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French A, Hollister-Lock J, Sullivan BA, Stas E, Hwa AJ, Weir GC, Bonner-Weir S. Enhancement of Subcutaneous Islet Transplant Performance by Collagen 1 Gel. Cell Transplant 2024; 33:9636897241283728. [PMID: 39361612 PMCID: PMC11457190 DOI: 10.1177/09636897241283728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 07/14/2024] [Accepted: 08/14/2024] [Indexed: 10/05/2024] Open
Abstract
Human islets can be transplanted into the portal vein for T1 diabetes, and a similar procedure is being used in a clinical trial for stem cell-derived beta-like cells. Efforts have been underway to find an alternative transplant site that will foster better islet cell survival and function. Although conceptually attractive, the subcutaneous (SC) site has yielded disappointing results, in spite of some improvements resulting from more attention paid to vascularization and differentiation factors, including collagen. We developed a method to transplant rat islets in a disk of type 1 collagen gel and found improved efficacy of these transplants. Survival of islets following transplantation (tx) was determined by comparing insulin content of the graft to that of the pre-transplant islets from the same isolation. At 14 days after transplantation, grafts of the disks had more than double the recovered insulin than islets transplanted in ungelled collagen. SC grafts of disks had similar insulin content to grafts in a kidney site and in epididymal fat pads. In vivo disks underwent contraction to 10% of initial volume within 24 h but the islets remained healthy and well distributed. Whole mount imaging showed that residual donor vascular cells within the islets expanded and connected to ingrowing host blood vessels. Islets (400 rat islet equivalents (IEQ)) in the collagen disks transplanted into an SC site of NOD scid IL2R gammanull (NSG) mice reversed streptozotocin (STZ)-induced diabetes within 10 days as effectively as transplants in the kidney site. Thus, a simple change of placing islets into a gel of collagen 1 prior to transplantation allowed a prompt reversal of STZ-induced diabetes using SC site.
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Affiliation(s)
- Anna French
- Harvard Medical School, Joslin Diabetes Center, Boston, MA, USA
- Section on Islet Cell & Regenerative Biology, Joslin Diabetes Center, Boston, MA, USA
| | - Jennifer Hollister-Lock
- Harvard Medical School, Joslin Diabetes Center, Boston, MA, USA
- Section on Islet Cell & Regenerative Biology, Joslin Diabetes Center, Boston, MA, USA
| | - Brooke A. Sullivan
- Harvard Medical School, Joslin Diabetes Center, Boston, MA, USA
- Section on Islet Cell & Regenerative Biology, Joslin Diabetes Center, Boston, MA, USA
| | - Eline Stas
- Harvard Medical School, Joslin Diabetes Center, Boston, MA, USA
- Section on Islet Cell & Regenerative Biology, Joslin Diabetes Center, Boston, MA, USA
| | - Albert J. Hwa
- Harvard Medical School, Joslin Diabetes Center, Boston, MA, USA
- Section on Islet Cell & Regenerative Biology, Joslin Diabetes Center, Boston, MA, USA
| | - Gordon C. Weir
- Harvard Medical School, Joslin Diabetes Center, Boston, MA, USA
- Section on Islet Cell & Regenerative Biology, Joslin Diabetes Center, Boston, MA, USA
| | - Susan Bonner-Weir
- Harvard Medical School, Joslin Diabetes Center, Boston, MA, USA
- Section on Islet Cell & Regenerative Biology, Joslin Diabetes Center, Boston, MA, USA
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Samadi A, Moammeri A, Pourmadadi M, Abbasi P, Hosseinpour Z, Farokh A, Shamsabadipour A, Heydari M, Mohammadi MR. Cell Encapsulation and 3D Bioprinting for Therapeutic Cell Transplantation. ACS Biomater Sci Eng 2023; 9:1862-1890. [PMID: 36877212 DOI: 10.1021/acsbiomaterials.2c01183] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/07/2023]
Abstract
The promise of cell therapy has been augmented by introducing biomaterials, where intricate scaffold shapes are fabricated to accommodate the cells within. In this review, we first discuss cell encapsulation and the promising potential of biomaterials to overcome challenges associated with cell therapy, particularly cellular function and longevity. More specifically, cell therapies in the context of autoimmune disorders, neurodegenerative diseases, and cancer are reviewed from the perspectives of preclinical findings as well as available clinical data. Next, techniques to fabricate cell-biomaterials constructs, focusing on emerging 3D bioprinting technologies, will be reviewed. 3D bioprinting is an advancing field that enables fabricating complex, interconnected, and consistent cell-based constructs capable of scaling up highly reproducible cell-biomaterials platforms with high precision. It is expected that 3D bioprinting devices will expand and become more precise, scalable, and appropriate for clinical manufacturing. Rather than one printer fits all, seeing more application-specific printer types, such as a bioprinter for bone tissue fabrication, which would be different from a bioprinter for skin tissue fabrication, is anticipated in the future.
