SD rats. Then they are expanded and through directed differentiation insulin-producing cells are formed. The differentiated cells are loaded onto a collagen scaffold. If one-stage transplantation is planned, a drug delivery system must be incorporated to ensure immediate oxygenation, promote vascularization and provide some growth factors. Some mechanisms involved in the immunomodulatory function of MSCs. These are implemented either by cell to cell contact or by the release of soluble factors. Collectively, these pathways results in an increase in T-regulatory cells.
Collapse
|
|
23
|
A scalable device-less biomaterial approach for subcutaneous islet transplantation. Biomaterials 2020; 269:120499. [PMID: 33168223 DOI: 10.1016/j.biomaterials.2020.120499] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 09/01/2020] [Accepted: 10/26/2020] [Indexed: 01/09/2023]
Abstract
The subcutaneous space has been shown to be a suitable site for islet transplantation, however an abundance of islets is required to achieve normoglycemia, often requiring multiple donors. The loss of islets is due to the hypoxic conditions islets experience during revascularization, resulting in apoptosis. Therefore, to reduce the therapeutic dosage required to achieve normoglycemia, pre-vascularization of the subcutaneous space has been pursued. In this study, we highlight a biomaterial-based approach using a methacrylic acid copolymer coating to generate a robust pre-vascularized subcutaneous cavity for islet transplantation. We also devised a simple, but not-trivial, procedure for filling the cavity with an islet suspension in collagen. We show that the pre-vascularized site can support a marginal mass of islets to rapidly return streptozotocin-induced diabetic SCID/bg mice to normoglycemia. Furthermore, immunocompetent Sprague Daley rats remained normoglycemia for up to 70 days until they experienced graft destabilization as they outgrew their implants. This work highlights methacrylic acid-based biomaterials as a suitable pre-vascularization strategy for the subcutaneous space that is scalable and doesn't require exogenous cells or growth factors.
Collapse
|
|
24
|
Lee YN, Yi HJ, Kim YH, Lee S, Oh J, Okano T, Shim IK, Kim SC. Evaluation of Multi-Layered Pancreatic Islets and Adipose-Derived Stem Cell Sheets Transplanted on Various Sites for Diabetes Treatment. Cells 2020; 9:1999. [PMID: 32878048 PMCID: PMC7563383 DOI: 10.3390/cells9091999] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 08/22/2020] [Accepted: 08/26/2020] [Indexed: 12/31/2022] Open
Abstract
Islet cell transplantation is considered an ideal treatment for insulin-deficient diabetes, but implantation sites are limited and show low graft survival. Cell sheet technology and adipose-derived stem cells (ADSCs) can be useful tools for improving islet cell transplantation outcomes since both can increase implantation efficacy and graft survival. Herein, the optimal transplantation site in diabetic mice was investigated using islets and stem cell sheets. We constructed multi-layered cell sheets using rat/human islets and human ADSCs. Cell sheets were fabricated using temperature-responsive culture dishes. Islet/ADSC sheet (AI sheet) group showed higher viability and glucose-stimulated insulin secretion than islet-only group. Compared to islet transplantation alone, subcutaneous AI sheet transplantation showed better blood glucose control and CD31+ vascular traits. Because of the adhesive properties of cell sheets, AI sheets were easily applied on liver and peritoneal surfaces. Liver or peritoneal surface grafts showed better glucose control, weight gain, and intraperitoneal glucose tolerance test (IPGTT) profiles than subcutaneous site grafts using both rat and human islets. Stem cell sheets increased the therapeutic efficacy of islets in vivo because mesenchymal stem cells enhance islet function and induce neovascularization around transplanted islets. The liver and peritoneal surface can be used more effectively than the subcutaneous site in future clinical applications.
Collapse
Affiliation(s)
- Yu Na Lee
- Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Korea; (Y.N.L.); (H.-J.Y.); (Y.H.K.); (S.L.); (J.O.)
- Department of Medical Science, Asan Medical Institute of Convergence Science and Technology (AMIST), Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Hye-Jin Yi
- Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Korea; (Y.N.L.); (H.-J.Y.); (Y.H.K.); (S.L.); (J.O.)
- Department of Medical Science, Asan Medical Institute of Convergence Science and Technology (AMIST), Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Yang Hee Kim
- Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Korea; (Y.N.L.); (H.-J.Y.); (Y.H.K.); (S.L.); (J.O.)
- Regenerative Medicine Research Center, Dalim Tissen Co., Ltd., 31, Yeonhui-ro, Mapo-gu, Seoul 03982, Korea
| | - Song Lee
- Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Korea; (Y.N.L.); (H.-J.Y.); (Y.H.K.); (S.L.); (J.O.)
| | - Jooyun Oh
- Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Korea; (Y.N.L.); (H.-J.Y.); (Y.H.K.); (S.L.); (J.O.)
- Department of Medical Science, Asan Medical Institute of Convergence Science and Technology (AMIST), Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Teruo Okano
- Cell Sheet Tissue Engineering Center, Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA;
| | - In Kyong Shim
- Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Korea; (Y.N.L.); (H.-J.Y.); (Y.H.K.); (S.L.); (J.O.)
- Department of Medical Science, Asan Medical Institute of Convergence Science and Technology (AMIST), Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Song Cheol Kim
- Department of Medical Science, Asan Medical Institute of Convergence Science and Technology (AMIST), Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
- Department of Surgery & Department of Biomedical Engineering, AMIST, University of Ulsan College of Medicine &Asan Medical Center, Seoul 05505, Korea
| |
Collapse
|
|
25
|
Li F, Lv Y, Li X, Yang Z, Guo T, Zhang J. Comparative Study of Two Different Islet Transplantation Sites in Mice: Hepatic Sinus Tract vs Splenic Parenchyma. Cell Transplant 2020; 29:963689720943576. [PMID: 32731817 PMCID: PMC7563812 DOI: 10.1177/0963689720943576] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Although 90% of clinical islet transplantations are performed via the portal vein approach, it is still far from the ideal transplant site. Alternative islet transplant sites are promising to reduce the islet dose required to reverse hyperglycemia, thereby improving the efficiency of islet transplantation. The aim of this study was to compare the differences in survival and metabolic function of islet grafts transplanted into the hepatic sinus tract (HST) and the splenic parenchyma (SP). Approximately 300 syngeneic mouse islets were transplanted into the HST (n = 6) and the SP (n = 6) of recipient diabetic mice, respectively. After transplantation, the glycemic control, glucose tolerance, and morphology of islet grafts were evaluated and compared in each group. The nonfasting blood glucose of the two groups of mice receiving islet transplantation gradually decreased to the normal range and sustained for more than 100 d. There is no significant difference in the time required to restore normoglycemia (P > 0.05). The results of the glucose tolerance test showed that the SP group presented a smaller area under the curve than the HST group (P < 0.05). Histopathological results showed that islet grafts in the HST and the SP were characterized with normal islet morphology and robust insulin production. Compared with the HST, islet transplantation in the SP presents better blood glucose regulation, although there is no significant difference in the time required to restore normoglycemia.
