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Juang JH, Chen CL, Kao CW, Wu ST, Shen CR. In Vivo Imaging of Immune Rejection of MIN6 Cells Transplanted in C3H Mice. Cells 2024; 13:1044. [PMID: 38920672 PMCID: PMC11201743 DOI: 10.3390/cells13121044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 06/06/2024] [Accepted: 06/12/2024] [Indexed: 06/27/2024] Open
Abstract
Recently, we successfully utilized noninvasive magnetic resonance and bioluminescence imaging to track MIN6 cells subcutaneously transplanted in immunocompromised nude mice for up to 64 days. In this study, we further used bioluminescence imaging to investigate the immune rejection of MIN6 cells in immunocompetent C3H mice. A total of 5 × 106 luciferase-transfected MIN6 cells were implanted into the subcutaneous space of each nude or C3H mouse. After transplantation, hypoglycemia and persistent bioluminescence signals were observed in eight of eight (100%) nude mice and five of nine (56%) C3H mice (p < 0.05). We then presensitized a group of C3H mice with C57BL/6 spleen cells just prior to transplantation (n = 14). Interestingly, none of them had hypoglycemia or persistent bioluminescence signals (p < 0.01 vs. C3H mice without presensitization). Histological examination of the grafts revealed a lack or minimal presence of insulin-positive cells in recipients without hypoglycemia and persistent bioluminescence signals. In contrast, recipients with hypoglycemia and persistent bioluminescence signals showed a significant presence of insulin-positive cells in their grafts. Our results indicate that rejection of MIN6 cells occurred in C3H mice and could be enhanced by presensitization with C57BL/6 spleen cells and that bioluminescence imaging is a useful noninvasive tool for detecting rejection of subcutaneously transplanted MIN6 cells.
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Affiliation(s)
- Jyuhn-Huarng Juang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Center for Tissue Engineering, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan; (C.-L.C.); (C.-W.K.)
| | - Chen-Ling Chen
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Center for Tissue Engineering, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan; (C.-L.C.); (C.-W.K.)
| | - Chen-Wei Kao
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Center for Tissue Engineering, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan; (C.-L.C.); (C.-W.K.)
| | - Shu-Ting Wu
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan;
| | - Chia-Rui Shen
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan;
- Department of Ophthalmology, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
- R&D Center of Biochemical Engineering Technology, Department of Chemical Engineering, Ming Chi University of Technology, New Taipei 24301, Taiwan
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Mizui T, Inagaki A, Nakamura Y, Imura T, Uematsu SS, Miyagi S, Kamei T, Unno M, Watanabe K, Goto M. A Recombinant Peptide Device Combined with Adipose Tissue-Derived Stem Cells Enhances Subcutaneous Islet Engraftment. Cells 2024; 13:499. [PMID: 38534342 PMCID: PMC10968997 DOI: 10.3390/cells13060499] [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: 01/05/2024] [Revised: 02/28/2024] [Accepted: 03/10/2024] [Indexed: 03/28/2024] Open
Abstract
Subcutaneous space has been considered an attractive site for islet graft transplantation; however, the oxygen tension and vascularization are insufficient for islet graft survival. We investigated whether subcutaneous pre-implantation of a recombinant peptide (RCP) device with adipose tissue-derived stem cells (ADSCs) enhanced subcutaneous islet engraftment. RCP devices with/without syngeneic ADSCs were pre-implanted into the subcutaneous space of C57BL/6 mice. Syngeneic islets (300 or 120 islet equivalents (IEQs)) were transplanted into the pre-treated space after diabetes induction using streptozotocin. The cure rates of groups in which RCP devices were implanted four weeks before transplantation were significantly better than the intraportal transplantation group when 300 IEQs of islets were transplanted (p < 0.01). The blood glucose changes in the RCP+ADSCs-4w group was significantly ameliorated in comparison to the RCP-4w group when 120 IEQs of islets were transplanted (p < 0.01). Immunohistochemical analyses showed the collagen III expression in the islet capsule of the RCP+ADSCs-4w group was significantly enhanced in comparison to the RCP-4w and RCP+ADSCs-d10 groups (p < 0.01, p < 0.01). In addition, the number of von Willebrand factor-positive vessels within islets in the RCP+ADSCs-4w group was significantly higher than the RCP-4w group. These results suggest that using ADSCs in combination with an RCP device could enhance the restoration of the extracellular matrices, induce more efficient prevascularization within islets, and improve the graft function.
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Affiliation(s)
- Takahiro Mizui
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai 980-0872, Japan; (T.M.); (S.S.U.); (S.M.); (T.K.); (M.U.)
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, Tokyo 104-0045, Japan
| | - Akiko Inagaki
- Division of Transplantation and Regenerative Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan; (A.I.); (T.I.); (K.W.)
| | - Yasuhiro Nakamura
- Division of Pathology, Graduate School of Medicine, Tohoku Medical and Pharmaceutical University, Sendai 983-8536, Japan;
| | - Takehiro Imura
- Division of Transplantation and Regenerative Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan; (A.I.); (T.I.); (K.W.)
| | - Satomi Suzuki Uematsu
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai 980-0872, Japan; (T.M.); (S.S.U.); (S.M.); (T.K.); (M.U.)
| | - Shigehito Miyagi
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai 980-0872, Japan; (T.M.); (S.S.U.); (S.M.); (T.K.); (M.U.)
| | - Takashi Kamei
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai 980-0872, Japan; (T.M.); (S.S.U.); (S.M.); (T.K.); (M.U.)
| | - Michiaki Unno
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai 980-0872, Japan; (T.M.); (S.S.U.); (S.M.); (T.K.); (M.U.)
| | - Kimiko Watanabe
- Division of Transplantation and Regenerative Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan; (A.I.); (T.I.); (K.W.)
| | - Masafumi Goto
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai 980-0872, Japan; (T.M.); (S.S.U.); (S.M.); (T.K.); (M.U.)
- Division of Transplantation and Regenerative Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan; (A.I.); (T.I.); (K.W.)
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3
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Hu X, White K, Olroyd AG, DeJesus R, Dominguez AA, Dowdle WE, Friera AM, Young C, Wells F, Chu EY, Ito CE, Krishnapura H, Jain S, Ankala R, McGill TJ, Lin A, Egenberger K, Gagnon A, Michael Rukstalis J, Hogrebe NJ, Gattis C, Basco R, Millman JR, Kievit P, Davis MM, Lanier LL, Connolly AJ, Deuse T, Schrepfer S. Hypoimmune induced pluripotent stem cells survive long term in fully immunocompetent, allogeneic rhesus macaques. Nat Biotechnol 2024; 42:413-423. [PMID: 37156915 PMCID: PMC10940156 DOI: 10.1038/s41587-023-01784-x] [Citation(s) in RCA: 59] [Impact Index Per Article: 59.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 04/06/2023] [Indexed: 05/10/2023]
Abstract
Genetic engineering of allogeneic cell therapeutics that fully prevents rejection by a recipient's immune system would abolish the requirement for immunosuppressive drugs or encapsulation and support large-scale manufacturing of off-the-shelf cell products. Previously, we generated mouse and human hypoimmune pluripotent (HIP) stem cells by depleting HLA class I and II molecules and overexpressing CD47 (B2M-/-CIITA-/-CD47+). To determine whether this strategy is successful in non-human primates, we engineered rhesus macaque HIP cells and transplanted them intramuscularly into four allogeneic rhesus macaques. The HIP cells survived unrestricted for 16 weeks in fully immunocompetent allogeneic recipients and differentiated into several lineages, whereas allogeneic wild-type cells were vigorously rejected. We also differentiated human HIP cells into endocrinologically active pancreatic islet cells and showed that they survived in immunocompetent, allogeneic diabetic humanized mice for 4 weeks and ameliorated diabetes. HIP-edited primary rhesus macaque islets survived for 40 weeks in an allogeneic rhesus macaque recipient without immunosuppression, whereas unedited islets were quickly rejected.
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Affiliation(s)
- Xiaomeng Hu
- Sana Biotechnology, Inc., South San Francisco, CA, USA
| | - Kathy White
- Sana Biotechnology, Inc., South San Francisco, CA, USA
| | - Ari G Olroyd
- Sana Biotechnology, Inc., South San Francisco, CA, USA
| | | | | | | | | | - Chi Young
- Sana Biotechnology, Inc., South San Francisco, CA, USA
| | - Frank Wells
- Sana Biotechnology, Inc., South San Francisco, CA, USA
| | - Elaine Y Chu
- Sana Biotechnology, Inc., South San Francisco, CA, USA
| | | | | | - Surbhi Jain
- Sana Biotechnology, Inc., South San Francisco, CA, USA
| | - Ramya Ankala
- Sana Biotechnology, Inc., South San Francisco, CA, USA
| | | | - August Lin
- Sana Biotechnology, Inc., South San Francisco, CA, USA
| | | | | | | | - Nathaniel J Hogrebe
- Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, MO, USA
| | - Corie Gattis
- Sana Biotechnology, Inc., South San Francisco, CA, USA
| | - Ron Basco
- Sana Biotechnology, Inc., South San Francisco, CA, USA
| | | | - Paul Kievit
- Division of Cardiometabolic Health, Oregon National Primate Research Center, Beaverton, OR, USA
| | - Mark M Davis
- Howard Hughes Medical Institute, Institute for Immunity, Transplantation and Infection, and Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
| | - Lewis L Lanier
- Department of Microbiology and Immunology and the Parker Institute for Cancer Immunotherapy, University of California, San Francisco, San Francisco, CA, USA
| | - Andrew J Connolly
- Department of Pathology, University of California, San Francisco, San Francisco, CA, USA
| | - Tobias Deuse
- Transplant and Stem Cell Immunobiology (TSI) Lab, Department of Surgery, Division of Cardiothoracic Surgery, University of California, San Francisco, San Francisco, CA, USA
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Sethia N, Rao JS, Khashim Z, Schornack AMR, Etheridge ML, Peterson QP, Finger EB, Bischof JC, Dutcher CS. On Chip Sorting of Stem Cell-Derived β Cell Clusters Using Traveling Surface Acoustic Waves. LANGMUIR : THE ACS JOURNAL OF SURFACES AND COLLOIDS 2024; 40:3453-3462. [PMID: 38318799 PMCID: PMC10883307 DOI: 10.1021/acs.langmuir.3c02934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 12/05/2023] [Accepted: 01/04/2024] [Indexed: 02/07/2024]
Abstract
There is a critical need for sorting complex materials, such as pancreatic islets of Langerhans, exocrine acinar tissues, and embryoid bodies. These materials are cell clusters, which have highly heterogeneous physical properties (such as size, shape, morphology, and deformability). Selecting such materials on the basis of specific properties can improve clinical outcomes and help advance biomedical research. In this work, we focused on sorting one such complex material, human stem cell-derived β cell clusters (SC-β cell clusters), by size. For this purpose, we developed a microfluidic device in which an image detection system was coupled to an actuation mechanism based on traveling surface acoustic waves (TSAWs). SC-β cell clusters of varying size (∼100-500 μm in diameter) were passed through the sorting device. Inside the device, the size of each cluster was estimated from their bright-field images. After size identification, larger clusters, relative to the cutoff size for separation, were selectively actuated using TSAW pulses. As a result of this selective actuation, smaller and larger clusters exited the device from different outlets. At the current sample dilutions, the experimental sorting efficiency ranged between 78% and 90% for a separation cutoff size of 250 μm, yielding sorting throughputs of up to 0.2 SC-β cell clusters/s using our proof-of-concept design. The biocompatibility of this sorting technique was also established, as no difference in SC-β cell cluster viability due to TSAW pulse usage was found. We conclude the proof-of-concept sorting work by discussing a few ways to optimize sorting of SC-β cell clusters for potentially higher sorting efficiency and throughput. This sorting technique can potentially help in achieving a better distribution of islets for clinical islet transplantation (a potential cure for type 1 diabetes). Additionally, the use of this technique for sorting islets can help in characterizing islet biophysical properties by size and selecting suitable islets for improved islet cryopreservation.
