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Ahmed HS, Dias AF, Pulkurthi SR. Thymus transplantation for DiGeorge Syndrome: a systematic review. Pediatr Surg Int 2025; 41:82. [PMID: 39960552 DOI: 10.1007/s00383-025-05976-1] [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] [Accepted: 01/26/2025] [Indexed: 05/09/2025]
Abstract
BACKGROUND DiGeorge syndrome (DGS) is a condition typically associated with athymia, parathyroid hypoplasia or aplasia, and congenital heart defects. Athymia in these patients causes severe immunodeficiency, causing high mortality and morbidity, often requiring thymic tissue transplantation. The present systematic review aims to consolidate the present evidence on thymus transplantation in DGS. METHODS An electronic literature search of five databases (PubMed, Medline, Scopus, EBSCOhost, and CINAHL) was performed from inception till September 2024. Relevant articles were selected, and data was extracted by two independent reviewers. RESULTS A total of 16 articles were included from an initial set of 1227 articles. Patients diagnosed with DGS in the included studies were predominantly male, and the age at which thymus transplantation was done typically varied from 0.8 to 26 months. Several patients had chromosome 22q11 hemizygosity. Thymic tissue was taken from tissues of pediatric patients undergoing cardiothoracic surgery. Pre-transplant medication included immunosuppressants with rabbit anti-thymocyte globulin (RATGAM) being frequently used alongside steroids and tacrolimus. This tissue was cultured and transplanted into the quadriceps muscle of the patients under general anesthesia. Thymopoiesis was well described in most patients with graft failures and rejections occurring rarely. Naive T-cell development was noted in almost all patients with clearance of infections in many cases. Common postoperative complications include sepsis, haemorrhage, gastrointestinal disturbances, among others. Mortality was uncommon but often associated with intracerebral hemorrhages and sepsis. CONCLUSION Thymus transplantation is a relatively safe and effective procedure in patients with DGS with athymia. Future research should explore the addition of allogenic parathyroid gland transplantation along with thymic tissue.
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Affiliation(s)
- H Shafeeq Ahmed
- Bangalore Medical College and Research Institute, K.R Road, Bangalore, 560002, Karnataka, India.
| | - Akhil Fravis Dias
- M S Ramaiah Medical College, M S Ramaiah Nagar, Bangalore, 560054, Karnataka, India
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Yang SN, Shi Y, Berggren PO. The anterior chamber of the eye technology and its anatomical, optical, and immunological bases. Physiol Rev 2024; 104:881-929. [PMID: 38206586 PMCID: PMC11381035 DOI: 10.1152/physrev.00024.2023] [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: 06/20/2023] [Revised: 11/30/2023] [Accepted: 01/05/2024] [Indexed: 01/12/2024] Open
Abstract
The anterior chamber of the eye (ACE) is distinct in its anatomy, optics, and immunology. This guarantees that the eye perceives visual information in the context of physiology even when encountering adverse incidents like inflammation. In addition, this endows the ACE with the special nursery bed iris enriched in vasculatures and nerves. The ACE constitutes a confined space enclosing an oxygen/nutrient-rich, immune-privileged, and less stressful milieu as well as an optically transparent medium. Therefore, aside from visual perception, the ACE unexpectedly serves as an excellent transplantation site for different body parts and a unique platform for noninvasive, longitudinal, and intravital microimaging of different grafts. On the basis of these merits, the ACE technology has evolved from the prototypical through the conventional to the advanced version. Studies using this technology as a versatile biomedical research platform have led to a diverse range of basic knowledge and in-depth understanding of a variety of cells, tissues, and organs as well as artificial biomaterials, pharmaceuticals, and abiotic substances. Remarkably, the technology turns in vivo dynamic imaging of the morphological characteristics, organotypic features, developmental fates, and specific functions of intracameral grafts into reality under physiological and pathological conditions. Here we review the anatomical, optical, and immunological bases as well as technical details of the ACE technology. Moreover, we discuss major achievements obtained and potential prospective avenues for this technology.