Collapse
Affiliation(s)
- Feng Li
- Hepatobiliary Surgery Department, the First Hospital of China Medical University, Shenyang, China
| | - Yi Lv
- Hepatobiliary Surgery Department, the First Hospital of China Medical University, Shenyang, China
| | - Xiaohang Li
- Hepatobiliary Surgery Department, the First Hospital of China Medical University, Shenyang, China
| | - Zhaoming Yang
- Hepatobiliary Surgery Department, the First Hospital of China Medical University, Shenyang, China
| | - Tingwei Guo
- Hepatobiliary Surgery Department, the First Hospital of China Medical University, Shenyang, China
| | - Jialin Zhang
- Hepatobiliary Surgery Department, the First Hospital of China Medical University, Shenyang, China
| |
Collapse
|
|
26
|
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]
|
|
27
|
Gattás-Asfura KM, Abuid NJ, Labrada I, Stabler CL. Promoting Dendrimer Self-Assembly Enhances Covalent Layer-by-Layer Encapsulation of Pancreatic Islets. ACS Biomater Sci Eng 2020; 6:2641-2651. [PMID: 32587885 PMCID: PMC7316358 DOI: 10.1021/acsbiomaterials.9b01033] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
For type 1 diabetics, islet transplantation can induce beneficial outcomes, including insulin independence and improved glycemic control. The long-term function of the grafted tissue, however, is challenged by host inflammatory and immune responses. Cell encapsulation can decrease detrimental host responses to the foreign implant, but standard microencapsulation imparts large transplant volumes and impaired metabolite and nutrient diffusion. To mitigate these effects, we developed an efficient covalent Layer-by-Layer (cLbL) approach for live-cell nanoencapsulation, based on oppositely charged hyperbranched polymers functionalized with complementary Staudinger ligation groups. Reliance on cationic polymers for cLbL, however, is problematic due to their poor biocompatibility. Herein, we incorporated the additional feature of supramolecular self-assembly of the dendritic polymers to enhance layer uniformity and decrease net polymer charge. Functionalization of poly (amino amide) (PAMAM) with triethoxysilane decreased polymer charge without compromising the uniformity and stability of resulting nanoscale islet coatings. Encapsulated pancreatic rat islets were viable and functional. The implantation of cLbL islets into diabetic mice resulted in stable normoglycemia, at equivalent dosage and efficiency as uncoated islets, with no observable alterations in cellular engraftment or foreign body responses. By balancing multi-functionality and self-assembly, nano-scale and stable covalent layer-by-layer polymeric coatings could be efficiently generated onto cellular organoids, presenting a highly adaptable platform for broad use in cellular transplantation.
Collapse
Affiliation(s)
- KM Gattás-Asfura
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA
| | - NJ Abuid
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA
| | - I Labrada
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA
| | - CL Stabler
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA
- Interdisciplinary Program in Biomedical Sciences, University of Florida, Gainesville, FL, USA
- University of Florida Diabetes Institute, Gainesville, FL, USA
| |
Collapse
|
|
28
|
Zhang Y, Yang J, Zhang J, Li S, Zheng L, Zhang Y, Meng H, Zhang X, Wu Z. A bio-inspired injectable hydrogel as a cell platform for real-time glycaemic regulation. J Mater Chem B 2020; 8:4627-4641. [PMID: 32373901 DOI: 10.1039/d0tb00561d] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Frequent subcutaneous insulin injection and islet transplantation are promising therapeutic options for type 1 diabetes mellitus. However, poor patient compliance, insufficient appropriate islet β cell donors and body immune rejection limit their clinical applications. The design of a platform capable of encapsulating insulin-secreting cells and achieving real-time blood glucose regulation, is a so far unmet need. Herein, inspired by the natural processes of regulating blood glucose in pancreatic islet β cells, we developed a poly(N-isopropylacrylamide-co-dextran-maleic acid-co-3-acrylamidophenylboronic acid) (P(AAPBA-Dex-NIPAM)) hydrogel as a cell platform with glucose responsiveness and thermo-responsiveness for the therapy of diabetes. This platform showed good biocompatibility against insulin-secreting cells and presented glucose-dependent insulin release behaviour. The bioinspired P(AAPBA6-Dex-NIPAM64) hydrogel had a positive effect on real-time glycaemic regulation, as observed by intraperitoneal glucose tolerance tests. The non-fasting blood glucose of diabetic rats was restored to a normal level during the period of treatment. Additionally, the inflammatory response did not occur after administration of the platform. Collectively, we expected that the bio-mimetic platform combined with an insulin-secreting capability could be a new diabetic treatment strategy.
Collapse
Affiliation(s)
- Yu Zhang
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
29
|
Gastric submucosal alleviated pro-inflammation cytokines mediated initial dysfunction of islets allografts. Transpl Immunol 2020; 65:101292. [PMID: 32302641 DOI: 10.1016/j.trim.2020.101292] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Revised: 04/11/2020] [Accepted: 04/13/2020] [Indexed: 11/20/2022]
Abstract
BACKGROUND The liver and renal capsule are the most common site for experimental pancreatic islet transplantation, but it is not optimal. Gastric submucosa space may be an ideal site for islet transplantation; however, whether pro-inflammation factors mediated islet dysfunction could be avoided or alleviated is still unclear. METHODS Islets of Sprague Dawley (SD) rat were transplanted into the streptozotocin-induced diabetic SD rats. Transplantation sites included gastric submucosa (GS), intraportal vein (PV) and kidney capsule (KC), and the efficiency of glycemic control and site-specific differences of islet grafts were compared. RESULTS With limited number of islets (800 IEQ) transplanted, improvement of recipient glycometabolism was superior in the GS group. When transplanted with 1200 IEQ islets, the survival of islet grafts were significantly prolonged in the GS group (25.87 ± 4.08 days, compared to 15.97 ± 0.83 days and 17.33 ± 1.41 days in PV and KC groups, respectively, P < .05). Compared with the PV group, the levels of IL-1β and TNF-α were significantly depressed in GS group after 12 h transplantation (15.5 ± 0.70 pg/mL and 13.28 ± 2.80 pg/mL vs. 262.26 ± 53.37 pg/mL and 138.51 ± 39.58 pg/mL, P < .05). CONCLUSIONS Gastric submucosal would be a potential ideal site for islet transplantation in rat. Gastric submucosal might alleviate the early islet dysfunction triggered by the IL-1β and TNF-α, and which requires a low number of transplanted islets and have a good glycemic control in return.
Collapse
|
|
30
|
Infante M, Ricordi C, Padilla N, Alvarez A, Linetsky E, Lanzoni G, Mattina A, Bertuzzi F, Fabbri A, Baidal D, Alejandro R. The Role of Vitamin D and Omega-3 PUFAs in Islet Transplantation. Nutrients 2019; 11:2937. [PMID: 31816979 PMCID: PMC6950335 DOI: 10.3390/nu11122937] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Revised: 11/21/2019] [Accepted: 11/26/2019] [Indexed: 12/15/2022] Open
Abstract
Recurrence of autoimmunity and allograft rejection represent major challenges that impact the success of islet transplantation. Despite the remarkable improvements achieved in immunosuppression strategies after the publication of the Edmonton protocol, long-term data of intra-hepatic islet transplantation show a gradual decline in beta-cell function. Therefore, there is a growing interest in the investigation of novel, safe and effective anti-inflammatory and immunomodulatory strategies able to promote long-term islet graft survival and notable improvements in clinical outcomes of islet transplant recipients. Vitamin D has been shown to exert anti-inflammatory and immunomodulatory effects. Pre-clinical studies investigating the use of vitamin D and its analogs (alone or in combination with immunosuppressive agents and/or other anti-inflammatory agents, such as omega-3 polyunsaturated fatty acids) showed beneficial results in terms of islet graft survival and prevention of recurrence of autoimmunity/allograft rejection in animal models of syngeneic and allogeneic islet transplantation. Moreover, epidemiologic studies demonstrated that vitamin D deficiency is highly prevalent after solid organ transplantation (e.g., heart, liver or kidney transplantation). However, studies that critically assess the prevalence of vitamin D deficiency among islet transplant recipients have yet to be conducted. In addition, prospective studies aimed to address the safety and efficacy of vitamin D supplementation as an adjuvant immunomodulatory strategy in islet transplant recipients are lacking and are therefore awaited in the future.