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Affiliation(s)
- Nikhil Sethia
- Department
of Chemical Engineering and Materials Science, University of Minnesota, Minneapolis, Minnesota 55455, United States
| | - Joseph Sushil Rao
- Division
of Solid Organ Transplantation, Department of Surgery, University of Minnesota, Minneapolis, Minnesota 55455, United States
- Schulze
Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, Minnesota 55455, United States
| | - Zenith Khashim
- Department
of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota 55905, United States
| | - Anna Marie R. Schornack
- Department
of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota 55905, United States
| | - Michael L. Etheridge
- Department
of Mechanical Engineering, University of
Minnesota, Minneapolis, Minnesota 55455, United States
| | - Quinn P. Peterson
- Department
of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota 55905, United States
- Center for
Regenerative Biotherapeutics, Mayo Clinic, Rochester, Minnesota 55905, United States
| | - Erik B. Finger
- Division
of Solid Organ Transplantation, Department of Surgery, University of Minnesota, Minneapolis, Minnesota 55455, United States
| | - John C. Bischof
- Department
of Mechanical Engineering, University of
Minnesota, Minneapolis, Minnesota 55455, United States
- Department
of Biomedical Engineering, University of
Minnesota, Minneapolis, Minnesota 55455, United States
| | - Cari S. Dutcher
- Department
of Chemical Engineering and Materials Science, University of Minnesota, Minneapolis, Minnesota 55455, United States
- Department
of Mechanical Engineering, University of
Minnesota, Minneapolis, Minnesota 55455, United States
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5
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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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Saito R, Inagaki A, Nakamura Y, Imura T, Kanai N, Mitsugashira H, Endo Kumata Y, Katano T, Suzuki S, Tokodai K, Kamei T, Unno M, Watanabe K, Tabata Y, Goto M. A Gelatin Hydrogel Nonwoven Fabric Enhances Subcutaneous Islet Engraftment in Rats. Cells 2023; 13:51. [PMID: 38201255 PMCID: PMC10777905 DOI: 10.3390/cells13010051] [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: 11/26/2023] [Revised: 12/15/2023] [Accepted: 12/20/2023] [Indexed: 01/12/2024] Open
Abstract
Although subcutaneous islet transplantation has many advantages, the subcutaneous space is poor in vessels and transplant efficiency is still low in animal models, except in mice. Subcutaneous islet transplantation using a two-step approach has been proposed, in which a favorable cavity is first prepared using various materials, followed by islet transplantation into the preformed cavity. We previously reported the efficacy of pretreatment using gelatin hydrogel nonwoven fabric (GHNF), and the length of the pretreatment period influenced the results in a mouse model. We investigated whether the preimplantation of GHNF could improve the subcutaneous islet transplantation outcomes in a rat model. GHNF sheets sandwiching a silicone spacer (GHNF group) and silicone spacers without GHNF sheets (control group) were implanted into the subcutaneous space of recipients three weeks before islet transplantation, and diabetes was induced seven days before islet transplantation. Syngeneic islets were transplanted into the space where the silicone spacer was removed. Blood glucose levels, glucose tolerance, immunohistochemistry, and neovascularization were evaluated. The GHNF group showed significantly better blood glucose changes than the control group (p < 0.01). The cure rate was significantly higher in the GHNF group (p < 0.05). The number of vWF-positive vessels was significantly higher in the GHNF group (p < 0.01), and lectin angiography showed the same tendency (p < 0.05). The expression of laminin and collagen III around the transplanted islets was also higher in the GHNF group (p < 0.01). GHNF pretreatment was effective in a rat model, and the main mechanisms might be neovascularization and compensation of the extracellular matrices.
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Affiliation(s)
- Ryusuke Saito
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai 980-0872, Japan; (R.S.)
| | - Akiko Inagaki
- Division of Transplantation and Regenerative Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan
| | - Yasuhiro Nakamura
- Division of Pathology, Graduate School of Medicine, Tohoku Medical and Pharmaceutical University, Sendai 983-8536, Japan
| | - Takehiro Imura
- Division of Transplantation and Regenerative Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan
| | - Norifumi Kanai
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai 980-0872, Japan; (R.S.)
| | - Hiroaki Mitsugashira
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai 980-0872, Japan; (R.S.)
| | - Yukiko Endo Kumata
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai 980-0872, Japan; (R.S.)
| | - Takumi Katano
- Division of Transplantation and Regenerative Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan
| | - Shoki Suzuki
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai 980-0872, Japan; (R.S.)
| | - Kazuaki Tokodai
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai 980-0872, Japan; (R.S.)
| | - Takashi Kamei
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai 980-0872, Japan; (R.S.)
| | - Michiaki Unno
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai 980-0872, Japan; (R.S.)
| | - Kimiko Watanabe
- Division of Transplantation and Regenerative Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan
| | - Yasuhiko Tabata
- Laboratory of Biomaterials, Department of Regeneration Science and Engineering, Institute for Life and Medical Sciences (LiMe), Kyoto University, Kyoto 606-8507, Japan
| | - Masafumi Goto
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai 980-0872, Japan; (R.S.)
- Division of Transplantation and Regenerative Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan
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7
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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.
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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
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8
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Juang JH, Chen CL, Kao CW, Chen CY, Shen CR, Wang JJ, Tsai ZT, Chu IM. The Image-Histology Correlation of Subcutaneous mPEG-poly(Ala) Hydrogel-Embedded MIN6 Cell Grafts in Nude Mice. Polymers (Basel) 2023; 15:2584. [PMID: 37376231 DOI: 10.3390/polym15122584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 05/27/2023] [Accepted: 06/03/2023] [Indexed: 06/29/2023] Open
Abstract
Previously, we have successfully used noninvasive magnetic resonance (MR) and bioluminescence imaging to detect and monitor mPEG-poly(Ala) hydrogel-embedded MIN6 cells at the subcutaneous space for up to 64 days. In this study, we further explored the histological evolution of MIN6 cell grafts and correlated it with image findings. MIN6 cells were incubated overnight with chitosan-coated superparamagnetic iron oxide (CSPIO) and then 5 × 106 cells in the 100 μL hydrogel solution were injected subcutaneously into each nude mouse. Grafts were removed and examined the vascularization, cell growth and proliferation with anti-CD31, SMA, insulin and ki67 antibodies, respectively, at 8, 14, 21, 29 and 36 days after transplantation. All grafts were well-vascularized with prominent CD31 and SMA staining at all time points. Interestingly, insulin-positive cells and iron-positive cells were scattered in the graft at 8 and 14 days; while clusters of insulin-positive cells without iron-positive cells appeared in the grafts at 21 days and persisted thereafter, indicating neogrowth of MIN6 cells. Moreover, proliferating MIN6 cells with strong ki67 staining was observed in 21-, 29- and 36-day grafts. Our results indicate that the originally transplanted MIN6 cells proliferated from 21 days that presented distinctive bioluminescence and MR images.
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Affiliation(s)
- Jyuhn-Huarng Juang
- Division of Endocrinology and Metabolism, Department of Internal Medicine and Center for Tissue Engineering, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
- Department of Medicine, College of Medicine, Chang Gung University, Taoyuan 33305, Taiwan
| | - Chen-Ling Chen
- Division of Endocrinology and Metabolism, Department of Internal Medicine and Center for Tissue Engineering, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Chen-Wei Kao
- Division of Endocrinology and Metabolism, Department of Internal Medicine and Center for Tissue Engineering, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Chen-Yi Chen
- Division of Endocrinology and Metabolism, Department of Internal Medicine and Center for Tissue Engineering, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Chia-Rui Shen
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33305, Taiwan
- Department of Ophthalmology, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Jiun-Jie Wang
- Department of Medical Imaging and Radiological Sciences, College of Medicine, Chang Gung University, Taoyuan 33305, Taiwan
- Department of Diagnostic Radiology, Chang Gung Memorial Hospital, Keelung 20401, Taiwan
| | - Zei-Tsan Tsai
- Molecular Imaging Center, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - I-Ming Chu
- Department of Chemical Engineering, National Tsing Hua University, Hsinchu 300044, Taiwan
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9
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Madhusudhan KS, Sharma S, Srivastava DN. Percutaneous radiological interventions of the portal vein: a comprehensive review. Acta Radiol 2023; 64:441-455. [PMID: 35187977 DOI: 10.1177/02841851221080554] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The portal vein is the largest vessel supplying the liver. A number of radiological interventions are performed through the portal vein, namely for primary pathologies of the portal vein, for inducing liver hypertrophy or to treat the sequelae of portal hypertension among others. The routes used include direct transhepatic, transjugular, and, uncommonly, trans-splenic and through subcutaneous varices. Portal vein embolization and transjugular intrahepatic portosystemic shunt are among the most common portal vein interventions that are performed to induce hypertrophy of the future liver remnant and to treat complications of portal hypertension, respectively. Other interventions include transhepatic obliteration of varices and shunts, portal vein thrombolysis, portal vein recanalization, pancreatic islet cell transplantation, and embolization of portal vein injuries. We present a detailed illustrative review of the various radiological portal vein interventions.
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Affiliation(s)
- Kumble Seetharama Madhusudhan
- Department of Radiodiagnosis and Interventional Radiology, 28730All India Institute of Medical Sciences, New Delhi, India
| | - Sanjay Sharma
- Department of Radiodiagnosis and Interventional Radiology, 28730All India Institute of Medical Sciences, New Delhi, India
| | - Deep Narayan Srivastava
- Department of Radiodiagnosis and Interventional Radiology, 28730All India Institute of Medical Sciences, New Delhi, India
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10
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Naqvi RA, Naqvi A. Co-transplantation with mesenchymal stem cells and endothelial cells improvise islet engraftment and survival in STZ treated hyperglycemic mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.24.525444. [PMID: 36747732 PMCID: PMC9900768 DOI: 10.1101/2023.01.24.525444] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Though intra-portal islet transplantation demonstrated as best suited strategy for the reversal of hyperglycemia without the threat of iatrogenic hyperglycemia in type 1 diabetes (T1D) in patients, the inferior quality of post-transplantation (tx) vascularization needs to be addressed for the maximization of post-tx islet survival. Therefore, in this study, we have first generated MSCs and endothelial progenitor cells (EPC) from mice bone marrow by in house optimized protocol and then 3-D co-cultured them with mice islets. Secretion of in the culture supernatant suggested the pro-angiogenic nature of 3D cultured mice islets. After 5 days post-tx of these pro-angiogenic islets in the omental pouch of syngeneic mice led to: 1) restoration of normoglycemia, 2) secretion of mouse C-peptide and 3) induction of angiogenic factors after 3 days of post-tx. The induction of angiogenic factors was done by RT-qPCR of omental biopsies. Importantly, pro-angiogenic islet recipient mice also demonstrated the clearance of glucose within 75 min, reflecting their efficient function and engraftment. Our results highlights needs of 3-D co-culture islets for superior quality post-tx islet vasculature and better engraftment â€" crux to improvise the challenges associated with post-tx islet vascularization and functions.