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Affiliation(s)
- Amirmasoud Samadi
- Department of Chemical and Biomolecular Engineering, 6000 Interdisciplinary Science & Engineering Building (ISEB), Irvine, California 92617, United States
| | - Ali Moammeri
- School of Chemical Engineering, College of Engineering, University of Tehran, Enghelab Square, 16 Azar Street, Tehran 1417935840, Iran
| | - Mehrab Pourmadadi
- School of Chemical Engineering, College of Engineering, University of Tehran, Enghelab Square, 16 Azar Street, Tehran 1417935840, Iran
| | - Parisa Abbasi
- Department of Chemical and Petroleum Engineering, Sharif University of Technology, Azadi Avenue, Tehran 1458889694, Iran
| | - Zeinab Hosseinpour
- Biotechnology Research Laboratory, Faculty of Chemical Engineering, Babol Noshirvani University of Technology, Babol 4714871167, Mazandaran Province, Iran
| | - Arian Farokh
- School of Chemical Engineering, College of Engineering, University of Tehran, Enghelab Square, 16 Azar Street, Tehran 1417935840, Iran
| | - Amin Shamsabadipour
- School of Chemical Engineering, College of Engineering, University of Tehran, Enghelab Square, 16 Azar Street, Tehran 1417935840, Iran
| | - Maryam Heydari
- Department of Cell and Molecular Biology, Faculty of Biological Science, University of Kharazmi, Tehran 199389373, Iran
| | - M Rezaa Mohammadi
- Dale E. and Sarah Ann Fowler School of Engineering, Chapman University, Orange, California 92866, United States
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Suitability of denervated muscle flaps as recipient sites for pancreatic islet cell transplantation. Arch Plast Surg 2021; 48:133-143. [PMID: 33503758 PMCID: PMC7861985 DOI: 10.5999/aps.2020.01865] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 11/18/2020] [Indexed: 11/08/2022] Open
Abstract
BACKGROUND Extensive research has been conducted on islet transplantation as a possible cure for diabetes. Islet transplantation in the liver via the portal vein has shown remarkable results, but numerous other recipient sites are currently being investigated. We aimed to show the effectiveness of using a muscle flap as a recipient site for islet transplantation. METHODS Islet cells were harvested from 12 isogenic Lewis rats, and then diabetes was induced in another 12 isogenic Lewis rats by streptozotocin injection. In six rats, 3,000 islets were transplanted into gastrocnemius muscle flaps, and in the other six rats, the same number of islets were transplanted into the gastrocnemius muscle. The transplanted islet cell function between the two groups was compared by means of blood glucose tests, glucose tolerance tests, immunohistochemistry, and real-time reverse transcription polymerase chain reaction. RESULTS In the muscle flap group, blood glucose levels significantly decreased after islet transplantation. Blood glucose levels were significantly different between the two groups at 3 weeks after transplantation. The muscle flap group showed nearly normoglycemic results upon the glucose tolerance test, whereas the muscle group was hyperglycemic. Immunohistochemical evaluation showed positive results against insulin and glucagon in biopsies of both groups, and the islet cell density was higher in the muscle flap group. There were no statistically significant differences between the two groups in real-time reverse transcription polymerase chain reaction results. CONCLUSIONS Our results suggest that muscle flaps are promising candidates for islet cell transplantation.