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Affiliation(s)
- Shao-Nian Yang
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden
| | - Yue Shi
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden
| | - Per-Olof Berggren
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden
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3
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Leishman DJ, Oppler SH, Stone LLH, O’Brien TD, Ramachandran S, Willenberg BJ, Adams AB, Hering BJ, Graham ML. Targeted mapping and utilization of the perihepatic surface for therapeutic beta cell replacement and retrieval in diabetic non-human primates. FRONTIERS IN TRANSPLANTATION 2024; 3:1352777. [PMID: 38993753 PMCID: PMC11235263 DOI: 10.3389/frtra.2024.1352777] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Accepted: 01/09/2024] [Indexed: 07/13/2024]
Abstract
Introduction Successful diabetes reversal using pancreatic islet transplantation by various groups illustrates the significant achievements made in cell-based diabetes therapy. While clinically, intraportal islet delivery is almost exclusively used, it is not without obstacles, including instant blood-mediated inflammatory reaction (IBMIR), relative hypoxia, and loss of function over time, therefore hindering long-term success. Here we demonstrate the perihepatic surface of non-human primates (NHPs) as a potential islet delivery site maximizing favorable characteristics, including proximity to a dense vascular network for adequate oxygenation while avoiding IBMIR exposure, maintenance of portal insulin delivery, and relative ease of accessibility through minimally invasive surgery or percutaneous means. In addition, we demonstrate a targeted mapping technique of the perihepatic surface, allowing for the testing of multiple experimental conditions, including a semi-synthetic hydrogel as a possible three-dimensional framework to improve islet viability. Methods Perihepatic allo-islet cell transplants were performed in immunosuppressed cynomolgus macaques using a targeted mapping technique to test multiple conditions for biocompatibility. Transplant conditions included islets or carriers (including hydrogel, autologous plasma, and media) alone or in various combinations. Necropsy was performed at day 30, and histopathology was performed to assess biocompatibility, immune response, and islet viability. Subsequently, single-injection perihepatic allo-islet transplant was performed in immunosuppressed diabetic cynomolgus macaques. Metabolic assessments were measured frequently (i.e., blood glucose, insulin, C-peptide) until final graft retrieval for histopathology. Results Targeted mapping biocompatibility studies demonstrated mild inflammatory changes with islet-plasma constructs; however, significant inflammatory cell infiltration and fibrosis were seen surrounding sites with the hydrogel carrier affecting islet viability. In diabetic NHPs, perihepatic islet transplant using an autologous plasma carrier demonstrated prolonged function up to 6 months with improvements in blood glucose, exogenous insulin requirements, and HbA1c. Histopathology of these islets was associated with mild peri-islet mononuclear cell infiltration without evidence of rejection. Discussion The perihepatic surface serves as a viable site for islet cell transplantation demonstrating sustained islet function through 6 months. The targeted mapping approach allows for the testing of multiple conditions simultaneously to evaluate immune response to biomaterials at this site. Compared to traditional intraportal injection, the perihepatic site is a minimally invasive approach that allows the possibility for graft recovery and avoids IBMIR.
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Affiliation(s)
- David J. Leishman
- Preclinical Research Center, Department of Surgery, University of Minnesota, Minneapolis, MN, United States
| | - Scott H. Oppler
- Preclinical Research Center, Department of Surgery, University of Minnesota, Minneapolis, MN, United States
| | - Laura L. Hocum Stone
- Preclinical Research Center, Department of Surgery, University of Minnesota, Minneapolis, MN, United States
| | - Timothy D. O’Brien
- Department of Veterinary Population Medicine, University of Minnesota, St. Paul, MN, United States
| | - Sabarinathan Ramachandran
- Preclinical Research Center, Department of Surgery, University of Minnesota, Minneapolis, MN, United States
| | - Bradley J. Willenberg
- Department of Internal Medicine, University of Central Florida College of Medicine, Orlando, FL, United States
| | - Andrew B. Adams
- Division of Transplantation, Department of Surgery, University of Minnesota, Minneapolis, MN, United States
| | - Bernhard J. Hering
- Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, MN, United States
| | - Melanie L. Graham
- Preclinical Research Center, Department of Surgery, University of Minnesota, Minneapolis, MN, United States
- Department of Veterinary Population Medicine, University of Minnesota, St. Paul, MN, United States
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4
