|
1
|
Deshpande R, Augustine T. Smart transplants: emerging role of nanotechnology and big data in kidney and islet transplantation, a frontier in precision medicine. Front Immunol 2025; 16:1567685. [PMID: 40264762 PMCID: PMC12011751 DOI: 10.3389/fimmu.2025.1567685] [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: 01/27/2025] [Accepted: 03/25/2025] [Indexed: 04/24/2025] Open
Abstract
Kidney and islet transplantation has revolutionized the management of renal failure and diabetes. Transplantation is considered as excellent therapeutic intervention for most suitable patients. While advancements in the surgical aspects, immunosuppression and outcomes have potentially plateaued, new technologies have developed which could enhance transplantation with benefits to patients and clinical teams alike. The science of nanotechnology and big data advancements are two such technologies, collectively paving the way for smarter transplantation solutions. Nanotechnology offers novel strategies to overcome critical challenges, including organ preservation, ischemia-reperfusion injury and immune modulation. Innovations such as nanoparticle-based drug delivery systems, biocompatible encapsulation technologies for islet transplants, and implantable artificial kidneys are redefining the standards of care. Meanwhile, big data analytics harness vast datasets to optimize donor-recipient matching, refine predictive models for post-transplant outcomes, and personalize therapeutic regimens. Integrating these technologies forms a synergistic framework where nanotechnology enhances therapeutic precision and big data provides actionable insights, enabling clinicians to adopt proactive, patient-specific strategies. By addressing unmet needs and leveraging the combined potential of nanotechnology and big data, this transformative approach promises to improve graft survival, functionality, and overall patient outcomes, marking a paradigm shift in transplantation medicine. These developments will also be accelerated with integration of the rapidly advancing science of artificial intelligence.
Collapse
Affiliation(s)
- Rajkiran Deshpande
- Department of Renal and Pancreas Transplantation and General Surgery, Manchester Royal Infirmary, Manchester University Foundation Trust, Manchester, United Kingdom
| | - Titus Augustine
- Department of Renal and Pancreas Transplantation and General Surgery, Manchester Royal Infirmary, Manchester University Foundation Trust, Manchester, United Kingdom
- Department Faculty of Biology, Medicine and Health, Division of Diabetes, Endocrinology and Gastroenterology, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom
| |
Collapse
|
|
2
|
Pham JA, Coronel MM. Unlocking Transplant Tolerance with Biomaterials. Adv Healthc Mater 2025; 14:e2400965. [PMID: 38843866 PMCID: PMC11834385 DOI: 10.1002/adhm.202400965] [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: 03/14/2024] [Revised: 05/31/2024] [Indexed: 07/04/2024]
Abstract
For patients suffering from organ failure due to injury or autoimmune disease, allogeneic organ transplantation with chronic immunosuppression is considered the god standard in terms of clinical treatment. However, the true "holy grail" of transplant immunology is operational tolerance, in which the recipient exhibits a sustained lack of alloreactivity toward unencountered antigen presented by the donor graft. This outcome is resultant from critical changes to the phenotype and genotype of the immune repertoire predicated by the activation of specific signaling pathways responsive to soluble and mechanosensitive cues. Biomaterials have emerged as a medium for interfacing with and reprogramming these endogenous pathways toward tolerance in precise, minimally invasive, and spatiotemporally defined manners. By viewing seminal and contemporary breakthroughs in transplant tolerance induction through the lens of biomaterials-mediated immunomodulation strategies-which include intrinsic material immunogenicity, the depot effect, graft coatings, induction and delivery of tolerogenic immune cells, biomimicry of tolerogenic immune cells, and in situ reprogramming-this review emphasizes the stunning diversity of approaches in the field and spotlights exciting future directions for research to come.