Collapse
Affiliation(s)
- Marco Infante
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (C.R.); (N.P.); (A.A.); (G.L.); (D.B.); (R.A.)
- Department of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy;
| | - Camillo Ricordi
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (C.R.); (N.P.); (A.A.); (G.L.); (D.B.); (R.A.)
| | - Nathalia Padilla
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (C.R.); (N.P.); (A.A.); (G.L.); (D.B.); (R.A.)
| | - Ana Alvarez
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (C.R.); (N.P.); (A.A.); (G.L.); (D.B.); (R.A.)
| | - Elina Linetsky
- Diabetes Research Institute (DRI) and Cell Transplant Center, cGMP Cell Processing Facility, Miller School of Medicine, University of Miami, Miami, FL 33136, USA;
| | - Giacomo Lanzoni
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (C.R.); (N.P.); (A.A.); (G.L.); (D.B.); (R.A.)
| | - Alessandro Mattina
- Diabetes and Islet Transplantation Unit, Department of Diagnostic and Therapeutic Services, IRCCS-ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), UPMC, 90127 Palermo, Italy;
| | | | - Andrea Fabbri
- Department of Systems Medicine, University of Rome “Tor Vergata”, 00133 Rome, Italy;
| | - David Baidal
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (C.R.); (N.P.); (A.A.); (G.L.); (D.B.); (R.A.)
| | - Rodolfo Alejandro
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (C.R.); (N.P.); (A.A.); (G.L.); (D.B.); (R.A.)
| |
Collapse
|
|
31
|
Islet Allotransplantation in the Bone Marrow of Patients With Type 1 Diabetes: A Pilot Randomized Trial. Transplantation 2019; 103:839-851. [PMID: 30130323 DOI: 10.1097/tp.0000000000002416] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Results in murine and nonhuman primate suggested that the bone marrow (BM) might be an alternative site for pancreatic islet transplantation. METHODS We report the results of 2 clinical studies in patients with type 1 diabetes receiving an intra-BM allogeneic islet transplantation: a feasibility study in patients with hepatic contraindications for liver islet allotransplantation receiving a single intra-BM islet infusion (n = 4) and a pilot randomized trial (1:1 allocation using blocks of size 6) in which patients were randomized to receive islets into either the liver (n = 6) or BM (n = 3) to evaluate islet transplant function and survival. RESULTS We observed no adverse events related to the intrabone injection procedure or the presence of islets in the BM. None of the recipient of an intra-BM allogeneic islet transplantation had a primary nonfunction, as shown by measurable posttransplantation C-peptide levels and histopathological evidence of insulin-producing cells or molecular markers of endocrine tissue in BM biopsy samples collected during follow-up. All patients receiving islets in the BM except 1 lost islet function during the first 4 months after infusion (2 with an early graft loss). Based on biopsies and immunomonitoring, we concluded that the islet loss was primarily caused by the recurrence of autoimmunity. CONCLUSIONS Bone marrow is not a suitable alternative site for pancreatic islet allotransplantation in patients with type 1 diabetes.
Collapse
|
|
32
|
Selective local irradiation improves islet engraftment and survival in intra-bone marrow islet transplantation. Cytotherapy 2019; 21:1025-1032. [PMID: 31444049 DOI: 10.1016/j.jcyt.2019.07.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 07/16/2019] [Accepted: 07/22/2019] [Indexed: 01/28/2023]
Abstract
BACKGROUND Bone marrow (BM) is as an alternative site for islet transplantation, but it is not an immunoprotected microenvironment and allogeneic islets are rejected. However, the BM, for its structure and anatomic position, offers the possibility to modulate microenvironment by local interventions. We here investigate whether local irradiation is able to improve islet engraftment and prevent rejection in BM in the absence of immunosuppression. METHODS A model of BM local irradiation was set up. Islets were transplanted in syngeneic and fully major histocompatibility complex-mismatched recipients in control and locally irradiated BM; gain of normoglycemia and time to rejection were evaluated. RESULTS BM local irradiation proved to be a selective and safe procedure. Syngeneic islet transplantation into locally irradiated BM had better outcome compared with not irradiated recipients in terms of capacity to gain normoglycemia (100% versus 56% in irradiated versus not irradiated mice). In the allogenic setting, glycemia was significantly lower in the first days after transplantation in the group of irradiated mice and local irradiation also delayed time to graft rejection (from 4 ± 1 days for not irradiated to 11 ± 1 days for locally irradiated mice). DISCUSSION These data indicate that local immunosuppression by irradiation before islet transplantation in BM favors islet engraftment and delays time to rejection.
Collapse
|
|
33
|
Abstract
PURPOSE OF REVIEW Pancreatic islet cell transplantation is currently the only curative cell therapy for type 1 diabetes mellitus. However, its potential to treat many more patients is limited by several challenges. The emergence of 3D bioprinting technology from recent advances in 3D printing, biomaterials, and cell biology has provided the means to overcome these challenges. RECENT FINDINGS 3D bioprinting allows for the precise fabrication of complex 3D architectures containing spatially distributed cells, biomaterials (bioink), and bioactive factors. Different strategies to capitalize on this ability have been investigated for the 3D bioprinting of pancreatic islets. In particular, with co-axial bioprinting technology, the co-printability of islets with supporting cells such as endothelial progenitor cells and regulatory T cells, which have been shown to accelerate revascularization of islets and improve the outcome of various transplantations, respectively, has been achieved. 3D bioprinting of islets for generation of an artificial pancreas is a newly emerging field of study with a vast potential to improve islet transplantation.
Collapse
Affiliation(s)
- Juewan Kim
- Department of Molecular & Cellular Biology, School of Biological Sciences, The University of Adelaide, Adelaide, South Australia, 5005, Australia
| | - Kyungwon Kang
- Discipline of Medicine, School of Medicine, The University of Adelaide, Adelaide, South Australia, 5000, Australia
| | - Christopher J Drogemuller
- Discipline of Medicine, School of Medicine, The University of Adelaide, Adelaide, South Australia, 5000, Australia
- Central Northern Adelaide Renal and Transplantation Service (CNARTS), The Royal Adelaide Hospital, Adelaide, South Australia, 5000, Australia
| | - Gordon G Wallace
- Intelligent Polymer Research Institute, ARC Centre of Excellence for Electromaterial Science, University of Wollongong, Wollongong, New South Wales, 2522, Australia
| | - P Toby Coates
- Discipline of Medicine, School of Medicine, The University of Adelaide, Adelaide, South Australia, 5000, Australia.