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Sabet Sarvestani F, Tamaddon AM, Yaghoobi R, Geramizadeh B, Abolmaali SS, Kaviani M, Keshtkar S, Pakbaz S, Azarpira N. Indirect co-culture of islet cells in 3D biocompatible collagen/laminin scaffold with angiomiRs transfected mesenchymal stem cells. Cell Biochem Funct 2023; 41:296-308. [PMID: 36815688 DOI: 10.1002/cbf.3781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 02/05/2023] [Accepted: 02/06/2023] [Indexed: 02/24/2023]
Abstract
Diabetes is an autoimmune disease in which the pancreatic islets produce insufficient insulin. One of the treatment strategies is islet isolation, which may damage these cells as they lack vasculature. Biocompatible scaffolds are one of the efficient techniques for dealing with this issue. The current study is aimed to determine the effect of transfected BM-MSCS with angiomiR-126 and -210 on the survival and functionality of islets loaded into a 3D scaffold via laminin (LMN). AngiomiRs/Poly Ethylenimine polyplexes were transfected into bone marrow-mesenchymal stem cells (BM-MSCs), followed by 3-day indirect co-culturing with islets laden in collagen (Col)-based hydrogel scaffolds containing LMN. Islet proliferation and viability were significantly increased in LMN-containing scaffolds, particularly in the miRNA-126 treated group. Insulin gene expression was superior in Col scaffolds, especially, in the BM-MSCs/miRNA-126 treated group. VEGF was upregulated in the LMN-containing scaffolds in both miRNA-treated groups, specifically in the miRNA-210, leading to VEGF secretion. MiRNAs' target genes showed no downregulation in LMN-free scaffolds; while a drastic downregulation was seen in the LMN-containing scaffolds. The highest insulin secretion was recorded in the Oxidized dextran (Odex)/ColLMN+ group with miRNA-126. LMN-containing biocompatible scaffolds, once combined with angiomiRs and their downstream effectors, promote islets survival and restore function, leading to enhanced angiogenesis and glycemic status.
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Affiliation(s)
| | - Ali-Mohammad Tamaddon
- Department of Pharmaceutical Nanotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Islamic Republic of Iran, Shiraz, Iran.,Center for Nanotechnology in Drug Delivery, Shiraz University of Medical Sciences, Shiraz, Islamic Republic of Iran, Shiraz, Iran
| | - Ramin Yaghoobi
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Bita Geramizadeh
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Samira Sadat Abolmaali
- Department of Pharmaceutical Nanotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Islamic Republic of Iran, Shiraz, Iran
| | - Maryam Kaviani
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Somayeh Keshtkar
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Molecular Dermatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sara Pakbaz
- Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.,Department of Laboratory Medicine & Pathobiology, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Espona-Noguera A, Ciriza J, Cañibano-Hernández A, Saenz Del Burgo L, Pedraz JL. Immobilization of INS1E Insulin-Producing Cells Within Injectable Alginate Hydrogels. Methods Mol Biol 2020; 2100:395-405. [PMID: 31939138 DOI: 10.1007/978-1-0716-0215-7_26] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Alginate has demonstrated high applicability as a matrix-forming biomaterial for cell immobilization due to its ability to make hydrogels combined with cells in a rapid and non-toxic manner in physiological conditions, while showing excellent biocompatibility, preserving immobilized cell viability and function. Moreover, depending on its application, alginate hydrogel physicochemical properties such as porosity, stiffness, gelation time, and injectability can be tuned. This technology has been applied to several cell types that are able to produce therapeutic factors. In particular, alginate has been the most commonly used material in pancreatic islet entrapment for type 1 diabetes mellitus treatment. This chapter compiles information regarding the alginate handling, and we describe the most important steps and recommendations to immobilize insulin-producing cells within a tuned injectable alginate hydrogel using a syringe-based mixing system, detailing how to assess the viability and the biological functionality of the embedded cells.
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Affiliation(s)
- Albert Espona-Noguera
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz, Spain
- Biomedical Research Networking Center in Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Vitoria-Gasteiz, Spain
| | - Jesús Ciriza
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz, Spain
- Biomedical Research Networking Center in Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Vitoria-Gasteiz, Spain
| | - Alberto Cañibano-Hernández
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz, Spain
- Biomedical Research Networking Center in Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Vitoria-Gasteiz, Spain
| | - Laura Saenz Del Burgo
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz, Spain.
- Biomedical Research Networking Center in Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Vitoria-Gasteiz, Spain.
| | - Jose Luis Pedraz
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz, Spain.