Collapse
Affiliation(s)
- John‐Paul A. Pham
- Department of Biomedical EngineeringUniversity of MichiganAnn ArborMI48109USA
- Elizabeth Caswell Diabetes InstituteUniversity of MichiganAnn ArborMI48109USA
| | - María M. Coronel
- Department of Biomedical EngineeringUniversity of MichiganAnn ArborMI48109USA
- Elizabeth Caswell Diabetes InstituteUniversity of MichiganAnn ArborMI48109USA
| |
Collapse
|
|
3
|
Primavera R, Wang J, Buchwald P, Ganguly A, Patel S, Bettencourt L, Chetty S, Yarani R, Regmi S, Levitte S, Kevadiya B, Guindani M, Decuzzi P, Thakor AS. Controlled Nutrient Delivery to Pancreatic Islets Using Polydopamine-Coated Mesoporous Silica Nanoparticles. NANO LETTERS 2025; 25:939-950. [PMID: 39791700 DOI: 10.1021/acs.nanolett.4c03613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/12/2025]
Abstract
In this study, we designed a nanoscale platform for sustained amino acid delivery to support transplanted pancreatic islets. The platform features mesoporous silica nanoparticles (MSNPs) loaded with glutamine (G), an essential amino acid required for islet survival and function, and coated with polydopamine (PD). We investigated various PD concentrations (0.5-2 mg/mL) and incubation times (0.5-2 h) to optimize G release, identifying that a PD concentration of 0.5 mg/mL incubated for 0.5 h yielded the best results to support islet viability and functionality ex vivo, particularly under inflammatory conditions. In syngeneic islet transplantation in STZ-diabetic mice, G alone provided only temporary benefits; however, PD-G-MSNPs significantly improved islet engraftment and function, with animals maintaining glycemic control for 30 days due to controlled G release. Our findings support the use of this nanoscale platform to provide essential nutrients like G to transplanted islets until they can establish their own blood and nutrient supply.
Collapse
Affiliation(s)
- Rosita Primavera
- Department of Radiology, Interventional Radiology Innovation at Stanford (IRIS), Stanford University School of Medicine, Palo Alto, California 94304, United States
| | - Jing Wang
- Department of Radiology, Interventional Radiology Innovation at Stanford (IRIS), Stanford University School of Medicine, Palo Alto, California 94304, United States
| | - Peter Buchwald
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, Florida 33136, United States
| | - Abantika Ganguly
- Department of Radiology, Interventional Radiology Innovation at Stanford (IRIS), Stanford University School of Medicine, Palo Alto, California 94304, United States
| | - Shaini Patel
- Department of Radiology, Interventional Radiology Innovation at Stanford (IRIS), Stanford University School of Medicine, Palo Alto, California 94304, United States
| | - Lili Bettencourt
- Department of Radiology, Interventional Radiology Innovation at Stanford (IRIS), Stanford University School of Medicine, Palo Alto, California 94304, United States
| | - Shashank Chetty
- Department of Radiology, Interventional Radiology Innovation at Stanford (IRIS), Stanford University School of Medicine, Palo Alto, California 94304, United States
| | - Reza Yarani
- Translational Type 1 Diabetes Research, Department of Clinical, Research, Steno Diabetes Center Copenhagen, Herlev 2730, Denmark
| | - Shobha Regmi
- Department of Radiology, Interventional Radiology Innovation at Stanford (IRIS), Stanford University School of Medicine, Palo Alto, California 94304, United States
| | - Steven Levitte
- Department of Radiology, Interventional Radiology Innovation at Stanford (IRIS), Stanford University School of Medicine, Palo Alto, California 94304, United States
| | - Bhavesh Kevadiya
- Department of Radiology, Interventional Radiology Innovation at Stanford (IRIS), Stanford University School of Medicine, Palo Alto, California 94304, United States
| | - Michele Guindani
- Department of Biostatistics, Jonathan and Karin Fielding School of Public Health, University of California Los Angeles, Los Angeles, California 90095, United States
| | - Paolo Decuzzi
- Laboratory of Nanotechnology for Precision Medicine, Fondazione Istituto Italiano di Tecnologia, Via Morego 30, Genoa 16163, Italy
| | - Avnesh S Thakor
- Department of Radiology, Interventional Radiology Innovation at Stanford (IRIS), Stanford University School of Medicine, Palo Alto, California 94304, United States
| |
Collapse
|
|
4
|