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11
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Saito R, Inagaki A, Nakamura Y, Imura T, Kanai N, Mitsugashira H, Endo Y, Katano T, Suzuki S, Tokodai K, Kamei T, Unno M, Watanabe K, Tabata Y, Goto M. Ideal Duration of Pretreatment Using a Gelatin Hydrogel Nonwoven Fabric Prior to Subcutaneous Islet Transplantation. Cell Transplant 2023; 32:9636897231186063. [PMID: 37466120 PMCID: PMC10363859 DOI: 10.1177/09636897231186063] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Revised: 04/05/2023] [Accepted: 06/19/2023] [Indexed: 07/20/2023] Open
Abstract
Subcutaneous islet transplantation is a promising treatment for severe diabetes; however, poor engraftment hinders its prevalence. We previously revealed that a gelatin hydrogel nonwoven fabric (GHNF) markedly improved subcutaneous islet engraftment in comparison with intraportal islet transplantation. We herein investigated whether the duration of pretreatment using GHNF affected the outcome of subcutaneous islet transplantation. A silicone spacer with GHNF was implanted into the subcutaneous space of healthy mice at 2, 4, 6, or 8 weeks before transplantation, and then diabetes was induced 7 days before transplantation. Syngeneic islets were transplanted into the pretreated space. Blood glucose, intraperitoneal glucose tolerance, immunohistochemistry, inflammatory mediators, and gene expression were evaluated. The 6-week group showed significantly better blood glucose changes than the other groups (P < 0.05). The cure rate of the 6-week group (60.0%) was the highest among the groups (2-week = 0%, 4-week = 50.0%, 8-week = 15.4%). The number of von Willebrand factor (vWF)-positive vessels in the 6-week group was significantly higher than in the other groups at pre-islet and post-islet transplantation (P < 0.01 [vs 2-and 4-week groups] and P < 0.05 [vs all other groups], respectively). Notably, this beneficial effect was also observed when GHNF was implanted into diabetic mice injected with streptozotocin 7 days before GHNF implantation. The positive rates for laminin, collagen III, and collagen IV increased as the duration of pretreatment became longer and were significantly higher in the 8-week group (P < 0.01). Inflammatory mediators, including interleukin (IL)-1b, granulocyte colony-stimulating factor (G-CSF), and interferon (IFN)-γ, were gradually downregulated according to the duration of GHNF pretreatment and re-elevated in the 8-week group. Taken together, the duration of GHNF pretreatment apparently had an impact on the outcomes of subcutaneous islet transplantation, and 6 weeks appeared to be the ideal duration. Islet graft revascularization, extracellular matrix compensation of the islet capsule, and the inflammatory status at the subcutaneous space would be crucial factors for successful subcutaneous islet transplantation.
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Affiliation(s)
- Ryusuke Saito
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Akiko Inagaki
- Division of Transplantation and Regenerative Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yasuhiro Nakamura
- Division of Pathology, Graduate School of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Takehiro Imura
- Division of Transplantation and Regenerative Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Norifumi Kanai
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hiroaki Mitsugashira
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yukiko Endo
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takumi Katano
- Division of Transplantation and Regenerative Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Shoki Suzuki
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kazuaki Tokodai
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takashi Kamei
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Michiaki Unno
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kimiko Watanabe
- Division of Transplantation and Regenerative Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yasuhiko Tabata
- Laboratory of Biomaterials, Department of Regeneration Science and Engineering, Institute for Life and Medical Sciences (LiMe), Kyoto University, Kyoto, Japan
| | - Masafumi Goto
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
- Division of Transplantation and Regenerative Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
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12
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Co-transplantation of pancreatic islets and microvascular fragments effectively restores normoglycemia in diabetic mice. NPJ Regen Med 2022; 7:67. [PMCID: PMC9636251 DOI: 10.1038/s41536-022-00262-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 10/12/2022] [Indexed: 11/06/2022] Open
Abstract
AbstractInsufficient revascularization of pancreatic islets is one of the major obstacles impairing the success of islet transplantation. To overcome this problem, we introduce in the present study a straightforward strategy to accelerate the engraftment of isolated islets. For this purpose, we co-transplanted 250 islets and 20,000 adipose tissue-derived microvascular fragments (MVF) from donor mice under the kidney capsule as well as 500 or 1000 islets with 40,000 MVF into the subcutaneous space of diabetic mice. We found that the co-transplantation of islets and MVF markedly accelerates the restoration of normoglycemia in diabetic recipients compared with the transplantation of islets alone. In fact, the transplantation of 250 islets with 20,000 MVF under the kidney capsule reversed diabetes in 88% of mice and the subcutaneous transplantation of 500 or 1000 islets with 40,000 MVF restored normoglycemia in 100% of mice. Moreover, diabetic mice receiving islets and MVF exhibited plasma insulin levels similar to nondiabetic control animals. Additional immunohistochemical analyses of the grafts revealed a significantly higher number of islet cells and microvessels in the co-transplantation groups. These findings demonstrate that the co-transplantation of islets and MVF is a promising strategy to improve the success rates of islet transplantation, which could be easily implemented into future clinical practice.
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13
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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.
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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.
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14
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Development of a novel method for measuring tissue oxygen pressure to improve the hypoxic condition in subcutaneous islet transplantation. Sci Rep 2022; 12:14731. [PMID: 36042259 PMCID: PMC9427780 DOI: 10.1038/s41598-022-19189-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 08/25/2022] [Indexed: 11/08/2022] Open
Abstract
Subcutaneous tissue is a promising site for islet transplantation, but poor engraftment, due to hypoxia and low vascularity, hinders its prevalence. However, oxygen partial pressure (pO2) of the subcutaneous space (SC) and other sites were reported to be equivalent in several previous reports. This contradiction may be based on accidental puncture to the indwelling micro-vessels in target tissues. We therefore developed a novel optical sensor system, instead of a conventional Clark-type needle probe, for measuring tissue pO2 and found that pO2 of the SC was extremely low in comparison to other sites. To verify the utility of this method, we transplanted syngeneic rat islets subcutaneously into diabetic recipients under several oxygenation conditions using an oxygen delivery device, then performed pO2 measurement, glucose tolerance, and immunohistochemistry. The optical sensor system was validated by correlating the pO2 values with the transplanted islet function. Interestingly, this novel technique revealed that islet viability estimated by ATP/DNA assay reduced to less than 75% by hypoxic condition at the SC, indicating that islet engraftment may substantially improve if the pO2 levels reach those of the renal subcapsular space. Further refinements for a hypoxic condition using the present technique may contribute to improving the efficiency of subcutaneous islet transplantation.
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15
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Zhou Q, Li T, Wang K, Zhang Q, Geng Z, Deng S, Cheng C, Wang Y. Current status of xenotransplantation research and the strategies for preventing xenograft rejection. Front Immunol 2022; 13:928173. [PMID: 35967435 PMCID: PMC9367636 DOI: 10.3389/fimmu.2022.928173] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 07/07/2022] [Indexed: 12/13/2022] Open
Abstract
Transplantation is often the last resort for end-stage organ failures, e.g., kidney, liver, heart, lung, and pancreas. The shortage of donor organs is the main limiting factor for successful transplantation in humans. Except living donations, other alternatives are needed, e.g., xenotransplantation of pig organs. However, immune rejection remains the major challenge to overcome in xenotransplantation. There are three different xenogeneic types of rejections, based on the responses and mechanisms involved. It includes hyperacute rejection (HAR), delayed xenograft rejection (DXR) and chronic rejection. DXR, sometimes involves acute humoral xenograft rejection (AHR) and cellular xenograft rejection (CXR), which cannot be strictly distinguished from each other in pathological process. In this review, we comprehensively discussed the mechanism of these immunological rejections and summarized the strategies for preventing them, such as generation of gene knock out donors by different genome editing tools and the use of immunosuppressive regimens. We also addressed organ-specific barriers and challenges needed to pave the way for clinical xenotransplantation. Taken together, this information will benefit the current immunological research in the field of xenotransplantation.
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Affiliation(s)
- Qiao Zhou
- Department of Rheumatology and Immunology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Ting Li
- Department of Rheumatology, Wenjiang District People’s Hospital, Chengdu, China
| | - Kaiwen Wang
- School of Medicine, Faculty of Medicine and Health, The University of Leeds, Leeds, United Kingdom
| | - Qi Zhang
- School of Medicine, University of Electronics and Technology of China, Chengdu, China
| | - Zhuowen Geng
- School of Medicine, Faculty of Medicine and Health, The University of Leeds, Leeds, United Kingdom
| | - Shaoping Deng
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
- Institute of Organ Transplantation, Sichuan Academy of Medical Science and Sichuan Provincial People’s Hospital, Chengdu, China
| | - Chunming Cheng
- Department of Radiation Oncology, James Comprehensive Cancer Center and College of Medicine at The Ohio State University, Columbus, OH, United States
- *Correspondence: Chunming Cheng, ; Yi Wang,
| | - Yi Wang
- Department of Critical Care Medicine, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Chengdu, China
- *Correspondence: Chunming Cheng, ; Yi Wang,
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16
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Shi Y, Zhao YZ, Jiang Z, Wang Z, Wang Q, Kou L, Yao Q. Immune-Protective Formulations and Process Strategies for Improved Survival and Function of Transplanted Islets. Front Immunol 2022; 13:923241. [PMID: 35903090 PMCID: PMC9315421 DOI: 10.3389/fimmu.2022.923241] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 06/13/2022] [Indexed: 11/25/2022] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disease caused by the immune system attacking and destroying insulin-producing β cells in the pancreas. Islet transplantation is becoming one of the most promising therapies for T1D patients. However, its clinical use is limited by substantial cell loss after islet infusion, closely related to immune reactions, including instant blood-mediated inflammatory responses, oxidative stress, and direct autoimmune attack. Especially the grafted islets are not only exposed to allogeneic immune rejection after transplantation but are also subjected to an autoimmune process that caused the original disease. Due to the development and convergence of expertise in biomaterials, nanotechnology, and immunology, protective strategies are being investigated to address this issue, including exploring novel immune protective agents, encapsulating islets with biomaterials, and searching for alternative implantation sites, or co-transplantation with functional cells. These methods have significantly increased the survival rate and function of the transplanted islets. However, most studies are still limited to animal experiments and need further studies. In this review, we introduced the immunological challenges for islet graft and summarized the recent developments in immune-protective strategies to improve the outcomes of islet transplantation.
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Affiliation(s)
- Yannan Shi
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Ying-Zheng Zhao
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Zhikai Jiang
- The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zeqing Wang
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Qian Wang
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Longfa Kou
- The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- *Correspondence: Qing Yao, ; Longfa Kou,
| | - Qing Yao
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
- *Correspondence: Qing Yao, ; Longfa Kou,
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17
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Zhang M, Du H, Guan Y, Liu J, Wang S, Li H, Zhang W, Han H, Zhang M, Chen L. Study on the Effect of PDA-PLGA Scaffold Loaded With Islet Cells for Skeletal Muscle Transplantation in the Treatment of Diabetes. Front Bioeng Biotechnol 2022; 10:927348. [PMID: 35845408 PMCID: PMC9280155 DOI: 10.3389/fbioe.2022.927348] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Accepted: 06/10/2022] [Indexed: 11/13/2022] Open
Abstract
At present, islet cells transplantation was limited by the way in which islet cells are implanted into the body, their ability to adapt to the microenvironment and the maintenance time for relieving diabetic symptoms. In order to solve this problem, we made PDA-PLGA scaffold loaded with islet cells and used it for skeletal muscle transplantation to investigate its therapeutic effect in the treatment of diabetes. The PLGA scaffold was prepared by the electrospinning method, and modified by polydopamine coating. A rat diabetic model was established to evaluate the efficacy of PDA-PLGA scaffold loaded with RINm5f islet cells through skeletal muscle transplantation. The results showed that the PDA-PLGA scaffold has good biosafety performance. At the same time, transplantation of the stent to the skeletal muscle site had little effect on the serum biochemical indicators of rats, which was conducive to angiogenesis. The PDA-PLGA scaffold had no effect on the secretory function of pancreatic islet cells. The PDA-PLGA scaffold carrying RINm5f cells was transplanted into the skeletal muscle of type I diabetic rats. 1 week after the transplantation of the PDA-PLGA cell scaffold complex, the blood glucose of the treatment group was significantly lower than that of the model group (p < 0.001) and lasted for approximately 3 weeks, which further indicated the skeletal muscle transplantation site was a new choice for islet cell transplantation in the future.