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Addison P, Fatakhova K, Rodriguez Rilo HL. Considerations for an Alternative Site of Islet Cell Transplantation. J Diabetes Sci Technol 2020; 14:338-344. [PMID: 31394934 PMCID: PMC7196852 DOI: 10.1177/1932296819868495] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Islet cell transplantation has been limited most by poor graft survival. Optimizing the site of transplantation could improve clinical outcomes by minimizing required donor cells, increasing graft integration, and simplifying the transplantation and monitoring process. In this article, we review the history and significant human and animal data for clinically relevant sites, including the liver, spleen, and kidney subcapsule, and identify promising new sites for further research. While the liver was the first studied site and has been used the most in clinical practice, the majority of transplanted islets become necrotic. We review the potential causes for graft death, including the instant blood-mediated inflammatory reaction, exposure to immunosuppressive agents, and low oxygen tension. Significant research exists on alternative sites for islet cell transplantation, suggesting a promising future for patients undergoing pancreatectomy.
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Affiliation(s)
- Poppy Addison
- Donald and Barbara Zucker School of
Medicine at Hofstra/Northwell, Hempstead, NY, USA
- Pancreas Disease Center, Northwell
Health System, Manhasset, NY, USA
| | - Karina Fatakhova
- Donald and Barbara Zucker School of
Medicine at Hofstra/Northwell, Hempstead, NY, USA
- Pancreas Disease Center, Northwell
Health System, Manhasset, NY, USA
| | - Horacio L. Rodriguez Rilo
- Donald and Barbara Zucker School of
Medicine at Hofstra/Northwell, Hempstead, NY, USA
- Pancreas Disease Center, Northwell
Health System, Manhasset, NY, USA
- Horacio L. Rodriguez Rilo, MD, Pancreas
Disease Center, 350 Lakeville Road, New Hyde Park, NY 11042, USA.
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5
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Brboric A, Vasylovska S, Saarimäki-Vire J, Espes D, Caballero-Corbalan J, Larfors G, Otonkoski T, Lau J. Characterization of neural crest-derived stem cells isolated from human bone marrow for improvement of transplanted islet function. Ups J Med Sci 2019; 124:228-237. [PMID: 31623497 PMCID: PMC6968573 DOI: 10.1080/03009734.2019.1658661] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Background: Murine boundary cap-derived neural crest stem cells (NCSCs) are capable of enhancing islet function by stimulating beta cell proliferation as well as increasing the neural and vascular density in the islets both in vitro and in vivo. This study aimed to isolate NCSC-like cells from human bone marrow.Methods: CD271 magnetic cell separation and culture techniques were used to purify a NCSC-enriched population of human bone marrow. Analyses of the CD271+ and CD271- fractions in terms of protein expression were performed, and the capacity of the CD271+ bone marrow cells to form 3-dimensional spheres when grown under non-adherent conditions was also investigated. Moreover, the NCSC characteristics of the CD271+ cells were evaluated by their ability to migrate toward human islets as well as human islet-like cell clusters (ICC) derived from pluripotent stem cells.Results: The CD271+ bone marrow population fulfilled the criterion of being multipotent stem cells, having the potential to differentiate into glial cells, neurons as well as myofibroblasts in vitro. They had the capacity to form 3-dimensional spheres as well as an ability to migrate toward human islets, further supporting their NCSC identity. Additionally, we demonstrated similar migration features toward stem cell-derived ICC.Conclusion: The results support the NCSC identity of the CD271-enriched human bone marrow population. It remains to investigate whether the human bone marrow-derived NCSCs have the ability to improve transplantation efficacy of not only human islets but stem cell-derived ICC as well.
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Affiliation(s)
- Anja Brboric
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | | | - Jonna Saarimäki-Vire
- Research Programs Unit, Molecular Neurology and Biomedicum Stem Cell Centre, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Daniel Espes
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | | | - Gunnar Larfors
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Timo Otonkoski
- Research Programs Unit, Molecular Neurology and Biomedicum Stem Cell Centre, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Joey Lau
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
- CONTACT Joey Lau Department of Medical Cell Biology, Uppsala University, Husargatan 3, Box 571, SE-751 23 Uppsala, Sweden
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Alekberzade AV, Krylov NN, Adzhun Z, Laftavi MR, Shakhbazov RO, Zuykova KS. [Current state of the problem of allotransplantation of Langerhans cells (achievements and prospects)]. Khirurgiia (Mosk) 2018:80-88. [PMID: 30531761 DOI: 10.17116/hirurgia201811180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Literature data devoted to transplantation of Langerhans cells have been analyzed. The main stages, indications, dissection of islets, immunosuppressive therapy, complications and data of the latest clinical trials were discussed.