Ajmal N, Bogart MC, Khan P, Max-Harry IM, Healy AM, Nunemaker CS. Identifying Promising Immunomodulators for Type 1 Diabetes (T1D) and Islet Transplantation. J Diabetes Res 2024; 2024:5151171. [PMID: 39735417 PMCID: PMC11679277 DOI: 10.1155/jdr/5151171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Accepted: 12/04/2024] [Indexed: 12/31/2024] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune chronic disorder that damages beta cells in the pancreatic islets of Langerhans and results in hyperglycemia due to the loss of insulin. Exogenous insulin therapy can save lives but does not stop disease progression. Thus, an effective therapy may require beta cell restoration and suppression of the autoimmune response. However, currently, there are no treatment options available that can reverse T1D. Within the National Clinical Trial (NCT) database, a majority of over 3000 trials to treat T1D are devoted to insulin therapy. This review focuses on noninsulin pharmacological therapies, specifically immunomodulators. Many investigational new drugs fall under this category, such as the recently FDA-approved CD3 monoclonal antibody teplizumab to delay the onset of T1D. In total, we identified 39 different immunomodulatory investigational drugs. FDA-approved teplizumab for Stage 2 T1D is discussed along with other immunomodulators that have been tested in Phase 3 clinical trials or higher, including otelixizumab (another anti-CD3 monoclonal antibody), daclizumab (an anti-CD25 monoclonal antibody), ladarixin (CXCR1/2 inhibitor), and antithymocyte globulin (ATG). Immunomodulators also play roles in islet transplantation and cellular therapies like FDA-approved Lantidra. Several immunomodulators involved in Phase 3 clinical studies of islet transplantation are also discussed, including alemtuzumab, basiliximab, etanercept, and reparixin, some already FDA-approved for other uses. These include alemtuzumab, basiliximab, etanercept, and reparixin, some of which have been FDA-approved for other uses. This review provides background, mechanism of action, results of completed trials, and adverse effects as well as details regarding ongoing clinical trials for each of these immunomodulators. Trial Registration: ClinicalTrials.gov identifier: NCT03875729, NCT01030861, NCT00129259, NCT00385697, NCT01280682; NCT03929601, NCT04598893, NCT05757713, NCT00678886, NCT01123083, NCT00064714, NCT00468117, NCT04628481, NCT01106157, NCT02215200, NCT00331162, NCT00679042, NCT01220856, NCT01817959.
Collapse
Affiliation(s)
- Nida Ajmal
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, USA
- Translational Biomedical Sciences Graduate Program, Ohio University, Athens, Ohio, USA
| | | | - Palwasha Khan
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, USA
- Translational Biomedical Sciences Graduate Program, Ohio University, Athens, Ohio, USA
| | - Ibiagbani M. Max-Harry
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, USA
- Molecular and Cellular Biology Graduate Program, Ohio University, Athens, Ohio, USA
| | - Amber M. Healy
- Department of Specialty Medicine, Ohio University, Athens, Ohio, USA
| | - Craig S. Nunemaker
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, USA
- Translational Biomedical Sciences Graduate Program, Ohio University, Athens, Ohio, USA
- Molecular and Cellular Biology Graduate Program, Ohio University, Athens, Ohio, USA
| |
Collapse
|
|
5
|
Sarvari M, Alavi-Moghadam S, Aghayan HR, Tayanloo-Beik A, Payab M, Tootee A, Sajjadi-Jazi SM, Larijani B, Arjmand B. Stem cells researches and therapies towards endocrine diseases treatment; strategies, challenges, and opportunities. J Diabetes Metab Disord 2024; 23:1461-1467. [PMID: 39610510 PMCID: PMC11599503 DOI: 10.1007/s40200-020-00674-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Accepted: 10/27/2020] [Indexed: 02/06/2023]
Abstract
Due to the limitations of organ transplantation and the urgent need for treatment of chronic diseases, the benefit of stem cells for treatment has been studied and evaluated as an effective approach worldwide. One of the leading countries in this field is Iran. In this respect, several research and treatment institutes, including endocrinology and metabolism research institute are active in the use of stem cells in Iran. Herein, the aim is to review strategies, challenges, and opportunities for stem cell research and treatment in endocrinology and metabolism research institute.