- Biomedical Research Networking Center in Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Vitoria-Gasteiz, Spain.
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Abstract
OBJECTIVES Autologous islet transplantation (AIT) is performed to preserve insulin secretory function in chronic pancreatitis patients undergoing total pancreatectomy (TP). No data exist on the effect of time lapse on beta cell function post TP-AIT. We aimed to investigate the factor of time lapse on beta cell function following TP-AIT. METHODS Retrospectively, we identified 31 adult patients with chronic pancreatitis who underwent TP-AIT between 2008 and 2016. Changes in beta cell function were assessed using (1) BETA-2 scores and (2) analysis of posttransplant mixed-meal tolerance testing. RESULTS Significant decrease in functional beta cell capacity expressed by BETA-2 scores was seen in the first 2 years following TP-AIT, with an annual decrease of 6.3 points in median BETA-2 score (interquartile range, 4.6-11.6; P = 0.002). In the mixed-meal tolerance testing analysis, nonsignificant trends toward higher glucose, lower insulin, and lower C-peptide were seen with time lapse. Additionally, higher hemoglobin A1c values (P = 0.033) and higher insulin requirements (P = 0.04) were seen with longer follow-up after AIT. CONCLUSIONS A steady drop in functional beta cell capacity was observed in the 2 years following TP and AIT. To our knowledge, to date this is the first report of the BETA-2 score applicability in the AIT setting.
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7
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Ali KF, San Martin VT, Stevens T, Walsh RM, Bottino R, Trucco M, Hatipoglu B. Autoimmunity in Autologous Islet Transplantation. ACTA ACUST UNITED AC 2018; 2. [PMID: 32095782 PMCID: PMC7039533 DOI: 10.21926/obm.transplant.1803014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
Total pancreatectomy (TP) is increasingly being utilized for definitive treatment in patients with debilitating chronic pancreatitis (CP). In an effort to prevent surgical diabetes, the procedure can be performed in conjunction with transplantation of islets of Langerhans recovered from the patients’ own resected pancreas (autologous islet transplantation, AIT). Given that patients undergoing TP and AIT are traditionally assumed not to be at risk for the development of beta-cell autoimmunity, it is possible that the presence of autoimmune islet graft failure has been overlooked and underreported in this patient population. Herein, we describe two cases who underwent TP and AIT and later developed new-onset beta-cell autoimmunity (as evidenced by de novo glutamic acid decarboxylase antibody positivity), accompanied by complete insulin-dependent states. These cases emphasize the need for considering a possible autoimmune phenomenon in the workup of TP and AIT patients who manifest with unexpected and rapid deterioration in their glycemic control.
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Affiliation(s)
- Khawla F Ali
- Endocrinology and Metabolism Institute, Cleveland Clinic, Cleveland, USA
| | | | - Tyler Stevens
- Digestive Disease Institute, Cleveland Clinic, Cleveland, USA
| | - R Matthew Walsh
- Digestive Disease Institute, Cleveland Clinic, Cleveland, USA
| | - Rita Bottino
- Institute for Cellular Therapeutics, Allegheny-Singer Research Institute, Pittsburgh, PA, USA
| | - Massimo Trucco
- Institute for Cellular Therapeutics, Allegheny-Singer Research Institute, Pittsburgh, PA, USA
| | - Betul Hatipoglu
- Endocrinology and Metabolism Institute, Cleveland Clinic, Cleveland, USA
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8
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Llacua LA, Hoek A, de Haan BJ, de Vos P. Collagen type VI interaction improves human islet survival in immunoisolating microcapsules for treatment of diabetes. Islets 2018; 10:60-68. [PMID: 29521546 PMCID: PMC5895175 DOI: 10.1080/19382014.2017.1420449] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Revised: 12/11/2017] [Accepted: 12/14/2017] [Indexed: 01/12/2023] Open
Abstract
Collagens are the most abundant fibrous protein in the human body and constitute the main structural element of the extracellular matrix. It provides mechanical and physiological support for cells. In the pancreas, collagen VI content is more than double that of collagen I or IV. It is a major component of the islet-exocrine interface and could be involved in islet-cell survival. To test the impact of collagen VI on human encapsulated pancreatic islets-cells, we tested the effects of exogenous collagen type VI on in vitro functional survival of alginate encapsulated human islet-cells. Concentrations tested ranged from 0.1 to 50 µg/ml. Islets in capsules without collagen type VI served as control. Islet-cell interaction with collagen type VI at concentrations of 0.1 and 10 µg/ml, promoted islet-cell viability (p<0.05). Although no improvement in glucose induced insulin secretion (GSIS) was observed, islets in capsules without incorporation of collagen type VI showed more dysfunction and oxygen consumption rates was improved by inclusion of collagen type VI. Our results demonstrate that incorporation of collagen type VI in immunoisolated human islets supports in vitro viability and survival of human pancreatic islets.