- Central Northern Adelaide Renal and Transplantation Service (CNARTS), The Royal Adelaide Hospital, Adelaide, South Australia, 5000, Australia.
| |
Collapse
|
|
34
|
Gálisová A, Herynek V, Swider E, Sticová E, Pátiková A, Kosinová L, Kříž J, Hájek M, Srinivas M, Jirák D. A Trimodal Imaging Platform for Tracking Viable Transplanted Pancreatic Islets In Vivo: F-19 MR, Fluorescence, and Bioluminescence Imaging. Mol Imaging Biol 2019; 21:454-464. [PMID: 30167995 PMCID: PMC6525139 DOI: 10.1007/s11307-018-1270-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
PURPOSE Combining specific and quantitative F-19 magnetic resonance imaging (MRI) with sensitive and convenient optical imaging provides complementary information about the distribution and viability of transplanted pancreatic islet grafts. In this study, pancreatic islets (PIs) were labeled with positively charged multimodal nanoparticles based on poly(lactic-co-glycolic acid) (PLGA-NPs) with encapsulated perfluoro-15-crown-5-ether and the near-infrared fluorescent dye indocyanine green. PROCEDURES One thousand and three thousand bioluminescent PIs were transplanted into subcutaneous artificial scaffolds, which served as an alternative transplant site. The grafts were monitored using in vivo F-19 MR, fluorescence, and bioluminescence imaging in healthy rats for 2 weeks. RESULTS Transplanted PIs were unambiguously localized in the scaffolds by F-19 MRI throughout the whole experiment. Fluorescence was detected in the first 4 days after transplantation only. Importantly, in vivo bioluminescence correlated with the F-19 MRI signal. CONCLUSIONS We developed a trimodal imaging platform for in vivo examination of transplanted PIs. Fluorescence imaging revealed instability of the fluorescent dye and its limited applicability for longitudinal in vivo studies. A correlation between the bioluminescence signal and the F-19 MRI signal indicated the fast clearance of PLGA-NPs from the transplantation site after cell death, which addresses a major issue with intracellular imaging labels. Therefore, the proposed PLGA-NP platform is reliable for reflecting the status of transplanted PIs in vivo.
Collapse
Affiliation(s)
- A Gálisová
- MR Unit, Department of Radiodiagnostic and Interventional Radiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - V Herynek
- MR Unit, Department of Radiodiagnostic and Interventional Radiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
- Center for Advanced Preclinical Imaging, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - E Swider
- Department of Tumor Immunology, Radboud University Medical Center, Nijmegen, Netherlands
| | - E Sticová
- Department of Clinical and Transplant Pathology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
- Department of Pathology, Third Faculty of Medicine, Charles University, Prague, Czech Republic
| | - A Pátiková
- Centre of Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - L Kosinová
- Centre of Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - J Kříž
- Diabetes Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - M Hájek
- MR Unit, Department of Radiodiagnostic and Interventional Radiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - M Srinivas
- Department of Tumor Immunology, Radboud University Medical Center, Nijmegen, Netherlands
| | - D Jirák
- MR Unit, Department of Radiodiagnostic and Interventional Radiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
- Institute of Biophysics and Informatics, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
| |
Collapse
|
|
35
|
Montanari E, Gonelle-Gispert C, Seebach JD, Knoll MF, Bottino R, Bühler LH. Immunological aspects of allogeneic pancreatic islet transplantation: a comparison between mouse and human. Transpl Int 2019; 32:903-912. [PMID: 31033036 DOI: 10.1111/tri.13445] [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: 09/24/2018] [Revised: 10/29/2018] [Accepted: 04/23/2019] [Indexed: 11/30/2022]
Abstract
Pancreatic islet allotransplantation is a treatment for patients with severe forms of type 1 diabetes. As long-term graft function and survival are not yet optimal, additional studies are warranted in order to continue improving transplant outcomes. The mechanisms of islet graft loss and tolerance induction are often studied in murine diabetes models. Despite numerous islet transplantation studies successfully performed over recent years, translation from experimental mouse models to human clinical application remains elusive. This review aims at critically discussing the strengths and limitations of current mouse models of diabetes and experimental islet transplantation. In particular, we will analyze the causes leading to diabetes and compare the immunological mechanisms responsible for rejection between mouse and human. A better understanding of the experimental mouse models should facilitate translation to human clinical application.
Collapse
Affiliation(s)
- Elisa Montanari
- Department of Surgery, Geneva University Hospitals and Medical Faculty, Geneva, Switzerland
| | - Carmen Gonelle-Gispert
- Department of Surgery, Geneva University Hospitals and Medical Faculty, Geneva, Switzerland
| | - Jörg D Seebach
- Division of Immunology and Allergy, Geneva University Hospitals and Medical Faculty, Geneva, Switzerland
| | - Michael F Knoll
- Institute of Cellular Therapeutics, Allegheny Health Network, Pittsburgh, PA, USA
| | - Rita Bottino
- Institute of Cellular Therapeutics, Allegheny Health Network, Pittsburgh, PA, USA
| | - Leo H Bühler
- Department of Surgery, Geneva University Hospitals and Medical Faculty, Geneva, Switzerland
| |
Collapse
|
|
36
|
Local release of rapamycin by microparticles delays islet rejection within the anterior chamber of the eye. Sci Rep 2019; 9:3918. [PMID: 30850640 PMCID: PMC6408557 DOI: 10.1038/s41598-019-40404-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Accepted: 02/14/2019] [Indexed: 12/23/2022] Open
Abstract
The anterior chamber of the eye (ACE) has emerged as a promising clinical islet transplantation site because of its multiple advantages over the conventional intra-hepatic portal site. This includes reduced surgical invasiveness and increased islet graft survival rate. It also allows for enhanced accessibility and monitoring of the islets. Although the ACE is initially an immuno-privileged site, this privilege is disrupted once the islet grafts are re-vascularized. Given that the ACE is a confined space, achieving graft immune tolerance through local immunosuppressive drug delivery is therefore feasible. Here, we show that islet rejection in the ACE of mice can be significantly suppressed through local delivery of rapamycin by carefully designed sustained-release microparticles. In this 30-day study, allogeneic islet grafts with blank microparticles were completely rejected 18 days post-transplantation into mice. Importantly, allogeneic islet grafts co-injected with rapamycin releasing microparticles into a different eye of the same recipient were preserved much longer, with some grafts surviving for more than 30 days. Hence, islet allograft survival was enhanced by a localized and prolonged delivery of an immunosuppressive drug. We envisage that this procedure will relieve diabetic transplant recipients from harsh systemic immune suppression, while achieving improved glycemic control and reduced insulin dependence.
Collapse
|
|
37
|
Senior PA, Pettus JH. Stem cell therapies for Type 1 diabetes: current status and proposed road map to guide successful clinical trials. Diabet Med 2019; 36:297-307. [PMID: 30362170 DOI: 10.1111/dme.13846] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/23/2018] [Indexed: 12/17/2022]
Abstract
Many people with Type 1 diabetes struggle with the burden of self-management and are unable to achieve optimal glycaemic control without risk of hypoglycaemia. Future therapies with the potential to reduce the risk for short- and long-term complications while simultaneously reducing the burden of diabetes are therefore attractive. β-cell replacement is one strategy which might achieve this. Islet transplantation is limited by organ supply and the risks of long-term immunosuppression. Encapsulated stem-cell-derived β cells have the potential to address both of these issues and phase I/II clinical trials of encapsulated pancreatic progenitors have begun. A significant risk associated with the translation of stem-cell science to the clinical management of Type 1 diabetes is an underestimation of the complexity of the process and a mismatch between the hype and the expectations of both people with Type 1 diabetes and the public. We provide an update on progress in clinical trials of encapsulated stem-cell-derived β cells and propose a road map for the design and conduct of future trials to facilitate the translation of this exciting science to clinical care.