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Affiliation(s)
- Meishuang Zhang
- Department of Pharmacology, College of Basic Medical Sciences, School of Nursing, Jilin University, Changchun, China
| | - Hongwei Du
- Research Institution of Paediatrics, Department of Pediatric Endocrinology, The First Clinical Hospital Affiliated to Jilin University, Changchun, China
| | - Yueqi Guan
- Department of Pharmacology, College of Basic Medical Sciences, School of Nursing, Jilin University, Changchun, China
| | - Jingyue Liu
- Department of Pharmacology, College of Basic Medical Sciences, School of Nursing, Jilin University, Changchun, China
| | - Sushan Wang
- Department of Pharmacology, College of Basic Medical Sciences, School of Nursing, Jilin University, Changchun, China
| | - Haoran Li
- Department of Pharmacology, College of Basic Medical Sciences, School of Nursing, Jilin University, Changchun, China
| | - Wenyou Zhang
- Department of Pharmacology, College of Basic Medical Sciences, School of Nursing, Jilin University, Changchun, China
| | - Hao Han
- Department of Pharmacology, College of Basic Medical Sciences, School of Nursing, Jilin University, Changchun, China
| | - Ming Zhang
- Department of Pharmacology, College of Basic Medical Sciences, School of Nursing, Jilin University, Changchun, China
- *Correspondence: Ming Zhang, ; Li Chen,
| | - Li Chen
- Department of Pharmacology, College of Basic Medical Sciences, School of Nursing, Jilin University, Changchun, China
- *Correspondence: Ming Zhang, ; Li Chen,
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18
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Habeeb MA, Vishwakarma SK, Habeeb S, Khan AA. Current progress and emerging technologies for generating extrapancreatic functional insulin-producing cells. World J Transl Med 2022; 10:1-13. [DOI: 10.5528/wjtm.v10.i1.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 03/05/2022] [Accepted: 06/03/2022] [Indexed: 02/06/2023] Open
Affiliation(s)
- Md Aejaz Habeeb
- Centre for Liver Research and Diagnostics, Deccan College of Medical Sciences, Hyderabad 500058, Telangana, India
| | - Sandeep Kumar Vishwakarma
- Centre for Liver Research and Diagnostics, Deccan College of Medical Sciences, Hyderabad 500058, Telangana, India
| | - Safwaan Habeeb
- Centre for Liver Research and Diagnostics, Deccan College of Medical Sciences, Hyderabad 500058, Telangana, India
| | - Aleem Ahmed Khan
- Centre for Liver Research and Diagnostics, Deccan College of Medical Sciences, Hyderabad 500058, Telangana, India
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19
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Opara A, Jost A, Dagogo-Jack S, Opara EC. Islet cell encapsulation - Application in diabetes treatment. Exp Biol Med (Maywood) 2021; 246:2570-2578. [PMID: 34666516 PMCID: PMC8669170 DOI: 10.1177/15353702211040503] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
In this minireview, we briefly outline the hallmarks of diabetes, the distinction between type 1 and type 2 diabetes, the global incidence of diabetes, and its associated comorbidities. The main goal of the review is to highlight the great potential of encapsulated pancreatic islet transplantation to provide a cure for type 1 diabetes. Following a short overview of the different approaches to islet encapsulation, we provide a summary of the merits and demerits of each approach of the encapsulation technology. We then discuss various attempts to clinical translation with each model of encapsulation as well as the factors that have mitigated the full clinical realization of the promise of the encapsulation technology, the progress that has been made and the challenges that remain to be overcome. In particular, we pay significant attention to the emerging strategies to overcome these challenges. We believe that these strategies to enhance the performance of the encapsulated islet constructs discussed herein provide good platforms for additional work to achieve successful clinical translation of the encapsulated islet technology.
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Affiliation(s)
- Amoge Opara
- Diabetes Section, Biologics Delivery Technologies, Reno, NV 89502, USA
| | - Alec Jost
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | - Sam Dagogo-Jack
- Division of Endocrinology, Diabetes & Metabolism, University of Tennessee Health Science Center, Memphis, TN 38103, USA
| | - Emmanuel C Opara
- Diabetes Section, Biologics Delivery Technologies, Reno, NV 89502, USA
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
- Virginia Tech-Wake Forest School of Biomedical Engineering and Sciences (SBES), Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
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20
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Razavi M, Wang J, Thakor AS. Localized drug delivery graphene bioscaffolds for cotransplantation of islets and mesenchymal stem cells. SCIENCE ADVANCES 2021; 7:eabf9221. [PMID: 34788097 PMCID: PMC8597999 DOI: 10.1126/sciadv.abf9221] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Accepted: 09/28/2021] [Indexed: 06/01/2023]
Abstract
In the present work, we developed, characterized, and tested an implantable graphene bioscaffold which elutes dexamethasone (Dex) that can accommodate islets and adipose tissue–derived mesenchymal stem cells (AD-MSCs). In vitro studies demonstrated that islets in graphene–0.5 w/v% Dex bioscaffolds had a substantial higher viability and function compared to islets in graphene-alone bioscaffolds or islets cultured alone (P < 0.05). In vivo studies, in which bioscaffolds were transplanted into the epididymal fat pad of diabetic mice, demonstrated that, when islet:AD-MSC units were seeded into graphene–0.5 w/v% Dex bioscaffolds, this resulted in complete restoration of glycemic control immediately after transplantation with these islets also showing a faster response to glucose challenges (P < 0.05). Hence, this combination approach of using a graphene bioscaffold that can be functionalized for local delivery of Dex into the surrounding microenvironment, together with AD-MSC therapy, can significantly improve the survival and function of transplanted islets.
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Affiliation(s)
- Mehdi Razavi
- Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University School of Medicine, Palo Alto, CA 94304, USA
- Biionix™ (Bionic Materials, Implants & Interfaces) Cluster, Department of Internal Medicine, College of Medicine, University of Central Florida, Orlando, FL 32827, USA
- Department of Materials Science and Engineering, University of Central Florida, Orlando, FL 32816, USA
| | - Jing Wang
- Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University School of Medicine, Palo Alto, CA 94304, USA
| | - Avnesh S. Thakor
- Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University School of Medicine, Palo Alto, CA 94304, USA
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21
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Aghazadeh Y, Poon F, Sarangi F, Wong FTM, Khan ST, Sun X, Hatkar R, Cox BJ, Nunes SS, Nostro MC. Microvessels support engraftment and functionality of human islets and hESC-derived pancreatic progenitors in diabetes models. Cell Stem Cell 2021; 28:1936-1949.e8. [PMID: 34480863 DOI: 10.1016/j.stem.2021.08.001] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 04/27/2021] [Accepted: 08/04/2021] [Indexed: 12/19/2022]
Abstract
Islet transplantation is a promising treatment for type 1 diabetes (T1D), yet the low donor pool, poor islet engraftment, and life-long immunosuppression prevent it from becoming the standard of care. Human embryonic stem cell (hESC)-derived pancreatic cells could eliminate donor shortages, but interventions to improve graft survival are needed. Here, we enhanced subcutaneous engraftment by employing a unique vascularization strategy based on ready-made microvessels (MVs) isolated from the adipose tissue. This resulted in improved cell survival and effective glucose response of both human islets and hESC-derived pancreatic cells, which ameliorated preexisting diabetes in three mouse models of T1D.
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Affiliation(s)
- Yasaman Aghazadeh
- McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada
| | - Frankie Poon
- McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Deparment of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Farida Sarangi
- McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada
| | - Frances T M Wong
- Deparment of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Safwat T Khan
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada
| | - Xuetao Sun
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada
| | - Rupal Hatkar
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada
| | - Brian J Cox
- Deparment of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Obstetrics and Gynecology, University of Toronto, Toronto, ON M5G 1E2, Canada
| | - Sara S Nunes
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada; Laboratory of Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Heart & Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, ON M5S 3H2, Canada.
| | - M Cristina Nostro
- McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Deparment of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
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22
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Mishra V, Nayak P, Sharma M, Albutti A, Alwashmi ASS, Aljasir MA, Alsowayeh N, Tambuwala MM. Emerging Treatment Strategies for Diabetes Mellitus and Associated Complications: An Update. Pharmaceutics 2021; 13:1568. [PMID: 34683861 PMCID: PMC8538773 DOI: 10.3390/pharmaceutics13101568] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 09/10/2021] [Accepted: 09/13/2021] [Indexed: 12/13/2022] Open
Abstract
The occurrence of diabetes mellitus (DM) is increasing rapidly at an accelerating rate worldwide. The status of diabetes has changed over the last three generations; whereas before it was deemed a minor disease of older people but currently it is now one of the leading causes of morbidity and mortality among middle-aged and young people. High blood glucose-mediated functional loss, insulin sensitivity, and insulin deficiency lead to chronic disorders such as Type 1 and Type 2 DM. Traditional treatments of DM, such as insulin sensitization and insulin secretion cause undesirable side effects, leading to patient incompliance and lack of treatment. Nanotechnology in diabetes studies has encouraged the development of new modalities for measuring glucose and supplying insulin that hold the potential to improve the quality of life of diabetics. Other therapies, such as β-cells regeneration and gene therapy, in addition to insulin and oral hypoglycemic drugs, are currently used to control diabetes. The present review highlights the nanocarrier-based drug delivery systems and emerging treatment strategies of DM.
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Affiliation(s)
- Vijay Mishra
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara 144411, Punjab, India;
| | - Pallavi Nayak
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara 144411, Punjab, India;
- Faculty of Pharmaceutical Sciences, PCTE Group of Institutes, Ludhiana 142021, Punjab, India
| | - Mayank Sharma
- SVKM’s NMIMS School of Pharmacy & Technology Management, Shirpur 425405, Maharashtra, India;
| | - Aqel Albutti
- Department of Medical Biotechnology, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia
| | - Ameen S. S. Alwashmi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia; (A.S.S.A.); (M.A.A.)
| | - Mohammad Abdullah Aljasir
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia; (A.S.S.A.); (M.A.A.)
| | - Noorah Alsowayeh
- Biology Department, College of Education, Majmaah University, Majmaah 11932, Saudi Arabia;
| | - Murtaza M. Tambuwala
- School of Pharmacy and Pharmaceutical Sciences, Ulster University, Coleraine BT52 1SA, UK;
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23
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Tissue Engineering Strategies for Improving Beta Cell Transplantation Outcome. CURRENT TRANSPLANTATION REPORTS 2021. [DOI: 10.1007/s40472-021-00333-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Abstract
Purpose of Review
Beta cell replacement therapy as a form of islet transplantation is a promising alternative therapy with the possibility to make selected patients with type 1 diabetes (T1D) insulin independent. However, this technique faces challenges such as extensive activation of the host immune system post-transplantation, lifelong need for immunosuppression, and the scarcity of islet donor pancreas. Advancement in tissue engineering strategies can improve these challenges and allow for a more widespread application of this therapy. This review will discuss the recent development and clinical translation of tissue engineering strategies in beta cell replacement therapy.
Recent Findings
Tissue engineering offers innovative solutions for producing unlimited glucose responsive cells and fabrication of appropriate devices/scaffolds for transplantation applications. Generation of pancreatic organoids with supporting cells in biocompatible biomaterials is a powerful technique to improve the function of insulin-producing cell clusters. Fabrication of physical barriers such as encapsulation strategies can protect the cells from the host immune system and allow for graft retrieval, although this strategy still faces major challenges to fully restore physiological glucose regulation.
Summary
The three main components of tissue engineering strategies including the generation of stem cell-derived insulin-producing cells and organoids and the possibilities for therapeutic delivery of cell-seeded devices to extra-hepatic sites need to come together in order to provide safe and functional insulin-producing devices for clinical beta cell replacement therapy.