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Affiliation(s)
- A V Alekberzade
- Sechenov First Moscow State Medical University of Healthcare Ministry of the Russian Federation, Moscow, Russia
| | - N N Krylov
- Sechenov First Moscow State Medical University of Healthcare Ministry of the Russian Federation, Moscow, Russia
| | - Z Adzhun
- Upstate Medical University, Syracuse, NY, USA
| | - M R Laftavi
- Upstate Medical University, Syracuse, NY, USA
| | | | - K S Zuykova
- Sechenov First Moscow State Medical University of Healthcare Ministry of the Russian Federation, Moscow, Russia
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7
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c-Jun N-terminal kinase 1 defective CD4+CD25+FoxP3+ cells prolong islet allograft survival in diabetic mice. Sci Rep 2018; 8:3310. [PMID: 29459675 PMCID: PMC5818514 DOI: 10.1038/s41598-018-21477-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Accepted: 02/05/2018] [Indexed: 02/06/2023] Open
Abstract
CD4+CD25+FoxP3+ cells (Tregs) inhibit inflammatory immune responses to allografts. Here, we found that co-transplantation of allogeneic pancreatic islets with Tregs that are defective in c-Jun N-terminal kinase 1 (JNK1) signaling prolongs islet allograft survival in the liver parenchyma of chemically induced diabetic mice (CDM). Adoptively transferred JNK1−/− but not wild-type (WT) Tregs survive longer in the liver parenchyma of CDM. JNK1−/− Tregs are resistant to apoptosis and express anti-apoptotic molecules. JNK1−/− Tregs express higher levels of lymphocyte activation gene-3 molecule (LAG-3) on their surface and produce higher amounts of the anti-inflammatory cytokine interleukin (IL)-10 compared with WT Tregs. JNK1−/− Tregs inhibit liver alloimmune responses more efficiently than WT Tregs. JNK1−/− but not WT Tregs are able to inhibit IL-17 and IL-21 production through enhanced LAG-3 expression and IL-10 production. Our study identifies a novel role of JNK1 signaling in Tregs that enhances islet allograft survival in the liver parenchyma of CDM.
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Zhu H, Li W, Liu Z, Li W, Chen N, Lu L, Zhang W, Wang Z, Wang B, Pan K, Zhang X, Chen G. Selection of Implantation Sites for Transplantation of Encapsulated Pancreatic Islets. TISSUE ENGINEERING PART B-REVIEWS 2018; 24:191-214. [PMID: 29048258 DOI: 10.1089/ten.teb.2017.0311] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Pancreatic islet transplantation has been validated as a valuable therapy for type 1 diabetes mellitus patients with exhausted insulin treatment. However, this therapy remains limited by the shortage of donor and the requirement of lifelong immunosuppression. Islet encapsulation, as an available bioartificial pancreas (BAP), represents a promising approach to enable protecting islet grafts without or with minimal immunosuppression and possibly expanding the donor pool. To develop a clinically implantable BAP, some key aspects need to be taken into account: encapsulation material, capsule design, and implant site. Among them, the implant site exerts an important influence on the engraftment, stability, and biocompatibility of implanted BAP. Currently, an optimal site for encapsulated islet transplantation may include sufficient capacity to host large graft volumes, portal drainage, ease of access using safe and reproducible procedure, adequate blood/oxygen supply, minimal immune/inflammatory reaction, pliable for noninvasive imaging and biopsy, and potential of local microenvironment manipulation or bioengineering. Varying degrees of success have been confirmed with the utilization of liver or extrahepatic sites in an experimental or preclinical setting. However, the ideal implant site remains to be further engineered or selected for the widespread application of encapsulated islet transplantation.