Collapse
Affiliation(s)
- Masoumeh Sarvari
- Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Sepideh Alavi-Moghadam
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Hamid Reza Aghayan
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Akram Tayanloo-Beik
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Moloud Payab
- Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Tootee
- Diabetes Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Sayed Mahmoud Sajjadi-Jazi
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Babak Arjmand
- Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
6
|
Kaibagarova I, Saparbaev S, Aringazina R, Zhumabaev M, Nurgaliyeva Z. The role of fetal pancreatic islet cell transplantation in the treatment of type 2 diabetes mellitus. J Diabetes Metab Disord 2024; 23:1949-1957. [PMID: 39610528 PMCID: PMC11599508 DOI: 10.1007/s40200-024-01448-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 05/24/2024] [Indexed: 11/30/2024]
Abstract
Objectives Diabetes mellitus has a negative impact on patients' lives and is a significant medical and social problem. Due to the high prevalence of diabetes mellitus, shortage of donor materials, immune rejection of the pancreas and limited efficacy of existing treatment methods, the study of promising and more effective approaches to the treatment of this disease, such as transplantation of fetal pancreatic islet cells, becomes relevant. The aim of the study is to determine the efficacy and necessity of fetal pancreatic islet cell transplantation in the treatment of type 2 diabetes mellitus. Methods The study was carried out with the help of analytical-synthetic method, literature review and analysis of medical databases corresponding to the topic of work, clinical and experimental studies conducted by other authors were considered. Results As a result of this work, it was found that the use of fetal stem cell transplantation is an effective method in the treatment of diabetes. Studies confirm that this method reduces hyperglycaemia and NOMA index, increases c-peptide values without serious side effects on the background of treatment. Conclusions Fetal islet cells have advantages in cell culture, relatively low immunogenicity, effective engraftment, although they may produce less insulin relative to adult somatic stem cells. Transplanted islet cells are able to replace and renew the function of the recipient's own pancreatic β-cells, and prevent their destruction. Fetal pancreatic islet cell transplantation is a promising treatment option for type 2 diabetes that can complement or replace existing therapies, improving patients' glucose control.
Collapse
Affiliation(s)
- Indira Kaibagarova
- Department of Pharmacology, West Kazakhstan Marat Ospanov Medical University, 68 Maresyev Str, Aktobe, 030012 Republic of Kazakhstan
| | - Samat Saparbaev
- Medical Center Al-Jami, 23 Mailin Str, Astana, 010000 Republic of Kazakhstan
| | - Raisa Aringazina
- Department of Internal Diseases No. 1, West Kazakhstan Marat Ospanov Medical University, 68 Maresyev Str., 030012 Aktobe, Republic of Kazakhstan
| | - Marat Zhumabaev
- Department of Surgical Diseases No. 1, West Kazakhstan Marat Ospanov Medical University, 68 Maresyev Str., 030012 Aktobe, Republic of Kazakhstan
| | - Zhansulu Nurgaliyeva
- Department of Pharmacology, West Kazakhstan Marat Ospanov Medical University, 68 Maresyev Str, Aktobe, 030012 Republic of Kazakhstan
| |
Collapse
|
|
7
|
Langlois A, Pinget M, Kessler L, Bouzakri K. Islet Transplantation: Current Limitations and Challenges for Successful Outcomes. Cells 2024; 13:1783. [PMID: 39513890 PMCID: PMC11544954 DOI: 10.3390/cells13211783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 10/22/2024] [Accepted: 10/25/2024] [Indexed: 11/16/2024] Open
Abstract
Islet transplantation is a promising approach for treating patients with unstable T1DM. However, it is confronted with numerous obstacles throughout the various stages of the transplantation procedure. Significant progress has been made over the last 25 years in understanding the mechanisms behind the loss of functional islet mass and in developing protective strategies. Nevertheless, at present, two to three pancreases are still needed to treat a single patient, which limits the maximal number of patients who can benefit from islet transplantation. Thus, this publication provides an overview of recent scientific findings on the various issues affecting islet transplantation. Specifically, we will focus on the understanding of the mechanisms involved and the strategies developed to alleviate these problems from the isolation stage to the post-transplantation phase. Finally, we hope that this review will highlight new avenues of action, enabling us to propose pancreatic islet transplantation to a maximum number of patients with T1DM.
Collapse
Affiliation(s)
- Allan Langlois
- UR «Diabète et Thérapeutiques», Centre Européen d’Étude du Diabète, Université de Strasbourg, Boulevard René Leriche, 67200 Strasbourg, France; (A.L.); (M.P.)
| | - Michel Pinget
- UR «Diabète et Thérapeutiques», Centre Européen d’Étude du Diabète, Université de Strasbourg, Boulevard René Leriche, 67200 Strasbourg, France; (A.L.); (M.P.)
| | - Laurence Kessler
- Department of Endocrinology, Diabetes and Nutrition, University Hospital of Strasbourg, 67200 Strasbourg, France;
- Inserm UMR 1260, Nanomédicine Regenerative, University of Strasbourg, 67085 Strasbourg, France
| | - Karim Bouzakri
- UR «Diabète et Thérapeutiques», Centre Européen d’Étude du Diabète, Université de Strasbourg, Boulevard René Leriche, 67200 Strasbourg, France; (A.L.); (M.P.)