Collapse
Affiliation(s)
- P A Senior
- Division of Endocrinology, University of Alberta, Edmonton, Alberta, Canada
| | - J H Pettus
- Division of Endocrinology, University of California, San Diego, CA, USA
| |
Collapse
|
|
38
|
Meivar-Levy I, Zoabi F, Nardini G, Manevitz-Mendelson E, Leichner GS, Zadok O, Gurevich M, Mor E, Dima S, Popescu I, Barzilai A, Ferber S, Greenberger S. The role of the vasculature niche on insulin-producing cells generated by transdifferentiation of adult human liver cells. Stem Cell Res Ther 2019; 10:53. [PMID: 30760321 PMCID: PMC6373031 DOI: 10.1186/s13287-019-1157-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 01/10/2019] [Accepted: 01/27/2019] [Indexed: 02/07/2023] Open
Abstract
Background Insulin-dependent diabetes is a multifactorial disorder that could be theoretically cured by functional pancreatic islets and insulin-producing cell (IPC) implantation. Regenerative medicine approaches include the potential for growing tissues and organs in the laboratory and transplanting them when the body cannot heal itself. However, several obstacles remain to be overcome in order to bring regenerative medicine approach for diabetes closer to its clinical implementation; the cells generated in vitro are typically of heterogenic and immature nature and the site of implantation should be readily vascularized for the implanted cells to survive in vivo. The present study addresses these two limitations by analyzing the effect of co-implanting IPCs with vasculature promoting cells in an accessible site such as subcutaneous. Secondly, it analyzes the effects of reconstituting the in vivo environment in vitro on the maturation and function of insulin-producing cells. Methods IPCs that are generated by the transdifferentiation of human liver cells are exposed to the paracrine effects of endothelial colony-forming cells (ECFCs) and human bone marrow mesenchymal stem cells (MSCs), which are the “building blocks” of the blood vessels. The role of the vasculature on IPC function is analyzed upon subcutaneous implantation in vivo in immune-deficient rodents. The paracrine effects of vasculature on IPC maturation are analyzed in culture. Results Co-implantation of MSCs and ECFCs with IPCs led to doubling the survival rates and a threefold increase in insulin production, in vivo. ECFC and MSC co-culture as well as conditioned media of co-cultures resulted in a significant increased expression of pancreatic-specific genes and an increase in glucose-regulated insulin secretion, compared with IPCs alone. Mechanistically, we demonstrate that ECFC and MSC co-culture increases the expression of CTGF and ACTIVINβα, which play a key role in pancreatic differentiation. Conclusions Vasculature is an important player in generating regenerative medicine approaches for diabetes. Vasculature displays a paracrine effect on the maturation of insulin-producing cells and their survival upon implantation. The reconstitution of the in vivo niche is expected to promote the liver-to-pancreas transdifferentiation and bringing this cell therapy approach closer to its clinical implementation. Electronic supplementary material The online version of this article (10.1186/s13287-019-1157-5) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Irit Meivar-Levy
- The Sheba Regenerative Medicine, Stem Cell and Tissue Engineering Center, Sheba Medical Center, Tel Hashomer, Israel. .,Dia-Cure, Institute of Medical Scientific Research Acad. Nicolae Cajal, University Titu Maiorescu, Bucharest, Romania.
| | - Fatima Zoabi
- The Sheba Regenerative Medicine, Stem Cell and Tissue Engineering Center, Sheba Medical Center, Tel Hashomer, Israel.,Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Gil Nardini
- Department of Plastic Surgery, Sheba Medical Center, Tel Hashomer, Israel
| | | | - Gil S Leichner
- The Department of Dermatology, Sheba Medical Center, Tel Hashomer, Israel
| | - Oranit Zadok
- The Sheba Regenerative Medicine, Stem Cell and Tissue Engineering Center, Sheba Medical Center, Tel Hashomer, Israel
| | - Michael Gurevich
- The Organ Transplantation Division, Schneider Children Medical Center, Petach Tikvah, Israel
| | - Eytan Mor
- The Organ Transplantation Division, Schneider Children Medical Center, Petach Tikvah, Israel
| | - Simona Dima
- Dia-Cure, Institute of Medical Scientific Research Acad. Nicolae Cajal, University Titu Maiorescu, Bucharest, Romania.,Center of Excellence in Translational Medicine - Fundeni Clinical Institute, Bucharest, Romania.,Center of Digestive Diseases and Liver Transplantation, Fundeni Clinical Institute, Bucharest, Romania
| | - Irinel Popescu
- Dia-Cure, Institute of Medical Scientific Research Acad. Nicolae Cajal, University Titu Maiorescu, Bucharest, Romania.,Center of Excellence in Translational Medicine - Fundeni Clinical Institute, Bucharest, Romania.,Center of Digestive Diseases and Liver Transplantation, Fundeni Clinical Institute, Bucharest, Romania
| | - Aviv Barzilai
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.,The Department of Dermatology, Sheba Medical Center, Tel Hashomer, Israel
| | - Sarah Ferber
- The Sheba Regenerative Medicine, Stem Cell and Tissue Engineering Center, Sheba Medical Center, Tel Hashomer, Israel.,Dia-Cure, Institute of Medical Scientific Research Acad. Nicolae Cajal, University Titu Maiorescu, Bucharest, Romania.,Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Shoshana Greenberger
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.,The Department of Dermatology, Sheba Medical Center, Tel Hashomer, Israel
| |
Collapse
|
|
39
|
Biofabrication of a vascularized islet organ for type 1 diabetes. Biomaterials 2019; 199:40-51. [PMID: 30735895 DOI: 10.1016/j.biomaterials.2019.01.035] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Revised: 11/27/2018] [Accepted: 01/18/2019] [Indexed: 12/17/2022]
Abstract
Islet transplantation is superior to extrinsic insulin supplementation in the treating severe Type 1 diabetes. However, its efficiency and longevity are limited by substantial islet loss post-transplantation due to lack of engraftment and vascular supply. To overcome these limitations, we developed a novel approach to bio-fabricate functional, vascularized islet organs (VIOs) ex vivo. We endothelialized acellular lung matrixes to provide a biocompatible multicompartment scaffold with an intact hierarchical vascular tree as a backbone for islet engraftment. Over seven days of culture, islets anatomically and functionally integrated into the surrounding bio-engineered vasculature, generating a functional perfusable endocrine organ. When exposed to supra-physiologic arterial glucose levels in vivo and ex vivo, mature VIOs responded with a physiologic insulin release from the vein and provided more efficient reduction of hyperglycemia compared to intraportally transplanted fresh islets. In long-term transplants in diabetic mice, subcutaneously implanted VIOs achieved normoglycemia significantly faster and more efficiently compared to islets that were transplanted in deviceless fashion. We conclude that ex vivo bio-fabrication of VIOs enables islet engraftment and vascularization before transplantation, and thereby helps to overcome limited islet survival and function observed in conventional islet transplantation. Given recent progress in stem cells, this technology may enable assembly of functional personalized endocrine organs.