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Affiliation(s)
- L. Alberto Llacua
- Section of Immunoendocrinology, Department of Pathology and Medical Biology, University of Groningen, Groningen, The Netherlands
| | - Arjan Hoek
- Section of Immunoendocrinology, Department of Pathology and Medical Biology, University of Groningen, Groningen, The Netherlands
| | - Bart J. de Haan
- Section of Immunoendocrinology, Department of Pathology and Medical Biology, University of Groningen, Groningen, The Netherlands
| | - Paul de Vos
- Section of Immunoendocrinology, Department of Pathology and Medical Biology, University of Groningen, Groningen, The Netherlands
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9
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Li X, Wang Y, Deng S. Meeting report: The first international conference on xenotransplantation in Chengdu, China. Xenotransplantation 2017; 24. [PMID: 29171695 DOI: 10.1111/xen.12376] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Affiliation(s)
- Xiang Li
- School of Medicine; University of Electronic Science and Technology of China; Chengdu Sichuan China
| | - Yi Wang
- Institute of Organ Transplantation; Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital; Chengdu Sichuan China
| | - Shaoping Deng
- Institute of Organ Transplantation; Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital; Chengdu Sichuan China
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10
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Pham-Hua D, Padgett LE, Xue B, Anderson B, Zeiger M, Barra JM, Bethea M, Hunter CS, Kozlovskaya V, Kharlampieva E, Tse HM. Islet encapsulation with polyphenol coatings decreases pro-inflammatory chemokine synthesis and T cell trafficking. Biomaterials 2017; 128:19-32. [PMID: 28285194 DOI: 10.1016/j.biomaterials.2017.03.002] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Revised: 02/28/2017] [Accepted: 03/02/2017] [Indexed: 12/27/2022]
Abstract
Type 1 Diabetes (T1D) is a chronic pro-inflammatory autoimmune disease consisting of islet-infiltrating leukocytes involved in pancreatic β-cell lysis. One promising treatment for T1D is islet transplantation; however, clinical application is constrained due to limited islet availability, adverse effects of immunosuppressants, and declining graft survival. Islet encapsulation may provide an immunoprotective barrier to preserve islet function and prevent immune-mediated rejection after transplantation. We previously demonstrated that a novel cytoprotective nanothin multilayer coating for islet encapsulation consisting of tannic acid (TA), an immunomodulatory antioxidant, and poly(N-vinylpyrrolidone) (PVPON), was efficacious in dampening in vitro immune responses involved in transplant rejection and preserving in vitro islet function. However, the ability of (PVPON/TA) to maintain islet function in vivo and reverse diabetes has not been tested. Recent evidence has demonstrated that modulation of redox status can affect pro-inflammatory immune responses. Therefore, we hypothesized that transplanted (PVPON/TA)-encapsulated islets can restore euglycemia to diabetic mice and provide an immunoprotective barrier. Our results demonstrate that (PVPON/TA) nanothin coatings can significantly decrease in vitro chemokine synthesis and diabetogenic T cell migration. Importantly, (PVPON/TA)-encapsulated islets restored euglycemia after transplantation into diabetic mice. Our results demonstrate that (PVPON/TA)-encapsulated islets may suppress immune responses and enhance islet allograft acceptance in patients with T1D.