| |
Collapse
|
|
8
|
Shin DY, Park JS, Lee HS, Shim W, Jin L, Lee KW, Park JB, Kim DH, Kim JH. The effect of hydroxyethyl starch as a cryopreservation agent during freezing of mouse pancreatic islets. Biochem Biophys Rep 2024; 38:101658. [PMID: 38362049 PMCID: PMC10867579 DOI: 10.1016/j.bbrep.2024.101658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 01/25/2024] [Accepted: 02/01/2024] [Indexed: 02/17/2024] Open
Abstract
Islet transplantation is the most effective treatment strategy for type 1 diabetes. Long-term storage at ultralow temperatures can be used to prepare sufficient islets of good quality for transplantation. For freezing islets, dimethyl sulfoxide (DMSO) is a commonly used penetrating cryoprotective agent (CPA). However, the toxicity of DMSO is a major obstacle to cell cryopreservation. Hydroxyethyl starch (HES) has been proposed as an alternative CPA. To investigate the effects of two types of nonpermeating CPA, we compared 4 % HES 130 and HES 200 to 10 % DMSO in terms of mouse islet yield, viability, and glucose-stimulated insulin secretion (GSIS). After one day of culture, islets were cryopreserved in each solution. After three days of cryopreservation, islet recovery was significantly higher in the HES 130 and HES 200 groups than in the DMSO group. Islet viability in the HES 200 group was also significantly higher than that in the DMSO group on Day 1 and Day 3. Stimulation indices determined by GSIS were higher in the HES 130 and 200 groups than in the DMSO group on Day 3. After three days of cryopreservation, HES 130 and HES 200 both reduced the expression of apoptosis- and necrosis-associated proteins and promoted the survival of islets. In conclusion, the use of HES as a CPA improved the survival and insulin secretion of cryopreserved islets compared with the use of a conventional CPA.
Collapse
Affiliation(s)
- Du Yeon Shin
- Transplantation Research Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, 06351, Republic of Korea
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Graduate School, Sungkyunkwan University, Seoul, 06351, Republic of Korea
| | - Jae Suh Park
- Department of Pediatrics, Hematology/Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06355, Republic of Korea
| | - Han-Sin Lee
- R&D Center, Cellstormer, Suwon-si, Gyeonggi-do, 16677, Republic of Korea
| | - Wooyoung Shim
- R&D Center, Cellstormer, Suwon-si, Gyeonggi-do, 16677, Republic of Korea
| | - Lauren Jin
- Department of Pediatrics, Hematology/Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06355, Republic of Korea
| | - Kyo Won Lee
- Transplantation Research Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, 06351, Republic of Korea
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Republic of Korea
| | - Jae Berm Park
- Transplantation Research Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, 06351, Republic of Korea
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Graduate School, Sungkyunkwan University, Seoul, 06351, Republic of Korea
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Republic of Korea
| | - Dong Hyun Kim
- Department of Pediatrics, Hematology/Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06355, Republic of Korea
| | - Jae Hyeon Kim
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Graduate School, Sungkyunkwan University, Seoul, 06351, Republic of Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06355, Republic of Korea
| |
Collapse
|
|
9
|
Srinivas Rao S, Pandey A, Mroueh N, Elias N, Katabathina VS, Kambadakone A. Comprehensive review of imaging in pancreas transplantation: a primer for radiologists. Abdom Radiol (NY) 2024; 49:2428-2448. [PMID: 38900315 DOI: 10.1007/s00261-024-04383-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 05/06/2024] [Accepted: 05/10/2024] [Indexed: 06/21/2024]
Abstract
Pancreas transplantation is a complex surgical procedure performed to restore normoglycemia in patients with type 1 diabetes and includes whole/segmental organ transplant and islet cell transplantation (ICT). In the United States, simultaneous pancreas-kidney transplant (SPK) is most commonly performed due to the higher occurrence of end-stage renal disease in diabetic patients. Understanding the surgical technique and postoperative anatomy is imperative for effective and accurate surveillance following transplantation. Imaging plays an essential role in patients with pancreatic transplants and is often used to evaluate viability, vascular and parenchymal anatomy, and identify potential complications. Imaging techniques such as ultrasound, color and spectral Doppler, computed tomography (CT), magnetic resonance imaging (MRI), and angiography have a complementary role in the postoperative evaluation following a pancreas transplant. The common complications after a whole organ pancreas transplant include vascular thrombosis, graft rejection, pancreatitis, and infections. Complications can be classified into vascular (partial or complete venous thrombosis, arterial thrombosis, stenosis or pseudoaneurysm), parenchymal (pancreatitis, graft rejection), and bowel-related or miscellaneous causes (bowel obstruction, anastomotic leak, and peripancreatic fluid collections). Islet cell transplantation is an innovative therapy for patients with type 1 diabetes. It involves isolating insulin-producing islet cells from donor pancreas and transplanting into recipients, to provide long-term insulin independence or significantly reduce insulin requirements. In recent years, isolation techniques, immunosuppressive regimens, and post-transplant monitoring advancements have propelled ICT as a viable therapeutic option. This comprehensive review aims to provide insights into the current state-of-the-art imaging techniques discussing both normal and abnormal features following pancreas transplantation.