Collapse
|
|
40
|
Localized immune tolerance from FasL-functionalized PLG scaffolds. Biomaterials 2018; 192:271-281. [PMID: 30458362 DOI: 10.1016/j.biomaterials.2018.11.015] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Revised: 11/02/2018] [Accepted: 11/09/2018] [Indexed: 12/13/2022]
Abstract
Intraportal allogeneic islet transplantation has been demonstrated as a potential therapy for type 1 diabetes (T1D). The placement of islets into the liver and chronic immunosuppression to control rejection are two major limitations of islet transplantation. We hypothesize that localized immunomodulation with a novel form of FasL chimeric with streptavidin, SA-FasL, can provide protection and long-term function of islets at an extrahepatic site in the absence of chronic immunosuppression. Allogeneic islets modified with biotin and engineered to transiently display SA-FasL on their surface showed sustained survival following transplantation on microporous scaffolds into the peritoneal fat in combination with a short course (15 days) of rapamycin treatment. The challenges with modifying islets for clinical translation motivated the modification of scaffolds with SA-FasL as an off-the-shelf product. Poly (lactide-co-glycolide) (PLG) was conjugated with biotin and fabricated into particles and subsequently formed into microporous scaffolds to allow for rapid and efficient conjugation with SA-FasL. Biotinylated particles and scaffolds efficiently bound SA-FasL and induced apoptosis in cells expressing Fas receptor (FasR). Scaffolds functionalized with SA-FasL were subsequently seeded with allogeneic islets and transplanted into the peritoneal fat under the short-course of rapamycin treatment. Scaffolds modified with SA-FasL had robust engraftment of the transplanted islets that restored normoglycemia for 200 days. Transplantation without rapamycin or without SA-FasL did not support long-term survival and function. This work demonstrates that scaffolds functionalized with SA-FasL support allogeneic islet engraftment and long-term survival and function in an extrahepatic site in the absence of chronic immunosuppression with significant potential for clinical translation.
Collapse
|
|
41
|
Survival and Metabolic Function of Syngeneic Mouse Islet Grafts Transplanted Into the Hepatic Sinus Tract. Transplantation 2018; 102:1850-1856. [DOI: 10.1097/tp.0000000000002289] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
|
|
42
|
Staels W, Verdonck Y, Heremans Y, Leuckx G, De Groef S, Heirman C, de Koning E, Gysemans C, Thielemans K, Baeyens L, Heimberg H, De Leu N. Vegf-A mRNA transfection as a novel approach to improve mouse and human islet graft revascularisation. Diabetologia 2018; 61:1804-1810. [PMID: 29789879 DOI: 10.1007/s00125-018-4646-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Accepted: 04/23/2018] [Indexed: 12/28/2022]
Abstract
AIMS/HYPOTHESIS The initial avascular period following islet transplantation seriously compromises graft function and survival. Enhancing graft revascularisation to improve engraftment has been attempted through virus-based delivery of angiogenic triggers, but risks associated with viral vectors have hampered clinical translation. In vitro transcribed mRNA transfection circumvents these risks and may be used for improving islet engraftment. METHODS Mouse and human pancreatic islet cells were transfected with mRNA encoding the angiogenic growth factor vascular endothelial growth factor A (VEGF-A) before transplantation under the kidney capsule in mice. RESULTS At day 7 post transplantation, revascularisation of grafts transfected with Vegf-A (also known as Vegfa) mRNA was significantly higher compared with non-transfected or Gfp mRNA-transfected controls in mouse islet grafts (2.11- and 1.87-fold, respectively) (vessel area/graft area, mean ± SEM: 0.118 ± 0.01 [n = 3] in Vegf-A mRNA transfected group (VEGF) vs 0.056 ± 0.01 [n = 3] in no RNA [p < 0.05] vs 0.063 ± 0.02 [n = 4] in Gfp mRNA transfected group (GFP) [p < 0.05]); EndoC-bH3 grafts (2.85- and 2.48-fold. respectively) (0.085 ± 0.02 [n = 4] in VEGF vs 0.030 ± 0.004 [n = 4] in no RNA [p < 0.05] vs 0.034 ± 0.01 [n = 5] in GFP [p < 0.05]); and human islet grafts (3.17- and 3.80-fold, respectively) (0.048 ± 0.013 [n = 3] in VEGF vs 0.015 ± 0.0051 [n = 4] in no RNA [p < 0.01] vs 0.013 ± 0.0046 [n = 4] in GFP [p < 0.01]). At day 30 post transplantation, human islet grafts maintained a vascularisation benefit (1.70- and 1.82-fold, respectively) (0.049 ± 0.0042 [n = 8] in VEGF vs 0.029 ± 0.0052 [n = 5] in no RNA [p < 0.05] vs 0.027 ± 0.0056 [n = 4] in GFP [p < 0.05]) and a higher beta cell volume (1.64- and 2.26-fold, respectively) (0.0292 ± 0.0032 μl [n = 7] in VEGF vs 0.0178 ± 0.0021 μl [n = 5] in no RNA [p < 0.01] vs 0.0129 ± 0.0012 μl [n = 4] in GFP [p < 0.001]). CONCLUSIONS/INTERPRETATION Vegf-A mRNA transfection before transplantation provides a promising and safe strategy to improve engraftment of islets and other cell-based implants.
Collapse
Affiliation(s)
- Willem Staels
- Beta Cell Neogenesis (BENE), Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
- Department of Paediatrics, Division of Paediatric Endocrinology, Ghent University, Ghent, Belgium
| | - Yannick Verdonck
- Beta Cell Neogenesis (BENE), Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
| | - Yves Heremans
- Beta Cell Neogenesis (BENE), Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
| | - Gunter Leuckx
- Beta Cell Neogenesis (BENE), Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
| | - Sofie De Groef
- Beta Cell Neogenesis (BENE), Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
| | - Carlo Heirman
- Laboratory of Molecular and Cellular Therapy, Vrije Universiteit Brussel, Brussels, Belgium
| | - Eelco de Koning
- Department of Medicine, Section of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands
| | - Conny Gysemans
- Laboratory of Clinical and Experimental Endocrinology, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Kris Thielemans
- Laboratory of Molecular and Cellular Therapy, Vrije Universiteit Brussel, Brussels, Belgium
| | - Luc Baeyens
- Beta Cell Neogenesis (BENE), Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium
| | - Harry Heimberg
- Beta Cell Neogenesis (BENE), Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.
| | - Nico De Leu
- Beta Cell Neogenesis (BENE), Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.
- Department of Endocrinology, UZ Brussel, Brussels, Belgium.
- Department of Endocrinology, ASZ Aalst, Aalst, Belgium.
| |
Collapse
|
|
43
|
Sackett SD, Tremmel DM, Ma F, Feeney AK, Maguire RM, Brown ME, Zhou Y, Li X, O'Brien C, Li L, Burlingham WJ, Odorico JS. Extracellular matrix scaffold and hydrogel derived from decellularized and delipidized human pancreas. Sci Rep 2018; 8:10452. [PMID: 29993013 PMCID: PMC6041318 DOI: 10.1038/s41598-018-28857-1] [Citation(s) in RCA: 170] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Accepted: 07/02/2018] [Indexed: 12/21/2022] Open
Abstract
Extracellular matrix (ECM) plays an important developmental role by regulating cell behaviour through structural and biochemical stimulation. Tissue-specific ECM, attained through decellularization, has been proposed in several strategies for tissue and organ replacement. Decellularization of animal pancreata has been reported, but the same methods applied to human pancreas are less effective due to higher lipid content. Moreover, ECM-derived hydrogels can be obtained from many decellularized tissues, but methods have not been reported to obtain human pancreas-derived hydrogel. Using novel decellularization methods with human pancreas we produced an acellular, 3D biological scaffold (hP-ECM) and hydrogel (hP-HG) amenable to tissue culture, transplantation and proteomic applications. The inclusion of a homogenization step in the decellularization protocol significantly improved lipid removal and gelation capability of the resulting ECM, which was capable of gelation at 37 °C in vitro and in vivo, and is cytocompatible with a variety of cell types and islet-like tissues in vitro. Overall, this study demonstrates the characterisation of a novel protocol for the decellularization and delipidization of human pancreatic tissue for the production of acellular ECM and ECM hydrogel suitable for cell culture and transplantation applications. We also report a list of 120 proteins present within the human pancreatic matrisome.