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Affiliation(s)
- Haitao Zhu
- 1 Department of Pediatrics (No. 3 Ward), Northwest Women's and Children's Hospital , Xi'an, China .,2 Department of Hepatobiliary Surgery, the First Affiliated Hospital, Medical School of Xi'an Jiaotong University , Xi'an, China
| | - Wenjing Li
- 1 Department of Pediatrics (No. 3 Ward), Northwest Women's and Children's Hospital , Xi'an, China
| | - Zhongwei Liu
- 3 Department of Cardiology, Shaanxi Provincial People's Hospital , Xi'an, China
| | - Wenliang Li
- 1 Department of Pediatrics (No. 3 Ward), Northwest Women's and Children's Hospital , Xi'an, China
| | - Niuniu Chen
- 1 Department of Pediatrics (No. 3 Ward), Northwest Women's and Children's Hospital , Xi'an, China
| | - Linlin Lu
- 1 Department of Pediatrics (No. 3 Ward), Northwest Women's and Children's Hospital , Xi'an, China
| | - Wei Zhang
- 1 Department of Pediatrics (No. 3 Ward), Northwest Women's and Children's Hospital , Xi'an, China
| | - Zhen Wang
- 1 Department of Pediatrics (No. 3 Ward), Northwest Women's and Children's Hospital , Xi'an, China
| | - Bo Wang
- 2 Department of Hepatobiliary Surgery, the First Affiliated Hospital, Medical School of Xi'an Jiaotong University , Xi'an, China .,4 Institute of Advanced Surgical Technology and Engineering, Xi'an Jiaotong University , Xi'an, China
| | - Kaili Pan
- 5 Department of Pediatrics (No. 2 Ward), Northwest Women's and Children's Hospital , Xi'an, China
| | - Xiaoge Zhang
- 1 Department of Pediatrics (No. 3 Ward), Northwest Women's and Children's Hospital , Xi'an, China
| | - Guoqiang Chen
- 1 Department of Pediatrics (No. 3 Ward), Northwest Women's and Children's Hospital , Xi'an, China
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9
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Liu Z, Hu W, He T, Dai Y, Hara H, Bottino R, Cooper DKC, Cai Z, Mou L. Pig-to-Primate Islet Xenotransplantation: Past, Present, and Future. Cell Transplant 2017; 26:925-947. [PMID: 28155815 PMCID: PMC5657750 DOI: 10.3727/096368917x694859] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 03/21/2017] [Indexed: 12/17/2022] Open
Abstract
Islet allotransplantation results in increasing success in treating type 1 diabetes, but the shortage of deceased human donor pancreata limits progress. Islet xenotransplantation, using pigs as a source of islets, is a promising approach to overcome this limitation. The greatest obstacle is the primate immune/inflammatory response to the porcine (pig) islets, which may take the form of rapid early graft rejection (the instant blood-mediated inflammatory reaction) or T-cell-mediated rejection. These problems are being resolved by the genetic engineering of the source pigs combined with improved immunosuppressive therapy. The results of pig-to-diabetic nonhuman primate islet xenotransplantation are steadily improving, with insulin independence being achieved for periods >1 year. An alternative approach is to isolate islets within a micro- or macroencapsulation device aimed at protecting them from the human recipient's immune response. Clinical trials using this approach are currently underway. This review focuses on the major aspects of pig-to-primate islet xenotransplantation and its potential for treatment of type 1 diabetes.
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Affiliation(s)
- Zhengzhao Liu
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong, P.R. China
| | - Wenbao Hu
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong, P.R. China
| | - Tian He
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong, P.R. China
| | - Yifan Dai
- Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, Jiangsu, P.R. China
| | - Hidetaka Hara
- Xenotransplantation Program/Department of Surgery, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Rita Bottino
- Institute for Cellular Therapeutics, Allegheny-Singer Research Institute, Pittsburgh, PA, USA
| | - David K. C. Cooper
- Xenotransplantation Program/Department of Surgery, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Zhiming Cai
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong, P.R. China
| | - Lisha Mou
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong, P.R. China
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10
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Zhu HT, Lu L, Liu XY, Yu L, Lyu Y, Wang B. Treatment of diabetes with encapsulated pig islets: an update on current developments. J Zhejiang Univ Sci B 2016; 16:329-43. [PMID: 25990050 DOI: 10.1631/jzus.b1400310] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
The potential use of allogeneic islet transplantation in curing type 1 diabetes mellitus has been adequately demonstrated, but its large-scale application is limited by the short supply of donor islets and the need for sustained and heavy immunosuppressive therapy. Encapsulation of pig islets was therefore suggested with a view to providing a possible alternative source of islet grafts and avoiding chronic immunosuppression and associated adverse or toxic effects. Nevertheless, several vital elements should be taken into account before this therapy becomes a clinical reality, including cell sources, encapsulation approaches, and implantation sites. This paper provides a comprehensive review of xenotransplantation of encapsulated pig islets for the treatment of type 1 diabetes mellitus, including current research findings and suggestions for future studies.