Collapse
Affiliation(s)
- Shravya Srinivas Rao
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, White 270, Boston, MA, 02114-2696, USA
| | - Ankur Pandey
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, White 270, Boston, MA, 02114-2696, USA
| | - Nayla Mroueh
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, White 270, Boston, MA, 02114-2696, USA
- Department of Internal Medicine, Allegheny General Hospital, Pittsburgh, PA, 15212, USA
| | - Nahel Elias
- Department of Surgery, Transplantation Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114-2696, USA
| | - Venkata S Katabathina
- Department of Radiology, University of Texas Health at San Antonio, Floyd Curl Drive, 7703, San Antonio, TX, 78229, USA
| | - Avinash Kambadakone
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, White 270, Boston, MA, 02114-2696, USA.
| |
Collapse
|
|
10
|
Wang Q, Huang YX, Liu L, Zhao XH, Sun Y, Mao X, Li SW. Pancreatic islet transplantation: current advances and challenges. Front Immunol 2024; 15:1391504. [PMID: 38887292 PMCID: PMC11180903 DOI: 10.3389/fimmu.2024.1391504] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Accepted: 05/20/2024] [Indexed: 06/20/2024] Open
Abstract
Diabetes is a prevalent chronic disease that traditionally requires severe reliance on medication for treatment. Oral medication and exogenous insulin can only temporarily maintain blood glucose levels and do not cure the disease. Most patients need life-long injections of exogenous insulin. In recent years, advances in islet transplantation have significantly advanced the treatment of diabetes, allowing patients to discontinue exogenous insulin and avoid complications.Long-term follow-up results from recent reports on islet transplantation suggest that they provide significant therapeutic benefit although patients still require immunotherapy, suggesting the importance of future transplantation strategies. Although organ shortage remains the primary obstacle for the development of islet transplantation, new sources of islet cells, such as stem cells and porcine islet cells, have been proposed, and are gradually being incorporated into clinical research. Further research on new transplantation sites, such as the subcutaneous space and mesenteric fat, may eventually replace the traditional portal vein intra-islet cell infusion. Additionally, the immunological rejection reaction in islet transplantation will be resolved through the combined application of immunosuppressant agents, islet encapsulation technology, and the most promising mesenchymal stem cells/regulatory T cell and islet cell combined transplantation cell therapy. This review summarizes the progress achieved in islet transplantation, and discusses the research progress and potential solutions to the challenges faced.