Collapse
Affiliation(s)
- Sara Dutton Sackett
- Division of Transplantation, Department of Surgery, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, 53705, USA.
| | - Daniel M Tremmel
- Division of Transplantation, Department of Surgery, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, 53705, USA
| | - Fengfei Ma
- School of Pharmacy, University of Wisconsin, Madison, Wisconsin, 53705, USA
| | - Austin K Feeney
- Division of Transplantation, Department of Surgery, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, 53705, USA
| | - Rachel M Maguire
- Division of Transplantation, Department of Surgery, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, 53705, USA
| | - Matthew E Brown
- Division of Transplantation, Department of Surgery, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, 53705, USA
| | - Ying Zhou
- Division of Transplantation, Department of Surgery, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, 53705, USA
| | - Xiang Li
- Division of Transplantation, Department of Surgery, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, 53705, USA
| | - Cori O'Brien
- Division of Transplantation, Department of Surgery, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, 53705, USA
| | - Lingjun Li
- School of Pharmacy, University of Wisconsin, Madison, Wisconsin, 53705, USA
- Department of Chemistry, University of Wisconsin, Madison, Wisconsin, 53705, USA
| | - William J Burlingham
- Division of Transplantation, Department of Surgery, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, 53705, USA
| | - Jon S Odorico
- Division of Transplantation, Department of Surgery, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wisconsin, 53705, USA
| |
Collapse
|
|
44
|
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.
Collapse
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
| |
Collapse
|
|
45
|
Venturini M, Sallemi C, Marra P, Palmisano A, Agostini G, Lanza C, Balzano G, Falconi M, Secchi A, Fiorina P, Piemonti L, Maffi P, Esposito A, De Cobelli F, Del Maschio A. Allo- and auto-percutaneous intra-portal pancreatic islet transplantation (PIPIT) for diabetes cure and prevention: the role of imaging and interventional radiology. Gland Surg 2018; 7:117-131. [PMID: 29770308 DOI: 10.21037/gs.2017.11.12] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Although the life expectancy of patients with type 1 diabetes mellitus (T1DM) has improved since the introduction of insulin therapy, the acute life-threatening and long-term complications from diabetes mellitus are significant causes of both mortality and morbidity. Percutaneous intra-portal pancreatic islet transplantation (PIPIT) is a minimally invasive, repeatable procedure which allows a β-cell replacement therapy through a liver islet engraftment, leading to insulin release and glycaemic control restoration in patients with diabetes. Allo-PIPIT, in which isolated and purified islets from cadaveric donor are used, does not require major surgery, and is potentially less expensive for the recipient. In case of long-term T1DM, islet-after-kidney (IAK) transplantation can simultaneously cure diabetes and chronic renal failure, while islet-transplant-alone (ITA) is performed in brittle, short-term T1DM, based on the infusion of an adequate islet mass and on a steroid-free immunosuppressive regimen according to the Edmonton protocol. Results of the Collaborative Islet Transplant Registry (CITR) demonstrate that allo-PIPIT reduces episodes of hypoglycemia and diabetic complications, and improves quality of life of diabetic patients. Auto-PIPIT, in which the own patient's islets are used, has been investigated as a preventive treatment for pancreatogenic diabetes in patients who undergo extensive pancreatectomy for malignant and non-malignant disease. This Review outlines the role of imaging and interventional radiology in allo- and auto-PIPIT.
Collapse
Affiliation(s)
- Massimo Venturini
- Department of Radiology, San Raffaele Scientific Institute, Milan, Italy
| | - Claudio Sallemi
- Department of Radiology, San Raffaele Scientific Institute, Milan, Italy
| | - Paolo Marra
- Department of Radiology, San Raffaele Scientific Institute, Milan, Italy
| | - Anna Palmisano
- Department of Radiology, San Raffaele Scientific Institute, Milan, Italy
| | - Giulia Agostini
- Department of Radiology, San Raffaele Scientific Institute, Milan, Italy
| | - Carolina Lanza
- Department of Radiology, San Raffaele Scientific Institute, Milan, Italy
| | - Gianpaolo Balzano
- Department of Pancreatic Surgery, San Raffaele Scientific Institute, Milan, Italy
| | - Massimo Falconi
- Department of Pancreatic Surgery, San Raffaele Scientific Institute, Milan, Italy.,Vita-Salute San Raffaele University, Milan, Italy
| | - Antonio Secchi
- Vita-Salute San Raffaele University, Milan, Italy.,Department of Internal Medicine, Transplant Unit, San Raffaele Scientific Institute, Milan, Italy
| | - Paolo Fiorina
- Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Lorenzo Piemonti
- Vita-Salute San Raffaele University, Milan, Italy.,Diabetes Research Institute, San Raffaele Scientific Institute, Milan, Italy
| | - Paola Maffi
- Department of Internal Medicine, Transplant Unit, San Raffaele Scientific Institute, Milan, Italy
| | - Antonio Esposito
- Department of Radiology, San Raffaele Scientific Institute, Milan, Italy.,Vita-Salute San Raffaele University, Milan, Italy
| | - Francesco De Cobelli
- Department of Radiology, San Raffaele Scientific Institute, Milan, Italy.,Vita-Salute San Raffaele University, Milan, Italy
| | - Alessandro Del Maschio
- Department of Radiology, San Raffaele Scientific Institute, Milan, Italy.,Vita-Salute San Raffaele University, Milan, Italy
| |
Collapse
|
|
46
|
Abstract
Background Methodology Results Conclusion
Collapse
|
|
47
|
Wszola M, Berman A, Gorski L, Ostaszewska A, Serwanska-Swietek M, Krajewska M, Lipinska A, Chmura A, Kwiatkowski A. Endoscopic Islet Autotransplantation Into Gastric Submucosa-1000-Day Follow-up of Patients. Transplant Proc 2018; 50:2119-2123. [PMID: 30177121 DOI: 10.1016/j.transproceed.2018.02.138] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2017] [Revised: 01/17/2018] [Accepted: 02/06/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND Total pancreatectomy and autologous transplantation of pancreatic islets is a treatment option for patients with severe pain due to chronic pancreatitis. In the standard procedure, pancreatic islets are isolated and subsequently administered into the portal vein. In the case of patients with a history of thrombosis or at risk of thrombosis, this route of administration is not viable. Animal studies conducted in our department led to the development of a technique of endoscopic islets transplantation into the gastric submucosa. In 2013 and 2014, the first human autologous transplant procedures were performed. The objective of this study was to present the results of a 3-year follow-up of these patients. METHODS Two pancreatectomies were performed in our department, the first in 2013 and another in 2014, along with subsequent autologous transplantation of pancreatic islets into the gastric submucosa. RESULTS Both patients had been diagnosed previously with diabetes, and both had endogenous islet activity detected. Peptide C concentration after pancreatectomy and before pancreatic cell transplantation was 0.1 ng/mL. After the transplantation, peptide C concentrations for the 2 patients were 0.8 and 0.5 ng/mL on day 7, 1.2 and 0.6 ng/mL on day 30, 1.3 and 0.8 ng/mL on day 180, 1.1 and 0.7 ng/mL on day 360, and 3.0 and 0.6 ng/mL at 3 years, respectively, after transplantation. The pain symptoms resolved in both cases. CONCLUSION Pancreatic islets may survive in the gastric wall. Endoscopic submucosal transplantation may present an alternative for the management of patients who cannot undergo a classic transplantation procedure.