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24
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Lee SJ, Kim HJ, Byun NR, Park CG. Donor-Specific Regulatory T Cell-Mediated Immune Tolerance in an Intrahepatic Murine Allogeneic Islet Transplantation Model with Short-Term Anti-CD154 mAb Single Treatment. Cell Transplant 2021; 29:963689720913876. [PMID: 32216448 PMCID: PMC7586274 DOI: 10.1177/0963689720913876] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Anti-CD154 blockade-based regimens remain unequaled in prolonging graft survival in various organ transplantation models. Several studies have focused on transplantation tolerance with the anti-CD154 blockade, but none of these studies has investigated the mechanisms associated with its use as the sole treatment in animal models, delaying our understanding of anti-CD154 blockade-mediated immune tolerance. The purpose of this study was to investigate the mechanism underlying the anti-CD154 monoclonal antibody (mAb) blockade in inducing immune tolerance using an intrahepatic murine allogeneic islet transplantation model. Allogeneic BALB/c AnHsd (BALB/c) islets were infused into the liver of diabetic C57BL/6 (B6) mice via the cecal vein. Anti-CD154 mAb (MR1) was administered on -1, 0, 1, 3, 5, and 7 d posttransplantation at 0.5 mg per mouse. We showed that short-term MR1 monotherapy could prolong the allogeneic islet grafts to more than 250 d in the murine intrahepatic islet transplantation model. The second islet grafts transplanted under the kidney capsule of the recipients were protected from rejection. We also found that rejection of same-donor skin grafts transplanted to the tolerant mice was modestly delayed. Using a DEREG mouse model, FoxP3+ regulatory T (Treg) cells were shown to play important roles in transplantation tolerance. In mixed lymphocyte reactions, Treg cells from the tolerant mice showed more potency in suppressing BALB/c splenocyte-stimulated Teff cell proliferation than those from naïve mice. In this study, we demonstrated for the first time that a short-term anti-CD154 mAb single treatment could induce FoxP3+ Treg cell-mediated immune tolerance in the intrahepatic murine allogeneic islet transplantation model.
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Affiliation(s)
- Seok-Joo Lee
- Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Korea
- Department of Biomedical Science, Seoul National University Graduate School, Seoul, Korea
- Xenotransplantation Research Center, Seoul National University College of Medicine, Seoul, Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
- Department of Oral Microbiology and Immunology, Seoul National University School of Dentistry, Seoul, Korea
| | - Hyun-Je Kim
- Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Korea
- Department of Biomedical Science, Seoul National University Graduate School, Seoul, Korea
- Xenotransplantation Research Center, Seoul National University College of Medicine, Seoul, Korea
- Department of Dermatology, Samsung Medical Center, Seoul, Korea
| | - Na-ri Byun
- Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Korea
- Department of Biomedical Science, Seoul National University Graduate School, Seoul, Korea
- Xenotransplantation Research Center, Seoul National University College of Medicine, Seoul, Korea
- Byun is now with the Hanmi R&D center, Hwaseong-si, Gyeonggi-do18469, Korea
| | - Chung-Gyu Park
- Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Korea
- Department of Biomedical Science, Seoul National University Graduate School, Seoul, Korea
- Xenotransplantation Research Center, Seoul National University College of Medicine, Seoul, Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
- Department of Dermatology, Samsung Medical Center, Seoul, Korea
- Institute of Endemic Diseases, Seoul National University College of Medicine, Seoul, Korea
- Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea
- Chung-Gyu Park, MD, PhD, 103 Daehak-ro, Jongno-gu, 110-799 Seoul, South Korea. Emails: ;
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25
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Noninvasive Tracking of mPEG-poly(Ala) Hydrogel-Embedded MIN6 Cells after Subcutaneous Transplantation in Mice. Polymers (Basel) 2021; 13:polym13060885. [PMID: 33805723 PMCID: PMC7998640 DOI: 10.3390/polym13060885] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/11/2021] [Accepted: 03/11/2021] [Indexed: 01/10/2023] Open
Abstract
Recently, we demonstrated the feasibility of subcutaneous transplantation of MIN6 cells embedded in a scaffold with poly(ethylene glycol) methyl ether (mPEG)-poly(Ala) hydrogels. In this study, we further tracked these grafts using magnetic resonance (MR) and bioluminescence imaging. After being incubated overnight with chitosan-coated superparamagnetic iron oxide (CSPIO) nanoparticles and then mixed with mPEG-poly(Ala) hydrogels, MIN6 cells appeared as dark spots on MR scans. For in vivo experiments, we transfected MIN6 cells with luciferase and/or incubated them overnight with CSPIO overnight; 5 × 106 MIN6 cells embedded in mPEG-poly(Ala) hydrogels were transplanted into the subcutaneous space of each nude mouse. The graft of CSPIO-labeled MIN6 cells was visualized as a distinct hypointense area on MR images located at the implantation site before day 21. However, this area became hyperintense on MR scans for up to 64 days. In addition, positive bioluminescence images were also observed for up to 64 days after transplantation. The histology of removed grafts showed positive insulin and iron staining. These results indicate mPEG-poly(Ala) is a suitable scaffold for β-cell encapsulation and transplantation. Moreover, MR and bioluminescence imaging are useful noninvasive tools for detecting and monitoring mPEG-poly(Ala) hydrogel-embedded MIN6 cells at a subcutaneous site.
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26
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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.
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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.
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27
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Xu K, Xie R, Lin X, Jia J, Zeng N, Li W, Xiao D, Du T. Brown Adipose Tissue: A Potential Site for Islet Transplantation. Transplantation 2020; 104:2059-2064. [PMID: 32453253 DOI: 10.1097/tp.0000000000003322] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Islet transplantation is a promising treatment in patients with complicated diabetes. The ideal transplant site that can extend islet graft survival and reduce the required number of engrafted islets remains to be established. METHODS Donor islets were isolated from red fluorescent protein (RFP) mice and transplanted into interscapular brown adipose tissue (BAT) or unilateral inguinal white adipose tissue of age-matched diabetic RFP mice. Blood glucose and body weight of the mice were monitored, and vitality and function of ectopic RFP islets were detected by fluorescence imaging, histological examination, and intraperitoneal glucose tolerance test (GTT). RESULTS BAT enabled the marginal number of grafted islets (80 islets) to restore blood glucose, insulin level, and GTT to normal values in all diabetic recipient mice in the short term after graft, and maintained these values for 1 year at the end of the experiment. Importantly, in the short term after transplantation, abundant extra- and intraislet neovasculatures were observed in BAT, but not in white adipose tissue, which allowed the ectopic islets to retain typical architecture and morphology and contributed to the normal GTT. Moreover, the islet-engrafted BAT displayed normal structure and morphology without significant immunocyte infiltration, and the recipient mice also showed normal lipid levels in the blood. CONCLUSIONS BAT remarkably enhances the viability and biological function of the transplanted ectopic islets. Moreover, the anatomical location of BAT lends itself to biopsy, removal, and islet retransplantation, which strongly suggests the BAT as a potential desirable site for islet transplantation in basic and clinical research.
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Affiliation(s)
- Kang Xu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
- Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Raoying Xie
- Department of Radiation and Medical Oncology, The First Affiliated Hospital, Wenzhou Medical University, Zhejiang, China
| | - Xiaolin Lin
- Cancer Research Institute, Southern Medical University, Guangzhou, China
| | - Junshuang Jia
- Cancer Research Institute, Southern Medical University, Guangzhou, China
| | - Nan Zeng
- Department of Endocrinology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Wangen Li
- Department of Endocrinology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Dong Xiao
- Cancer Research Institute, Southern Medical University, Guangzhou, China
- Institute of Comparative Medicine & Laboratory Animal Center, Southern Medical University, Guangzhou, China
| | - Tao Du
- Department of Endocrinology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
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28
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Grafting Islets to a Dissected Peritoneal Pouch to Improve Transplant Survival and Function. Transplantation 2020; 104:2307-2316. [PMID: 32541557 DOI: 10.1097/tp.0000000000003355] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
BACKGROUND Although the liver is the primary site for clinical islet transplantation, it poses several restrictions, especially limited tissue volume due to portal vein pressure. We evaluated the preperitoneal space as an extrahepatic islet transplant site to deliver high tissue volumes and sustain long-term graft function. METHODS A peritoneal pouch was formed by dissecting the parietal peritoneum from the transversalis fascia of mice. Syngeneic C57BL/6 donor islets were transplanted into the peritoneal pouch of diabetic mouse recipients. Blood glucose was monitored for islet function, and miR-375 was analyzed for islet damage. Islet graft morphology and vascularization were evaluated by immunohistochemistry. [F] fluoro-D-glucose positron emission tomography/computed tomography was used to image islet grafts. RESULTS Transplantation of 300 syngeneic islets into the peritoneal pouch of recipients reversed hyperglycemia for >60 days. Serum miR-375 was significantly lower in the peritoneal pouch group than in the peritoneal cavity group. Peritoneal pouch islet grafts showed high neovascularization and sustained insulin and glucagon expression up to 80 days posttransplantation. A peritoneal pouch graft with high tissue volume (1000 islets) could be visualized by positron emission tomography/computed tomography imaging. Human islets transplanted into the peritoneal pouch of diabetic nude mice also reversed hyperglycemia successfully. CONCLUSIONS Islets transplanted into a dissected peritoneal pouch show high efficiency to reverse diabetes and sustain islet graft function. The preperitoneal site has the advantages of capacity for high tissue volume, enriched revascularization and minimal inflammatory damage. It can also serve as an extrahepatic site for transplanting large volume of islets necessitated in islet autotransplantation.
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29
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Human beige adipocytes for drug discovery and cell therapy in metabolic diseases. Nat Commun 2020; 11:2758. [PMID: 32488069 PMCID: PMC7265435 DOI: 10.1038/s41467-020-16340-3] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Accepted: 04/20/2020] [Indexed: 12/17/2022] Open
Abstract
Human beige adipocytes (BAs) have potential utility for the development of therapeutics to treat diabetes and obesity-associated diseases. Although several reports have described the generation of beige adipocytes in vitro, their potential utility in cell therapy and drug discovery has not been reported. Here, we describe the generation of BAs from human adipose-derived stem/stromal cells (ADSCs) in serum-free medium with efficiencies >90%. Molecular profiling of beige adipocytes shows them to be similar to primary BAs isolated from human tissue. In vitro, beige adipocytes exhibit uncoupled mitochondrial respiration and cAMP-induced lipolytic activity. Following transplantation, BAs increase whole-body energy expenditure and oxygen consumption, while reducing body-weight in recipient mice. Finally, we show the therapeutic utility of BAs in a platform for high-throughput drug screening (HTS). These findings demonstrate the potential utility of BAs as a cell therapeutic and as a tool for the identification of drugs to treat metabolic diseases. Methods to generate beige adipocytes from a human cell source are inefficient. Here, the authors present a protocol that efficiently generates beige adipocytes from human adipose-derived stem cells (ADSCs), which have potential utility in therapeutic development relating to metabolic diseases such as type 2 diabetes.
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30
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Wartchow KM, Rodrigues L, Lissner LJ, Federhen BC, Selistre NG, Moreira A, Gonçalves CA, Sesterheim P. Insulin-producing cells from mesenchymal stromal cells: Protection against cognitive impairment in diabetic rats depends upon implant site. Life Sci 2020; 251:117587. [PMID: 32224027 DOI: 10.1016/j.lfs.2020.117587] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 03/21/2020] [Accepted: 03/22/2020] [Indexed: 12/11/2022]
Abstract
Diabetes mellitus (DM) is a serious public health problem and can cause long-term damage to the brain, resulting in cognitive impairment in these patients. Insulin therapy for type 1 DM (DM1) can achieve overall blood glucose control, but glycemic variations can occur during injection intervals, which may contribute to some complications. Among the additional therapies available for DM1 treatment is the implantation of insulin-producing cells (IPCs) to attenuate hyperglycemia and even reverse diabetes. Here, we studied the strategy of implanting IPCs obtained from mesenchymal stromal cells (MSCs) from adipose tissue, comparing two different IPC implant sites, subcapsular renal (SR) and subcutaneous (SC), to investigate their putative protection against hippocampal damage, induced by STZ, in a rat DM1 model. Both implants improved hyperglycemia and reduced the serum content of advanced-glycated end products in diabetic rats, but serum insulin was not observed in the SC group. The SC-implanted group demonstrated ameliorated cognitive impairment (evaluated by novel object recognition) and modulation of hippocampal astroglial reactivity (evaluated by S100B and GFAP). Using GFP+ cell implants, the survival of cells at the implant sites was confirmed, as well as their migration to the pancreas and hippocampus. The presence of undifferentiated MSCs in our IPC preparation may explain the peripheral reduction in AGEs and subsequent cognitive impairment recovery, mediated by autophagic depuration and immunomodulation at the hippocampus, respectively. Together, these data reinforce the importance of MSCs for use in neuroprotective strategies, and highlight the logistic importance of the subcutaneous route for their administration.