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Affiliation(s)
- Hai-tao Zhu
- Heart Center, Northwest Women's and Children's Hospital, Xi'an 710061, China; Department of Hepatobiliary Surgery, the First Affiliated Hospital, Medical College, Xi'an Jiaotong University, Xi'an 710061, China; Department of Hand Surgery, China-Japan Union Hospital, Norman Bethune Health Science Center, Jilin University, Changchun 130033, China; Institute of Advanced Surgical Technology and Engineering, Xi'an Jiaotong University, Xi'an 710061, China
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11
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Moore SJ, Gala-Lopez BL, Pepper AR, Pawlick RL, Shapiro AMJ. Bioengineered stem cells as an alternative for islet cell transplantation. World J Transplant 2015; 5:1-10. [PMID: 25815266 PMCID: PMC4371156 DOI: 10.5500/wjt.v5.i1.1] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2014] [Revised: 02/18/2014] [Accepted: 10/29/2014] [Indexed: 02/05/2023] Open
Abstract
Type 1 diabetes is an autoimmune and increasingly prevalent condition caused by immunological destruction of beta cells. Insulin remains the mainstay of therapy. Endeavours in islet transplantation have clearly demonstrated that type 1 diabetes is treatable by cellular replacement. Many challenges remain with this approach. The opportunity to use bioengineered embryonic or adult pluripotential stem cells, or islets derived from porcine xenograft sources could address future demands, but are still associated with considerable challenges. This detailed review outlines current progress in clinical islet transplantation, and places this in perspective for the remarkable scientific advances now occurring in stem cell and regenerative medicine approaches in the treatment of future curative treatment of diabetes.
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12
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Vågesjö E, Christoffersson G, Waldén TB, Carlsson PO, Essand M, Korsgren O, Phillipson M. Immunological Shielding by Induced Recruitment of Regulatory T-Lymphocytes Delays Rejection of Islets Transplanted in Muscle. Cell Transplant 2015; 24:263-76. [DOI: 10.3727/096368914x678535] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
The only clinically available curative treatment of type 1 diabetes mellitus is replacement of the pancreatic islets by allogeneic transplantation, which requires immunosuppressive therapies. Regimens used today are associated with serious adverse effects and impaired islet engraftment and function. The aim of the current study was to induce local immune privilege by accumulating immune-suppressive regulatory T-lymphocytes (Tregs) at the site of intramuscular islet transplantation to reduce the need of immunosuppressive therapy during engraftment. Islets were cotransplanted with a plasmid encoding the chemokine CCL22 into the muscle of MHC-mismatched mice, after which pCCL22 expression and leukocyte recruitment were studied in parallel with graft functionality. Myocyte pCCL22 expression and secretion resulted in local accumulation of Tregs. When islets were cotransplanted with pCCL22, significantly fewer effector T-lymphocytes were observed in close proximity to the islets, leading to delayed graft rejection. As a result, diabetic recipients cotransplanted with islets and pCCL22 intramuscularly became normoglycemic for 10 consecutive days, while grafts cotransplanted with control plasmid were rejected immediately, leaving recipients severely hyperglycemic. Here we propose a simple method to initially shield MHC-mismatched islets by the recruitment of endogenous Tregs during engraftment in order to improve early islet survival. Using this approach, the very high doses of systemic immunosuppression used initially following transplantation can thereby be avoided.