Collapse
Affiliation(s)
- M Wszola
- Foundation of Research and Science Development, Otwock, Poland.
| | - A Berman
- Foundation of Research and Science Development, Otwock, Poland
| | - L Gorski
- Department of General and Transplantation Surgery, Warsaw Medical University, Warsaw, Poland
| | - A Ostaszewska
- Department of General and Transplantation Surgery, Warsaw Medical University, Warsaw, Poland
| | | | - M Krajewska
- Department of Immunology, Transplantology and Internal Diseases, Warsaw Medical University, Warsaw, Poland
| | - A Lipinska
- Department of Internal Diseases and Cardiology, Warsaw Medical University, Warsaw, Poland
| | - A Chmura
- Department of General and Transplantation Surgery, Warsaw Medical University, Warsaw, Poland
| | - A Kwiatkowski
- Foundation of Research and Science Development, Otwock, Poland; Department of General and Transplantation Surgery, Warsaw Medical University, Warsaw, Poland
| |
Collapse
|
|
48
|
Jofra T, Galvani G, Georgia F, Silvia G, Gagliani N, Battaglia M. Murine Pancreatic Islets Transplantation under the Kidney Capsule. Bio Protoc 2018; 8:e2743. [PMID: 34179271 DOI: 10.21769/bioprotoc.2743] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Revised: 02/06/2018] [Accepted: 02/06/2018] [Indexed: 11/02/2022] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disease caused by the lack of insulin-producing pancreatic beta cells leading to systemic hyperglycemia. Pancreatic islet transplantation is a valid therapeutic approach to restore insulin loss and to promote adequate glycemic control. Pancreatic islet transplantation in mice is an optimal preclinical model to identify new therapeutic strategies aiming at preventing rejection and optimizing post-transplant immuno-suppressive/-tolerogenic therapies. Islet transplantation in preclinical animal models can be performed in different sites such the kidney capsule, spleen, bone marrow and pancreas. This protocol describes murine islet transplantation under the kidney capsule. This is a widely accepted procedure for research purposes. Stress caused in the animals is minimal and it leads to reliable and reproducible results.
Collapse
Affiliation(s)
- Tatiana Jofra
- Diabetes Research Institute (DRI), IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Giuseppe Galvani
- Diabetes Research Institute (DRI), IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Fousteri Georgia
- Diabetes Research Institute (DRI), IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Gregori Silvia
- San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Nicola Gagliani
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,Medical Department, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Manuela Battaglia
- Diabetes Research Institute (DRI), IRCCS San Raffaele Scientific Institute, Milan, Italy
| |
Collapse
|
|
49
|
Manzoli V, Villa C, Bayer AL, Morales L, Molano RD, Torrente Y, Ricordi C, Hubbell JA, Tomei AA. Immunoisolation of murine islet allografts in vascularized sites through conformal coating with polyethylene glycol. Am J Transplant 2018; 18:590-603. [PMID: 29068143 PMCID: PMC5820142 DOI: 10.1111/ajt.14547] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Revised: 09/21/2017] [Accepted: 10/15/2017] [Indexed: 01/25/2023]
Abstract
Islet encapsulation may allow transplantation without immunosuppression, but thus far islets in large microcapsules transplanted in the peritoneal cavity have failed to reverse diabetes in humans. We showed that islet transplantation in confined well-vascularized sites like the epididymal fat pad (EFP) improved graft outcomes, but only conformal coated (CC) islets can be implanted in these sites in curative doses. Here, we showed that CC using polyethylene glycol (PEG) and alginate (ALG) was not immunoisolating because of its high permselectivity and strong allogeneic T cell responses. We refined the CC composition and explored PEG and islet-like extracellular matrix (Matrigel; MG) islet encapsulation (PEG MG) to improve capsule immunoisolation by decreasing its permselectivity and immunogenicity while allowing physiological islet function. Although the efficiency of diabetes reversal of allogeneic but not syngeneic CC islets was lower than that of naked islets, we showed that CC (PEG MG) islets from fully MHC-mismatched Balb/c mice supported long-term (>100 days) survival after transplantation into diabetic C57BL/6 recipients in the EFP site (750-1000 islet equivalents/mouse) in the absence of immunosuppression. Lack of immune cell penetration and T cell allogeneic priming was observed. These studies support the use of CC (PEG MG) for islet encapsulation and transplantation in clinically relevant sites without chronic immunosuppression.
Collapse
Affiliation(s)
- Vita Manzoli
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA,Department of Electronics, Information and Bioengineering – Politecnico di Milano – Italy
| | - Chiara Villa
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA,Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy,Department of Pathophysiology and Transplantation, Universitá degli Studi di Milano, Italy
| | - Allison L Bayer
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA,Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Laura Morales
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - R Damaris Molano
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Yvan Torrente
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy,Department of Pathophysiology and Transplantation, Universitá degli Studi di Milano, Italy
| | - Camillo Ricordi
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA,Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA,Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA,Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA,Department of Biomedical Engineering, University of Miami, Miami, FL, USA
| | | | - Alice A Tomei
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA,Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA,Department of Biomedical Engineering, University of Miami, Miami, FL, USA,Corresponding author: Alice A. Tomei, 1450 NW 10 Avenue, Miami, FL-33136, USA; Phone: +1 305-243-3469;
| |
Collapse
|
|
50
|
Liu JMH, Zhang X, Joe S, Luo X, Shea LD. Evaluation of biomaterial scaffold delivery of IL-33 as a localized immunomodulatory agent to support cell transplantation in adipose tissue. ACTA ACUST UNITED AC 2018; 1:1-12. [PMID: 29869643 DOI: 10.1016/j.regen.2018.01.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Introduction The development of novel immunomodulatory strategies that might decrease the need for systemic immune suppression would greatly enable the utility of cell-based therapies. Cell transplantation on biomaterial scaffolds offers a unique opportunity to engineer a site to locally polarize immunogenic antigen generation. Herein, we investigated the localized delivery of IL-33, which is a novel cytokine that has been shown to have beneficial immunomodulatory effects in certain transplant models as mediating anti-inflammatory properties in the adipose tissue, to determine its feasibility for use as an immunomodulatory agent. Results Localized IL-33 delivery from poly(lactide-co-glycolide) (PLG) scaffolds implanted into the epididymal fat specifically increased the Foxp3+ population of CD4+ T cells in both blank scaffold implants and scaffolds seeded with allogeneic islets. In allogeneic islet transplantation, we found IL-33 delivery results in a local upregulation of graft-protective T cells where 80% of the local CD4+ population is Foxp3+ and overall numbers of graft destructive CD8+ T cells are decreased, resulting in a prolonged graft survival. Interestingly, local IL-33 also delayed islet engraftment by primarily inducing a local upregulation of Th2 cytokines, including IL-4 and IL-5, leading to increased populations of ST2+ Type 2 innate lymphoid cells (ILC2s) and Siglec F+ eosinophils. Conclusions These results suggest that local IL-33 delivery from biomaterial scaffolds can be used to increase Tregs enriched in adipose tissue and reduce graft-destructive T cell populations but may also promote innate cell populations that can delay cell engraftment.
Collapse
Affiliation(s)
- Jeffrey M H Liu
- Interdisciplinary Biological Sciences Program, Northwestern University, Evanston, IL, 60208, USA.,Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Xiaomin Zhang
- Department of Surgery, Division of Transplantation, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Shelby Joe
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Xunrong Luo
- Department of Surgery, Division of Transplantation, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.,Center for Kidney Research and Therapeutics, Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL, 60611, USA.,Department of Medicine, Division of Nephrology and Hypertension, Northwestern University, Chicago, IL, 60611, USA
| | - Lonnie D Shea
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA
| |
Collapse
|