Collapse
Affiliation(s)
- Qi Wang
- Department of Hepatobiliary and Pancreatic Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Yu-xi Huang
- Department of Hepatobiliary and Pancreatic Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Long Liu
- Department of Hepatobiliary and Pancreatic Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiao-hong Zhao
- Department of Pharmacy, Taizhou Hospital, Zhejiang University, Taizhou, Zhejiang, China
| | - Yi Sun
- MRL Global Medical Affairs, MSD China, Shanghai, China
| | - Xinli Mao
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
- Key Laboratory of Minimally Invasive Techniques and Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Shao-wei Li
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
- Key Laboratory of Minimally Invasive Techniques and Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| |
Collapse
|
|
11
|
Ho BX, Teo AKK, Ng NHJ. Innovations in bio-engineering and cell-based approaches to address immunological challenges in islet transplantation. Front Immunol 2024; 15:1375177. [PMID: 38650946 PMCID: PMC11033429 DOI: 10.3389/fimmu.2024.1375177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 03/11/2024] [Indexed: 04/25/2024] Open
Abstract
Human allogeneic pancreatic islet transplantation is a life-changing treatment for patients with severe Type 1 Diabetes (T1D) who suffer from hypoglycemia unawareness and high risk of severe hypoglycemia. However, intensive immunosuppression is required to prevent immune rejection of the graft, that may in turn lead to undesirable side effects such as toxicity to the islet cells, kidney toxicity, occurrence of opportunistic infections, and malignancies. The shortage of cadaveric human islet donors further limits islet transplantation as a treatment option for widespread adoption. Alternatively, porcine islets have been considered as another source of insulin-secreting cells for transplantation in T1D patients, though xeno-transplants raise concerns over the risk of endogenous retrovirus transmission and immunological incompatibility. As a result, technological advancements have been made to protect transplanted islets from immune rejection and inflammation, ideally in the absence of chronic immunosuppression, to improve the outcomes and accessibility of allogeneic islet cell replacement therapies. These include the use of microencapsulation or macroencapsulation devices designed to provide an immunoprotective environment using a cell-impermeable layer, preventing immune cell attack of the transplanted cells. Other up and coming advancements are based on the use of stem cells as the starting source material for generating islet cells 'on-demand'. These starting stem cell sources include human induced pluripotent stem cells (hiPSCs) that have been genetically engineered to avoid the host immune response, curated HLA-selected donor hiPSCs that can be matched with recipients within a given population, and multipotent stem cells with natural immune privilege properties. These strategies are developed to provide an immune-evasive cell resource for allogeneic cell therapy. This review will summarize the immunological challenges facing islet transplantation and highlight recent bio-engineering and cell-based approaches aimed at avoiding immune rejection, to improve the accessibility of islet cell therapy and enhance treatment outcomes. Better understanding of the different approaches and their limitations can guide future research endeavors towards developing more comprehensive and targeted strategies for creating a more tolerogenic microenvironment, and improve the effectiveness and sustainability of islet transplantation to benefit more patients.
Collapse
Affiliation(s)
- Beatrice Xuan Ho
- Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- BetaLife Pte Ltd, Singapore, Singapore
| | - Adrian Kee Keong Teo
- Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Precision Medicine Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Natasha Hui Jin Ng
- Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| |
Collapse
|
|
12
|
Wang Y, Ding H, Guo C, Bao Q, Li D, Xiong Y. LncRNA Malat1 regulates iPSC-derived β-cell differentiation by targeting the miR-15b-5p/Ihh axis. Cell Signal 2024; 113:110975. [PMID: 37972802 DOI: 10.1016/j.cellsig.2023.110975] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 10/18/2023] [Accepted: 11/13/2023] [Indexed: 11/19/2023]
Abstract
BACKGROUND Differentiation of induced pluripotent stem cells (iPSCs)-derived β-like cells is a novel strategy for treatment of type 1 diabetes. Elucidation of the regulatory mechanisms of long noncoding RNAs (lncRNAs) in β-like cells derived from iPSCs is important for understanding the development of the pancreas and pancreatic β-cells and may improve the quality of β-like cells for stem cell therapy. METHODS β-like cells were derived from iPSCs in a three-step protocol. RNA sequencing and bioinformatics analysis were carried out to screen the differentially expressed lncRNAs and identify the putative target genes separately. LncRNA Malat1 was chosen for further research. Series of loss and gain of functions experiments were performed to study the biological function of LncRNA Malat1. Quantitative real-time PCR (qRT-PCR), Western blot (WB) analysis and immunofluorescence (IF) staining were carried out to separately detect the functions of pancreatic β-cells at the mRNA and protein levels. Cytoplasmic and nuclear RNA fractionation and fluorescence in situ hybridization (FISH) were used to determine the subcellar location of lncRNA Malat1 in β-like cells. Enzyme-linked immunosorbent assays (ELISAs) were performed to examine the differentiation and insulin secretion of β-like cells after stimulation with different glucose concentrations. Structural interactions between lncRNA Malat1 and miR-15b-5p and between miR-15b-5p/Ihh were detected by dual luciferase reporter assays (LRAs). RESULTS We found that the expression of lncRNA Malat1 declined during differentiation, and overexpression (OE) of lncRNA Malat1 notably impaired the differentiation and maturation of β-like cells derived from iPSCs in vitro and in vivo. Most importantly, lncRNA Malat1 could function as a competing endogenous RNA (ceRNA) of miR-15b-5p to regulate the expression of Ihh according to bioinformatics prediction, mechanistic analysis and downstream experiments. CONCLUSION This study established an unreported regulatory network of lncRNA Malat1 and the miR-15b-5p/Ihh axis during the differentiation of iPSCs into β-like cells. In addition to acting as an oncogene promoting tumorigenesis, lncRNA Malat1 may be an effective and novel target for treatment of diabetes in the future.