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Affiliation(s)
- Krista Minéia Wartchow
- Federal University of Rio Grande do Sul (UFRGS), Biochemistry Post-Graduate Program, Porto Alegre, Brazil
| | - Leticia Rodrigues
- Federal University of Rio Grande do Sul (UFRGS), Biochemistry Post-Graduate Program, Porto Alegre, Brazil
| | - Lílian Juliana Lissner
- Federal University of Rio Grande do Sul (UFRGS), Biochemistry Post-Graduate Program, Porto Alegre, Brazil
| | - Barbara Carolina Federhen
- Federal University of Rio Grande do Sul (UFRGS), Biochemistry Post-Graduate Program, Porto Alegre, Brazil
| | - Nicholas Guerini Selistre
- Federal University of Rio Grande do Sul (UFRGS), Biochemistry Post-Graduate Program, Porto Alegre, Brazil
| | - Aline Moreira
- Federal University of Rio Grande do Sul (UFRGS), Biochemistry Post-Graduate Program, Porto Alegre, Brazil
| | - Carlos-Alberto Gonçalves
- Federal University of Rio Grande do Sul (UFRGS), Biochemistry Post-Graduate Program, Porto Alegre, Brazil.
| | - Patrícia Sesterheim
- Institute of Cardiology of Rio Grande do Sul, Experimental Center, Porto Alegre, Brazil
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31
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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: 12] [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] [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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Lin HC, Chen CY, Kao CW, Wu ST, Chen CL, Shen CR, Juang JH, Chu IM. In situ gelling-polypeptide hydrogel systems for the subcutaneous transplantation of MIN6 cells. JOURNAL OF POLYMER RESEARCH 2020. [DOI: 10.1007/s10965-020-2032-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
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Yu CP, Juang JH, Lin YJ, Kuo CW, Hsieh LH, Huang CC. Enhancement of Subcutaneously Transplanted β Cell Survival Using 3D Stem Cell Spheroids with Proangiogenic and Prosurvival Potential. ACTA ACUST UNITED AC 2020; 4:e1900254. [PMID: 32293147 DOI: 10.1002/adbi.201900254] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 01/08/2020] [Indexed: 01/20/2023]
Abstract
Islet transplantation has been demonstrated to be a promising therapy for type 1 diabetes mellitus. Although it is a minimally invasive operating procedure and provides easy access for graft monitoring, subcutaneous transplantation of the islet only has limited therapeutic outcomes, owing to the poor capacity of skin tissue to foster revascularization in a short period. Herein, 3D cell spheroids of clinically accessible umbilical cord blood mesenchymal stem cells and human umbilical vein endothelial cells are formed and employed for codelivery with β cells subcutaneously. The 3D stem cell spheroids, which can secrete multiple proangiogenic and prosurvival growth factors, induce robust angiogenesis and prevent β cell graft death, as indicated by the results of in vivo bioluminescent tracking and histological analysis. These experimental data highlight the efficacy of the 3D stem cell spheroids that are fabricated using translationally applicable cell types in promoting the survival and function of subcutaneously transplanted β cells.
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Affiliation(s)
- Chih-Ping Yu
- Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, 30013, Taiwan
| | - Jyuhn-Huarng Juang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung Memorial Hospital, Taoyuan, 33305, Taiwan.,Center for Tissue Engineering, Chang Gung Memorial Hospital, Taoyuan, 33305, Taiwan.,Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, 33302, Taiwan
| | - Yu-Jie Lin
- Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, 30013, Taiwan
| | - Ching-Wen Kuo
- Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, 30013, Taiwan.,Department of Chemical Engineering, National Tsing Hua University, Hsinchu, 30013, Taiwan
| | - Li-Hung Hsieh
- Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, 30013, Taiwan
| | - Chieh-Cheng Huang
- Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, 30013, Taiwan
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Schaschkow A, Sigrist S, Mura C, Barthes J, Vrana NE, Czuba E, Lemaire F, Neidl R, Dissaux C, Lejay A, Lavalle P, Bruant-Rodier C, Bouzakri K, Pinget M, Maillard E. Glycaemic control in diabetic rats treated with islet transplantation using plasma combined with hydroxypropylmethyl cellulose hydrogel. Acta Biomater 2020; 102:259-272. [PMID: 31811957 DOI: 10.1016/j.actbio.2019.11.047] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 11/15/2019] [Accepted: 11/22/2019] [Indexed: 12/18/2022]
Abstract
Islet transplantation is one of the most efficient cell therapies used in clinics and could treat a large proportion of patients with diabetes. However, it is limited by the high requirement of pancreas necessary to provide the sufficient surviving islet mass in the hepatic tissue and restore normoglycaemia. Reduction in organ procurement requirements could be achieved by extrahepatic transplantation using a biomaterial that enhances islet survival and function. We report a plasma-supplemented hydroxypropyl methylcellulose (HPMC) hydrogel, engineered specifically using a newly developed technique for intra-omental islet infusion, known as hOMING (h-Omental Matrix Islet filliNG). The HPMC hydrogel delivered islets with better performance than that of the classical intrahepatic infusion. After the validation of the HPMC suitability for islets in vivo and in vitro, plasma supplementation modified the rheological properties of HPMC without affecting its applicability with hOMING. The biomaterial association was proven to be more efficient both in vitro and in vivo, with better islet viability and function than that of the current clinical intrahepatic delivery technique. Indeed, when the islet mass was decreased by 25% or 35%, glycaemia control was observed in the group of plasma-supplemented hydrogels, whereas no regulation was observed in the hepatic group. Plasma gelation, observed immediately post infusion, decreased anoïkis and promoted vascularisation. To conclude, the threshold mass for islet transplantation could be decreased using HPMC-Plasma combined with the hOMING technique. The simplicity of the hOMING technique and the already validated use of its components could facilitate its transfer to clinics. STATEMENT OF SIGNIFICANCE: One of the major limitations for the broad deployment of current cell therapy for brittle type 1 diabetes is the islets' destruction during the transplantation process. Retrieved from their natural environment, the islets are grafted into a foreign tissue, which triggers massive cell loss. It is mandatory to provide the islets with an 3D environment specifically designed for promoting isletimplantation to improve cell therapy outcomes. For this aim, we combined HPMC and plasma. HPMC provides suitable rheological properties to the plasma to be injectable and be maintained in the omentum. Afterwards, the plasma polymerises around the graft in vivo, thereby allowing their optimal integration into their transplantation site. As a result, the islet mass required to obtain glycaemic control was reduced by 35%.
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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.
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Liang S, Louchami K, Holvoet B, Verbeke R, Deroose CM, Manshian B, Soenen SJ, Lentacker I, Himmelreich U. Tri-modal In vivo Imaging of Pancreatic Islets Transplanted Subcutaneously in Mice. Mol Imaging Biol 2019; 20:940-951. [PMID: 29671177 DOI: 10.1007/s11307-018-1192-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
PURPOSE Transplantation of pancreatic islets (PIs) is a promising therapeutic approach for type 1 diabetes. The main obstacle for this strategy is that the outcome of islet engraftment depends on the engraftment site. It was our aim to develop a strategy for using non-invasive imaging techniques to assess the location and fate of transplanted PIs longitudinally in vivo. PROCEDURES In order to overcome the limitations of individual imaging techniques and cross-validate findings by different modalities, we have combined fluorine magnetic resonance imaging (F-19 MRI), fluorescence imaging (FLI), and bioluminescent imaging (BLI) for studying subcutaneously transplanted PIs and beta cell-like cells (INS-1E cell line) in vivo. We optimized the transduction (using lentiviral vectors) and labeling procedures (using perfluoro crown ether nanoparticles with a fluorescence dye) for PIs and INS-1E cell imaging. RESULTS The feasibility of using the proposed imaging methods for PI assessment was demonstrated both in vitro and in vivo. Our data suggested that F-19 MRI is suitable for high-resolution localization of transplanted cells and PIs; FLI is essential for confirmation of contrast localization by histology; and BLI is a reliable method to assess cell viability and survival after transplantation. No significant side effects on cell viability and function have been observed. CONCLUSIONS The proposed tri-modal imaging platform is a valuable approach for the assessment of engrafted PIs in vivo. It is potentially suitable for comparing different transplantation sites and evaluating novel strategies for improving PI transplantation technique in the future.
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Affiliation(s)
- Sayuan Liang
- Biomedical MRI, Department of Imaging & Pathology, University of Leuven, Leuven, Belgium.,Bio-Imaging Lab, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Antwerp, Belgium.,Philips Research China, Shanghai, China
| | - Karim Louchami
- Biomedical MRI, Department of Imaging & Pathology, University of Leuven, Leuven, Belgium.,Laboratory of Experimental Hormonology, Université Libre de Bruxelles, Bruxelles, Belgium
| | - Bryan Holvoet
- Nuclear Medicine & Molecular Imaging, Department of Imaging & Pathology, University of Leuven, Leuven, Belgium
| | - Rein Verbeke
- Laboratory for General Biochemistry and Physical Pharmacy, Ghent University, Ghent, Belgium
| | - Christophe M Deroose
- Nuclear Medicine & Molecular Imaging, Department of Imaging & Pathology, University of Leuven, Leuven, Belgium
| | - Bella Manshian
- Biomedical MRI, Department of Imaging & Pathology, University of Leuven, Leuven, Belgium
| | - Stefaan J Soenen
- Biomedical MRI, Department of Imaging & Pathology, University of Leuven, Leuven, Belgium
| | - Ine Lentacker
- Laboratory for General Biochemistry and Physical Pharmacy, Ghent University, Ghent, Belgium
| | - Uwe Himmelreich
- Biomedical MRI, Department of Imaging & Pathology, University of Leuven, Leuven, Belgium.
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Minardi S, Guo M, Zhang X, Luo X. An elastin-based vasculogenic scaffold promotes marginal islet mass engraftment and function at an extrahepatic site. JOURNAL OF IMMUNOLOGY AND REGENERATIVE MEDICINE 2019; 3:1-12. [PMID: 31681866 PMCID: PMC6824601 DOI: 10.1016/j.regen.2018.12.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
In islet transplantation, one of the major obstacles to optimal engraftment is the loss of islet natural vascularization and islet-specific extracellular matrix (ECM) during the islet isolation process. Thus, transplanted islets must re-establish nutritional and physical support through formation of new blood vessels and new ECM. To promote this critical process, we developed an elastin-based vasculogenic and ECM-promoting scaffold engineered for extrahepatic islet transplantation. The scaffold by design consisted of type I collagen (Coll) blended with 20wt% of elastin (E) shown to promote angiogenesis as well as de novo ECM deposition. The resulting "CollE" scaffolds h ad interconnected pores with a size distribution tailored to accommodate seeding of islets as well as growth of new blood vessels. In vitro, CollE scaffolds enabled prolonged culture of murine islets for up to one week while preserving their integrity, viability and function. In vivo, after only four weeks post-transplant of a marginal islet mass, CollE scaffolds demonstrated enhanced vascularization of the transplanted islets in the epididymal fat pad and promoted a prompt reversal of hyperglycemia in previously diabetic recipients. This outcome was comparable to that of kidney capsular (KC) islet transplantation, and superior to that of islets transplanted on the control collagen-only scaffolds (Coll). Crucial genes associated with angiogenesis (VEGFA, PDGFB, FGF1, and COL3A1) as well as de novo islet-specific matrix deposition (COL6A1, COL4A1, LAMA2 and FN1) were all significantly upregulated in islets on CollE scaffolds in comparison to those on Coll scaffolds. Finally, CollE scaffolds were also able to support human islet culture in vitro. In conclusion, CollE scaffolds have the potential to improve the clinical outcome of marginal islet transplantation at extrahepatic sites by promoting angiogenesis and islet-specific ECM deposition.