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Affiliation(s)
- Dana Pham-Hua
- Science Technology Honors Program, University of Alabama at Birmingham, Birmingham, AL 35294-2182, USA
| | - Lindsey E Padgett
- Department of Microbiology, Comprehensive Diabetes Center, University of Alabama, Birmingham School of Medicine, Birmingham, AL 35294-2182, USA
| | - Bing Xue
- Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL 35294-2182, USA
| | - Brian Anderson
- Department of Microbiology, Comprehensive Diabetes Center, University of Alabama, Birmingham School of Medicine, Birmingham, AL 35294-2182, USA
| | - Michael Zeiger
- Department of Microbiology, Comprehensive Diabetes Center, University of Alabama, Birmingham School of Medicine, Birmingham, AL 35294-2182, USA
| | - Jessie M Barra
- Department of Microbiology, Comprehensive Diabetes Center, University of Alabama, Birmingham School of Medicine, Birmingham, AL 35294-2182, USA
| | - Maigen Bethea
- Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, AL 35294-2182, USA
| | - Chad S Hunter
- Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, AL 35294-2182, USA
| | - Veronika Kozlovskaya
- Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL 35294-2182, USA
| | - Eugenia Kharlampieva
- Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL 35294-2182, USA; Center of Nanoscale Materials and Biointegration, University of Alabama at Birmingham, Birmingham, AL 35294-2182, USA.
| | - Hubert M Tse
- Department of Microbiology, Comprehensive Diabetes Center, University of Alabama, Birmingham School of Medicine, Birmingham, AL 35294-2182, USA.
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11
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Chhasatia R, Sweetman MJ, Harding FJ, Waibel M, Kay T, Thomas H, Loudovaris T, Voelcker NH. Non-invasive, in vitro analysis of islet insulin production enabled by an optical porous silicon biosensor. Biosens Bioelectron 2017; 91:515-522. [PMID: 28082240 DOI: 10.1016/j.bios.2017.01.004] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2016] [Revised: 12/27/2016] [Accepted: 01/03/2017] [Indexed: 12/16/2022]
Abstract
A label-free porous silicon (pSi) based, optical biosensor, using both an antibody and aptamer bioreceptor motif has been developed for the detection of insulin. Two parallel biosensors were designed and optimised independently, based on each bioreceptor. Both bioreceptors were covalently attached to a thermally hydrosilylated pSi surface though amide coupling, with unreacted surface area rendered stable and low fouling by incorporation of PEG moieties. The insulin detection ability of each biosensor was determined using interferometric reflectance spectroscopy, using a range of different media both with and without serum. Sensing performance was compared in terms of response value, response time and limit of detection (LOD) for each platform. In order to demonstrate the capability of the best performing biosensor to detect insulin from real samples, an in vitro investigation with the aptamer-modified surface was performed. This biosensor was exposed to buffer conditioned by glucose-stimulated human islets, with the result showing a positive response and a high degree of selectivity towards insulin capture. The obtained results correlated well with the ELISA used in the clinic for assaying glucose-stimulated insulin release from donor islets. We anticipate that this type of sensor can be applied as a rapid point-of-use biosensor to assess the quality of donor islets in terms of their insulin production efficiency, prior to transplantation.
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Affiliation(s)
- Rinku Chhasatia
- ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Future Industries Institute, University of South Australia, Mawson Lakes, South Australia 5095, Australia
| | - Martin J Sweetman
- Experimental Therapeutics Laboratory, Hanson Institute and Samson Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA 5000, Australia
| | - Frances J Harding
- ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Future Industries Institute, University of South Australia, Mawson Lakes, South Australia 5095, Australia
| | - Michaela Waibel
- St. Vincent's Institute of Medical Research, Victoria 3065, Australia
| | - Tom Kay
- St. Vincent's Institute of Medical Research, Victoria 3065, Australia
| | - Helen Thomas
- St. Vincent's Institute of Medical Research, Victoria 3065, Australia
| | - Thomas Loudovaris
- St. Vincent's Institute of Medical Research, Victoria 3065, Australia
| | - Nicolas H Voelcker
- ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Future Industries Institute, University of South Australia, Mawson Lakes, South Australia 5095, Australia.