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Affiliation(s)
- Evelina Vågesjö
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | | | - Tomas B. Waldén
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Per-Ola Carlsson
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Magnus Essand
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Olle Korsgren
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Mia Phillipson
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
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13
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Chhabra P, Brayman KL. Overcoming barriers in clinical islet transplantation: current limitations and future prospects. Curr Probl Surg 2014; 51:49-86. [PMID: 24411187 DOI: 10.1067/j.cpsurg.2013.10.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
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Sakata N, Aoki T, Yoshimatsu G, Tsuchiya H, Hata T, Katayose Y, Egawa S, Unno M. Strategy for clinical setting in intramuscular and subcutaneous islet transplantation. Diabetes Metab Res Rev 2014; 30:1-10. [PMID: 24000195 DOI: 10.1002/dmrr.2463] [Citation(s) in RCA: 82] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2013] [Revised: 07/09/2013] [Accepted: 08/27/2013] [Indexed: 01/08/2023]
Abstract
Intraportal islet transplantation has a long history as a procedure for clinical islet transplantation. However, many recent studies revealed that the intraportal procedure has some disadvantages in transplant efficiency and safety. Many candidates as an optimal transplant site for islets have been assessed, but further studies and clinical trials are still necessary. Intramuscular and subcutaneous spaces are important candidates, because the transplant and biopsy procedures are simple approaches with minimal invasion and few complications. Although they are sites with hypovascularity and hypoxia, which contribute to the poor transplant efficiency, many experimental trials for improving the outcome in intramuscular and subcutaneous islet transplantations have been performed, focusing on early angiogenesis and scaffolds for engrafting transplanted islets. We review current progress in intramuscular and subcutaneous islet transplantations and discuss ways to develop them as optimal transplant sites for islets.
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Affiliation(s)
- Naoaki Sakata
- Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
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Transplantation of pancreatic islets to adrenal gland is promoted by agonists of growth-hormone-releasing hormone. Proc Natl Acad Sci U S A 2013; 110:2288-93. [PMID: 23345449 DOI: 10.1073/pnas.1221505110] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Here, we evaluate an alternative approach of preconditioning pancreatic islets before transplantation using a potent agonist of growth-hormone-releasing hormone (GHRH) to promote islet viability and function, and we explore the adrenal gland as an alternative transplantation site for islet engraftment. The endocrine microenvironment of the adrenal represents a promising niche with the unique advantages of exceptional high oxygen tension and local anti-inflammatory and immunosuppressive properties. GHRH agonists have been shown to promote islet graft survival and function, which may help to reduce the islet mass necessary to reverse diabetes. In the present study, the most potent GHRH agonist MR403 was tested on insulinoma cells, isolated rat islets, and adrenal β-cell cocultures in vitro. GHRH receptor is expressed on both adrenal cells and islets. MR403 caused a significant increase in cell viability and proliferation and revealed an antiapoptotic effect on insulinoma cells. Viability of rat islets was increased after treatment with the agonist and in coculture with adrenal cells. Rat islets were transplanted into diabetic mice to the intraadrenal transplant site and compared with the classical transplants underneath the kidney capsule. Graft function and integration were tested by metabolic follow-up and immunohistochemical staining of intraadrenal grafts. A rapid decrease occurred in blood glucose levels in both models, and all animals reached normoglycemia within the first days after transplantation. Our studies demonstrated that the adrenal may be an attractive site for islet transplantation and that GHRH analogs might allow reduction of the islet mass needed to reverse a diabetic status.
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Dufrane D, Gianello P. Macro- or microencapsulation of pig islets to cure type 1 diabetes. World J Gastroenterol 2012; 18:6885-93. [PMID: 23322985 PMCID: PMC3531671 DOI: 10.3748/wjg.v18.i47.6885] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2012] [Revised: 06/14/2012] [Accepted: 06/28/2012] [Indexed: 02/06/2023] Open
Abstract
Although allogeneic islet transplantation can successfully cure type 1 diabetes, it has limited applicability. For example, organs are in short supply; several human pancreas donors are often needed to treat one diabetic recipient; the intrahepatic site may not be the most appropriate site for islet implantation; and immunosuppressive regimens, which are associated with side effects, are often required to prolong survival of the islet graft. An alternative source of insulin-producing cells would therefore be of major interest. Pigs represent a possible alternative source of beta cells. Grafting of pig islets may appear difficult because of the immunologic species barrier, but pig islets have been shown to function in primates for at least 6 mo with clinically incompatible immunosuppression. Therefore, a bioartificial pancreas made of encapsulated pig islets may resolve issues associated with islet allotransplantation. Although several groups have shown that encapsulated pig islets are functional in small-animal models, less is known about the use of bioartificial pancreases in large-animal models. In this review, we summarize current knowledge of encapsulated pig islets, to determine obstacles to implantation in humans and possible solutions to overcome these obstacles.
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