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Affiliation(s)
- Silvia Minardi
- Center for Kidney Research and Therapeutics, Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
- Division of Nephrology and Hypertension, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Michelle Guo
- Weinberg College of Arts and Sciences, Northwestern University, Chicago, IL, United States
| | - Xiaomin Zhang
- Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
- Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Xunrong Luo
- Center for Kidney Research and Therapeutics, Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
- Division of Nephrology and Hypertension, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
- Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
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Komatsu H, Cook CA, Gonzalez N, Medrano L, Salgado M, Sui F, Li J, Kandeel F, Mullen Y, Tai YC. Oxygen transporter for the hypoxic transplantation site. Biofabrication 2018; 11:015011. [PMID: 30524058 PMCID: PMC9851375 DOI: 10.1088/1758-5090/aaf2f0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Cell transplantation is a promising treatment for complementing lost function by replacing new cells with a desired function, e.g. pancreatic islet transplantation for diabetics. To prevent cell obliteration, oxygen supply is critical after transplantation, especially until the graft is sufficiently re-vascularized. To supply oxygen during this period, we developed a chemical-/electrical-free implantable oxygen transporter that delivers oxygen to the hypoxic graft site from ambient air by diffusion potential. This device is simply structured using a biocompatible silicone-based body that holds islets, connected to a tube that opens outside the body. In computational simulations, the oxygen transporter increased the oxygen level to >120 mmHg within grafts; in contrast, a control device that did not transport oxygen showed <6.5 mmHg. In vitro experiments demonstrated similar results. To test the effectiveness of the oxygen transporter in vivo, we transplanted pancreatic islets, which are susceptible to hypoxia, subcutaneously into diabetic rats. Islets transplanted using the oxygen transporter showed improved graft viability and cellular function over the control device. These results indicate that our oxygen transporter, which is safe and easily fabricated, effectively supplies oxygen locally. Such a device would be suitable for multiple clinical applications, including cell transplantations that require changing a hypoxic microenvironment into an oxygen-rich site.
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Affiliation(s)
- Hirotake Komatsu
- Department of Translational Research & Cellular Therapeutics, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA 91010, USA.,Corresponding author: Hirotake Komatsu,
| | - Colin A. Cook
- Department of Electrical Engineering, California Institute of Technology, 1200 E. California Blvd., MC 136-93, Pasadena, CA 91125, USA
| | - Nelson Gonzalez
- Department of Translational Research & Cellular Therapeutics, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA 91010, USA
| | - Leonard Medrano
- Department of Translational Research & Cellular Therapeutics, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA 91010, USA
| | - Mayra Salgado
- Department of Translational Research & Cellular Therapeutics, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA 91010, USA
| | - Feng Sui
- Department of Translational Research & Cellular Therapeutics, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA 91010, USA
| | - Junfeng Li
- Department of Translational Research & Cellular Therapeutics, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA 91010, USA
| | - Fouad Kandeel
- Department of Translational Research & Cellular Therapeutics, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA 91010, USA
| | - Yoko Mullen
- Department of Translational Research & Cellular Therapeutics, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA 91010, USA
| | - Yu-Chong Tai
- Department of Electrical Engineering, California Institute of Technology, 1200 E. California Blvd., MC 136-93, Pasadena, CA 91125, USA
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Stephens CH, Orr KS, Acton AJ, Tersey SA, Mirmira RG, Considine RV, Voytik-Harbin SL. In situ type I oligomeric collagen macroencapsulation promotes islet longevity and function in vitro and in vivo. Am J Physiol Endocrinol Metab 2018; 315:E650-E661. [PMID: 29894201 PMCID: PMC6230705 DOI: 10.1152/ajpendo.00073.2018] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Widespread use of pancreatic islet transplantation for treatment of type 1 diabetes (T1D) is currently limited by requirements for long-term immunosuppression, limited donor supply, and poor long-term engraftment and function. Upon isolation from their native microenvironment, islets undergo rapid apoptosis, which is further exacerbated by poor oxygen and nutrient supply following infusion into the portal vein. Identifying alternative strategies to restore critical microenvironmental cues, while maximizing islet health and function, is needed to advance this cellular therapy. We hypothesized that biophysical properties provided through type I oligomeric collagen macroencapsulation are important considerations when designing strategies to improve islet survival, phenotype, and function. Mouse islets were encapsulated at various Oligomer concentrations (0.5 -3.0 mg/ml) or suspended in media and cultured for 14 days, after which viability, protein expression, and function were assessed. Oligomer-encapsulated islets showed a density-dependent improvement in in vitro viability, cytoarchitecture, and insulin secretion, with 3 mg/ml yielding values comparable to freshly isolated islets. For transplantation into streptozotocin-induced diabetic mice, 500 islets were mixed in Oligomer and injected subcutaneously, where rapid in situ macroencapsulation occurred, or injected with saline. Mice treated with Oligomer-encapsulated islets exhibited rapid (within 24 h) diabetes reversal and maintenance of normoglycemia for 14 (immunocompromised), 90 (syngeneic), and 40 days (allogeneic). Histological analysis showed Oligomer-islet engraftment with maintenance of islet cytoarchitecture, revascularization, and no foreign body response. Oligomer-islet macroencapsulation may provide a useful strategy for prolonging the health and function of cultured islets and has potential as a subcutaneous injectable islet transplantation strategy for treatment of T1D.
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Affiliation(s)
| | - Kara S Orr
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine , Indianapolis, Indiana
- Department of Pediatrics, Indiana University School of Medicine , Indianapolis, Indiana
| | - Anthony J Acton
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine , Indianapolis, Indiana
- Department of Medicine, Indiana University School of Medicine , Indianapolis, Indiana
| | - Sarah A Tersey
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine , Indianapolis, Indiana
- Department of Pediatrics, Indiana University School of Medicine , Indianapolis, Indiana
| | - Raghavendra G Mirmira
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine , Indianapolis, Indiana
- Department of Pediatrics, Indiana University School of Medicine , Indianapolis, Indiana
| | - Robert V Considine
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine , Indianapolis, Indiana
- Department of Medicine, Indiana University School of Medicine , Indianapolis, Indiana
| | - Sherry L Voytik-Harbin
- Weldon School of Biomedical Engineering, Purdue University , West Lafayette, Indiana
- Department of Basic Medical Sciences, Purdue University , West Lafayette, Indiana
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Perez-Basterrechea M, Esteban MM, Vega JA, Obaya AJ. Tissue-engineering approaches in pancreatic islet transplantation. Biotechnol Bioeng 2018; 115:3009-3029. [PMID: 30144310 DOI: 10.1002/bit.26821] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 08/08/2018] [Accepted: 08/14/2018] [Indexed: 12/15/2022]
Abstract
Pancreatic islet transplantation is a promising alternative to whole-pancreas transplantation as a treatment of type 1 diabetes mellitus. This technique has been extensively developed during the past few years, with the main purpose of minimizing the complications arising from the standard protocols used in organ transplantation. By using a variety of strategies used in tissue engineering and regenerative medicine, pancreatic islets have been successfully introduced in host patients with different outcomes in terms of islet survival and functionality, as well as the desired normoglycemic control. Here, we describe and discuss those strategies to transplant islets together with different scaffolds, in combination with various cell types and diffusible factors, and always with the aim of reducing host immune response and achieving islet survival, regardless of the site of transplantation.
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Affiliation(s)
- Marcos Perez-Basterrechea
- Unidad de Terapia Celular y Medicina Regenerativa, Servicio de Hematología y Hemoterapia, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain.,Plataforma de Terapias Avanzadas, Instituto de Investigación Biosanitaria del Principado de Asturias (ISPA), Oviedo, Spain
| | - Manuel M Esteban
- Departamento de Biología Funcional, Universidad de Oviedo, Oviedo, Spain
| | - Jose A Vega
- Departamento de Morfología y Biología Celular, Universidad de Oviedo, Oviedo, Spain.,Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Santiago, Chile
| | - Alvaro J Obaya
- Departamento de Biología Funcional, Universidad de Oviedo, Oviedo, Spain
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Nagaya M, Katsumata Y, Arai Y, Umeki I, Nakano K, Kasai Y, Hasegawa K, Okamoto K, Itazaki S, Matsunari H, Watanabe M, Umeyama K, Nagashima H. Effectiveness of bioengineered islet cell sheets for the treatment of diabetes mellitus. J Surg Res 2018; 227:119-129. [PMID: 29804843 DOI: 10.1016/j.jss.2018.02.019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Revised: 01/29/2018] [Accepted: 02/13/2018] [Indexed: 01/17/2023]
Abstract
BACKGROUND The present study aimed to evaluate whether bioengineered mouse islet cell sheets can be used for the treatment of diabetes mellitus. METHODS Isolated mouse pancreatic islets were dispersed, and cells were plated on temperature-responsive culture plates coated with iMatrix-551. On day 3 of culture, the sheets were detached from the plates and used for further analysis or transplantation. The following parameters were assessed: (1) morphology, (2) expression of β-cell-specific transcription factors and other islet-related proteins, (3) methylation level of the pancreatic duodenal homeobox-1 (Pdx-1) promoter, as determined by bisulfite sequencing, and (4) levels of serum glucose after transplantation of one or two islet cell sheets into the abdominal cavity of streptozotocin-induced diabetic severe combined immunodeficiency mice. RESULTS From each mouse, we recovered approximately 233.3 ± 12.5 islets and 1.4 ± 0.1 × 105 cells after dispersion. We estimate that approximately 68.2% of the cells were lost during dispersion. The viability of recovered single cells was 91.3 ± 0.9%. The engineered islet cell sheets were stable, but the messenger RNA levels of various β-cell-specific transcription factors were significantly lower than those of primary islets, whereas Pdx-1 promoter methylation and the expression of NeuroD, Pdx-1, and glucagon proteins were similar between sheets and islets. Moreover, transplantation of islet cell sheets did not revert serum hyperglycemia in any of the recipient mice. CONCLUSIONS Engineering effective islet cell sheets require further research efforts, as the currently produced sheets remain functionally inferior compared with primary islets.
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Affiliation(s)
- Masaki Nagaya
- Meiji University International Institute for Bio-Resource Research, Kawasaki, Japan; Department of Immunology, St. Marianna University School of Medicine, Kawasaki, Japan.
| | - Yuki Katsumata
- Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan
| | - Yoshikazu Arai
- Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan
| | - Ikuma Umeki
- Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan
| | - Kazuaki Nakano
- Meiji University International Institute for Bio-Resource Research, Kawasaki, Japan; Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan
| | - Yuri Kasai
- Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan
| | - Koki Hasegawa
- Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan
| | - Kazutoshi Okamoto
- Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan
| | - Shiori Itazaki
- Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan
| | - Hitomi Matsunari
- Meiji University International Institute for Bio-Resource Research, Kawasaki, Japan; Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan
| | - Masahito Watanabe
- Meiji University International Institute for Bio-Resource Research, Kawasaki, Japan; Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan
| | - Kazuhiro Umeyama
- Meiji University International Institute for Bio-Resource Research, Kawasaki, Japan; Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan
| | - Hiroshi Nagashima
- Meiji University International Institute for Bio-Resource Research, Kawasaki, Japan; Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan.