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12
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Tajima A, Pradhan I, Trucco M, Fan Y. Restoration of Thymus Function with Bioengineered Thymus Organoids. CURRENT STEM CELL REPORTS 2016; 2:128-139. [PMID: 27529056 PMCID: PMC4982700 DOI: 10.1007/s40778-016-0040-x] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The thymus is the primary site for the generation of a diverse repertoire of T-cells that are essential to the efficient function of adaptive immunity. Numerous factors varying from aging, chemotherapy, radiation exposure, virus infection and inflammation contribute to thymus involution, a phenomenon manifested as loss of thymus cellularity, increased stromal fibrosis and diminished naïve T-cell output. Rejuvenating thymus function is a challenging task since it has limited regenerative capability and we still do not know how to successfully propagate thymic epithelial cells (TECs), the predominant population of the thymic stromal cells making up the thymic microenvironment. Here, we will discuss recent advances in thymus regeneration and the prospects of applying bioengineered artificial thymus organoids in regenerative medicine and solid organ transplantation.
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Affiliation(s)
- Asako Tajima
- Institute of Cellular Therapeutics, Allegheny Health Network, Pittsburgh, PA 15212
| | - Isha Pradhan
- Institute of Cellular Therapeutics, Allegheny Health Network, Pittsburgh, PA 15212
| | - Massimo Trucco
- Institute of Cellular Therapeutics, Allegheny Health Network, Pittsburgh, PA 15212
- Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA 15213
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19104
| | - Yong Fan
- Institute of Cellular Therapeutics, Allegheny Health Network, Pittsburgh, PA 15212
- Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA 15213
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19104
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Co-combination of islets with bone marrow mesenchymal stem cells promotes angiogenesis. Biomed Pharmacother 2016; 78:156-164. [PMID: 26898437 DOI: 10.1016/j.biopha.2016.01.007] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Revised: 12/22/2015] [Accepted: 01/13/2016] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Islet transplantation is a commonly therapeutic strategy for diabetes mellitus. However, avascular phase and the poor formation of blood vessels in the late period lead to islet allograft loss which contributed to inefficiency and short-acting of islet transplantation. Recently, to speed up new angiogenesis and increase the density of blood vessels around transplanted islets became the hotspot in research of islet transplantation. METHODS In this study, we undergone co-combination transplantation of allogeneic islet and bone marrow mesenchymal stem cells (BM-MSCs) into non-obese diabetic (NOD) mice and investigated the influence of BM-MSCs in transplanted islet function and neovascularization. RESULTS In mice of co-combination transplantation of islet with BM-MSCs, level of blood glucose was improved compared with only BM-MSCs transplanted mice; proliferation of islet cell was enhanced while apoptosis of islet cell was reduced; 2, 4, and 8 weeks post transplantation, peripheral vascular density of islet grafts were significantly more than the islet transplantation group alone; donor lymphocytic chimerism in graft was increased. In result of immunofluorescence analysis, we observed that BM-MSCs can migrate to transplanted islet, differentiate into vascular smooth muscle cells (VSMC) and vascular endothelial cells (VEC), and also secrete vascular endothelial growth factor (VEGF). CONCLUSION BM-MSCs can migrate to transplanted islet and promote neovascularization. Also, it enhanced allograft immune tolerance of islet grafts via increasing donor lymphocytic chimerism.
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Bottino R, Trucco M. Use of genetically-engineered pig donors in islet transplantation. World J Transplant 2015; 5:243-250. [PMID: 26722651 PMCID: PMC4689934 DOI: 10.5500/wjt.v5.i4.243] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2015] [Revised: 10/23/2015] [Accepted: 11/25/2015] [Indexed: 02/05/2023] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disease wherein the pancreas does not produce enough insulin due to islet beta cell destruction. Despite improvements in delivering exogenous insulin to T1D patients, pancreas or islet transplantation remains the best way to regulate their glycaemia. Results from experimental islet transplantation have improved dramatically in the last 15 years, to the point where it can be comparable to pancreas transplantation, but without the accompanying morbidity associated with this procedure. As with other transplants, the limiting factor in islet allotransplantation is the relatively small number of organs made available by deceased human donors throughout the world. A strong case can be made for islet xenotransplantation to fill the gap between supply and demand; however, transplantation across species presents challenges that are unique to that setting. In the search for the most suitable animal for human xenotransplantation, the pig has many advantages that make it the likely animal of choice. Potentially one of the most beneficial advantages is the ability to genetically engineer porcine donors to be more compatible with human recipients. Several genetic manipulations have already proven useful in relation to hyperacute rejection and inflammation (instant blood mediated inflammatory reaction), with the potential of even further advancement in the near future.
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