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Fujita I, Utoh R, Yamamoto M, Okano T, Yamato M. The liver surface as a favorable site for islet cell sheet transplantation in type 1 diabetes model mice. Regen Ther 2018; 8:65-72. [PMID: 30271868 PMCID: PMC6147207 DOI: 10.1016/j.reth.2018.04.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 03/19/2018] [Accepted: 04/12/2018] [Indexed: 01/21/2023] Open
Abstract
INTRODUCTION Islet transplantation is one of the most promising therapeutic approaches for patients with severe type 1 diabetes mellitus (T1DM). Transplantation of engineered islet cell sheets holds great potential for treating T1DM as it enables the creation of stable neo-islet tissues. However, a large mass of islet cell sheets is required for the subcutaneous transplantation to reverse hyperglycemia in diabetic mice. Here, we investigated whether the liver surface could serve as an alternative site for islet cell sheet transplantation. METHODS Dispersed rat islet cells (0.8 × 106 cells) were cultured on laminin-332-coated thermoresponsive culture dishes. After 2 days of cultivation, we harvested the islet cell sheets by lowering the culture temperature using a support membrane with a gelatin gel. We transplanted two recovered islet cell sheets into the subcutaneous space or onto the liver surface of severe combined immunodeficiency (SCID) mice with streptozocin-induced diabetes. RESULTS In the liver surface group, the non-fasting blood glucose level decreased rapidly within several days after transplantation. In marked contrast, the hyperglycemia state was maintained in the subcutaneous space transplantation group. The levels of rat C-peptide and insulin in the liver surface group were significantly higher than those in the subcutaneous space group. An immunohistological analysis confirmed that most of the islet cells engrafted on the liver surface were insulin-positive. The CD31-positive endothelial cells formed vascular networks within the neo-islets and in the surrounding tissues. In contrast, viable islet cells were not found in the subcutaneous space group. CONCLUSIONS Compared with the subcutaneous space, a relatively small mass of islet cell sheets was enough to achieve normoglycemia in diabetic mice when the liver surface was selected as the transplantation site. Our results demonstrate that the optimization of the transplantation site for islet cell sheets leads to significant improvements in the therapeutic efficiency for T1DM.
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Affiliation(s)
- Izumi Fujita
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Rie Utoh
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
- Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
| | - Masakazu Yamamoto
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Teruo Okano
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Masayuki Yamato
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
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44
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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.
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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
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45
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Gebe JA, Preisinger A, Gooden MD, D'Amico LA, Vernon RB. Local, Controlled Release In Vivo of Vascular Endothelial Growth Factor Within a Subcutaneous Scaffolded Islet Implant Reduces Early Islet Necrosis and Improves Performance of the Graft. Cell Transplant 2018; 27:531-541. [PMID: 29756517 PMCID: PMC6038045 DOI: 10.1177/0963689718754562] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Islet transplantation remains the only alternative to daily insulin therapy for control of type 1 diabetes (T1D) in humans. To avoid the drawbacks of intrahepatic islet transplantation, we are developing a scaffolded islet implant to transplant islets into nonhepatic sites. The implant test bed, sized for mice, consists of a limited (2-mm) thickness, large-pore polymeric sponge scaffold perforated with peripheral cavities that contain islets suspended in a collagen hydrogel. A central cavity in the scaffold holds a 2-mm diameter alginate sphere for controlled release of the angiogenic cytokine vascular endothelial growth factor ( VEGF). Host microvessels readily penetrate the scaffold and collagen gel to vascularize the islets. Here, we evaluate the performance of the implant in a subcutaneous (SC) graft site. Implants incorporating 500 syngeneic islets reversed streptozotocin-induced diabetes in mice approximately 30 d after SC placement. Controlled release of a modest quantity (20 ng) of VEGF within the implant significantly reduced the time to normoglycemia compared to control implants lacking VEGF. Investigation of underlying causes for this effect revealed that inclusion of 20 ng of VEGF in the implants significantly reduced central necrosis of islets 24 h after grafting and increased implant vascularization (measured 12 d after grafting). Collectively, our results demonstrate (1) that the scaffolded islet implant design can reverse diabetes in SC sites in the absence of prevascularization of the graft site and (2) that relatively low quantities of VEGF, delivered by controlled release within the implant, can be a useful approach to limit islet stress after grafting.
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Affiliation(s)
- John A Gebe
- 1 Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA
| | - Anton Preisinger
- 1 Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA
| | - Michel D Gooden
- 1 Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA
| | - Leonard A D'Amico
- 1 Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA.,2 Cancer Immunotherapy Trials, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Robert B Vernon
- 1 Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA
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46
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Komatsu H, Rawson J, Barriga A, Gonzalez N, Mendez D, Li J, Omori K, Kandeel F, Mullen Y. Posttransplant oxygen inhalation improves the outcome of subcutaneous islet transplantation: A promising clinical alternative to the conventional intrahepatic site. Am J Transplant 2018; 18:832-842. [PMID: 28898528 DOI: 10.1111/ajt.14497] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Revised: 08/29/2017] [Accepted: 09/06/2017] [Indexed: 01/25/2023]
Abstract
Subcutaneous tissue is a promising site for islet transplantation, due to its large area and accessibility, which allows minimally invasive procedures for transplantation, graft monitoring, and removal of malignancies as needed. However, relative to the conventional intrahepatic transplantation site, the subcutaneous site requires a large number of islets to achieve engraftment success and diabetes reversal, due to hypoxia and low vascularity. We report that the efficiency of subcutaneous islet transplantation in a Lewis rat model is significantly improved by treating recipients with inhaled 50% oxygen, in conjunction with prevascularization of the graft bed by agarose-basic fibroblast growth factor. Administration of 50% oxygen increased oxygen tension in the subcutaneous site to 140 mm Hg, compared to 45 mm Hg under ambient air. In vitro, islets cultured under 140 mm Hg oxygen showed reduced central necrosis and increased insulin release, compared to those maintained in 45 mm Hg oxygen. Six hundred syngeneic islets subcutaneously transplanted into the prevascularized graft bed reversed diabetes when combined with postoperative 50% oxygen inhalation for 3 days, a number comparable to that required for intrahepatic transplantation; in the absence of oxygen treatment, diabetes was not reversed. Thus, we show oxygen inhalation to be a simple and promising approach to successfully establishing subcutaneous islet transplantation.
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Affiliation(s)
- H Komatsu
- Division of Developmental and Translational Diabetes and Endocrinology Research, Department of Diabetes and Metabolic Research, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - J Rawson
- Division of Developmental and Translational Diabetes and Endocrinology Research, Department of Diabetes and Metabolic Research, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - A Barriga
- Division of Developmental and Translational Diabetes and Endocrinology Research, Department of Diabetes and Metabolic Research, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - N Gonzalez
- Division of Developmental and Translational Diabetes and Endocrinology Research, Department of Diabetes and Metabolic Research, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - D Mendez
- Division of Developmental and Translational Diabetes and Endocrinology Research, Department of Diabetes and Metabolic Research, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - J Li
- Division of Developmental and Translational Diabetes and Endocrinology Research, Department of Diabetes and Metabolic Research, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - K Omori
- Division of Developmental and Translational Diabetes and Endocrinology Research, Department of Diabetes and Metabolic Research, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - F Kandeel
- Division of Developmental and Translational Diabetes and Endocrinology Research, Department of Diabetes and Metabolic Research, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Y Mullen
- Division of Developmental and Translational Diabetes and Endocrinology Research, Department of Diabetes and Metabolic Research, Beckman Research Institute of City of Hope, Duarte, CA, USA
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47
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Abstract
Background Methodology Results Conclusion
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48
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Long-term Functioning of Allogeneic Islets in Subcutaneous Tissue Pretreated With a Novel Cyclic Peptide Without Immunosuppressive Medication. Transplantation 2018; 102:417-425. [DOI: 10.1097/tp.0000000000001923] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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49
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The Optimal Timing for Pancreatic Islet Transplantation into Subcutaneous Scaffolds Assessed by Multimodal Imaging. CONTRAST MEDIA & MOLECULAR IMAGING 2017; 2017:5418495. [PMID: 29440984 PMCID: PMC5758856 DOI: 10.1155/2017/5418495] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Revised: 11/16/2017] [Accepted: 11/22/2017] [Indexed: 12/21/2022]
Abstract
Subcutaneously implanted polymeric scaffolds represent an alternative transplantation site for pancreatic islets (PIs) with the option of vascularisation enhancement by mesenchymal stem cells (MSC). Nevertheless, a proper timing of the transplantation steps is crucial. In this study, scaffolds supplemented with plastic rods were implanted into diabetic rats and two timing schemes for subsequent transplantation of bioluminescent PIs (4 or 7 days after rod removal) were examined by multimodal imaging. The cavities were left to heal spontaneously or with 10 million injected MSCs. Morphological and vascularisation changes were examined by MRI, while the localisation and viability of transplanted islets were monitored by bioluminescence imaging. The results show that PIs transplanted 4 days after rod removal showed the higher optical signal and vascularisation compared to transplantation after 7 days. MSCs slightly improved vascularisation of the graft but hindered therapeutic efficiency of PIs. Long-term glycaemia normalisation (4 months) was attained in 80% of animals. In summary, multimodal imaging confirmed the long-term survival and function of transplanted PIs in the devices. The best outcome was reached with PIs transplanted on day 4 after rod removal and therefore the suggested protocol holds a potential for further applications.
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50
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Pathak S, Regmi S, Gupta B, Poudel BK, Pham TT, Yong CS, Kim JO, Kim JR, Park MH, Bae YK, Yook S, Ahn CH, Jeong JH. Single synchronous delivery of FK506-loaded polymeric microspheres with pancreatic islets for the successful treatment of streptozocin-induced diabetes in mice. Drug Deliv 2017; 24:1350-1359. [PMID: 28911248 PMCID: PMC8241191 DOI: 10.1080/10717544.2017.1377317] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Revised: 09/02/2017] [Accepted: 09/05/2017] [Indexed: 12/18/2022] Open
Abstract
Immune rejection after transplantation is common, which leads to prompt failure of the graft. Therefore, to prolong the survival time of the graft, immunosuppressive therapy is the norm. Here, we report a robust immune protection protocol using FK506-loaded microspheres (FK506M) in injectable hydrogel. Pancreatic islets were codelivered with the FK506M into the subcutaneous space of streptozocin-induced diabetic mice. The islets codelivered with 10 mg/kg FK506M maintained normal blood glucose levels during the study period (survival rate: 60%). However, transplantation of islets and FK506M at different sites hardly controlled the blood glucose level (survival rate: 20%). Immunohistochemical analysis revealed an intact morphology of the islets transplanted with FK506M. In addition, minimal number of immune cells invaded inside the gel of the islet-FK506M group. The single injection of FK506M into the local microenvironment effectively inhibited immune rejection and prolonged the survival time of transplanted islets in a xenograft model.
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Affiliation(s)
- Shiva Pathak
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, Republic of Korea
| | - Shobha Regmi
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, Republic of Korea
| | - Biki Gupta
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, Republic of Korea
| | - Bijay K. Poudel
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, Republic of Korea
| | - Tung Thanh Pham
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, Republic of Korea
| | - Chul Soon Yong
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, Republic of Korea
| | - Jong Oh Kim
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, Republic of Korea
| | - Jae-Ryong Kim
- Department of Biochemistry and Molecular Biology and Smart-Aging Convergence Research Center, College of Medicine, Yeungnam University, Daegu, Republic of Korea
| | - Min Hui Park
- Department of Pathology, Yeungnam University College of Medicine, Daegu, Republic of Korea
| | - Young Kyung Bae
- Department of Pathology, Yeungnam University College of Medicine, Daegu, Republic of Korea
| | - Simmyung Yook
- College of Pharmacy, Keimyung University, Daegu, Republic of Korea
| | - Cheol-Hee Ahn
- Engineering Research Institute, Department of Materials Science and Engineering, Seoul National University, Seoul, Republic of Korea
| | - Jee-Heon Jeong
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, Republic of Korea
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