Collapse
Affiliation(s)
- Yao Wang
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University, Nantong 226001, China; Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, China
| | - Haoxiang Ding
- Nantong University Medical School, Nantong 226001, China
| | - Chengfeng Guo
- Nantong University Medical School, Nantong 226001, China
| | - Qian Bao
- Nantong University Medical School, Nantong 226001, China
| | - Dongqian Li
- Nantong University Medical School, Nantong 226001, China
| | - Yicheng Xiong
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University, Nantong 226001, China.
| |
Collapse
|
|
13
|
Walker SL, Noble J, Thomson A, Moran CM, Mellis D, Lee I, White LJ, Forbes S. Ultrasound-guided hepatic portal vein injection is not a reproducible technique for delivery of cell therapies to the liver in mice. Diabet Med 2023; 40:e15192. [PMID: 37531444 PMCID: PMC10947537 DOI: 10.1111/dme.15192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 07/24/2023] [Accepted: 07/31/2023] [Indexed: 08/04/2023]
Abstract
AIMS Our aim was to determine if ultrasound-guided HPV injection in mice would provide reproducible and reliable results, as is currently obtained via open laparotomy techniques, and offer a surgical refinement to emulate islet transplantation in humans. METHODS Fluorescent-polymer microparticles (20 μm) were injected (27G-needle) into the HPV via open laparotomy (n = 4) or under ultrasound-guidance (n = 4) using an MX550D-transducer with a Vevo3100-scanner (FUJIFILM VisualSonics, Inc.). Mice were culled 24-h post injection; organs were frozen, step sectioned (10 μm-slices) and 10 sections/mouse (50 μm-spacing) were quantified for microparticles in the liver and other organs by fluorescent microscopy. RESULTS Murine HPV injection, via open laparotomy-route, resulted in widespread distribution of microparticles in the liver, lungs and spleen; ultrasound-guided injection resulted in reduced microparticle delivery (p < 0.0001) and microparticle clustering in distinct areas of the liver at the site of needle penetration, with very few/no microparticles being seen in lung and spleen tissues, hypothesised to be due to flow into the body cavity: liver median (interquartile range) 4.15 (0.00-4.15) versus 0.00 (0.00-0.00) particle-count mm-2 , respectively. CONCLUSIONS Ultrasound-guided injection results in microparticle clustering in the liver, with an overall reduction in microparticle number when compared to open laparotomy HPV injection, and high variability in microparticle-counts detected between mice. Ultrasound-guided injection is not currently a technique that can replace open laparotomy HPV of islet transplantation in mice.
Collapse
Affiliation(s)
- Sophie L. Walker
- BHF Centre for Cardiovascular Science, Queens Medical Research InstituteUniversity of EdinburghEdinburghUK
| | - June Noble
- BHF Centre for Cardiovascular Science, Queens Medical Research InstituteUniversity of EdinburghEdinburghUK
| | - Adrian Thomson
- BHF Centre for Cardiovascular Science, Queens Medical Research InstituteUniversity of EdinburghEdinburghUK
| | - Carmel M. Moran
- BHF Centre for Cardiovascular Science, Queens Medical Research InstituteUniversity of EdinburghEdinburghUK
| | - David Mellis
- BHF Centre for Cardiovascular Science, Queens Medical Research InstituteUniversity of EdinburghEdinburghUK
| | - I‐Ning Lee
- School of Pharmacy, Biodiscovery InstituteUniversity of Nottingham, University ParkNottinghamUK
| | - Lisa J. White
- School of Pharmacy, Biodiscovery InstituteUniversity of Nottingham, University ParkNottinghamUK
| | - Shareen Forbes
- BHF Centre for Cardiovascular Science, Queens Medical Research InstituteUniversity of EdinburghEdinburghUK
| |
Collapse
|
|
14
|
Dhandapani V, Vermette P. Decellularized bladder as scaffold to support proliferation and functionality of insulin-secreting pancreatic cells. J Biomed Mater Res B Appl Biomater 2023; 111:1890-1902. [PMID: 37306142 DOI: 10.1002/jbm.b.35292] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 05/07/2023] [Accepted: 05/31/2023] [Indexed: 06/13/2023]
Abstract
Loss in the number or function of insulin-producing β-cells in pancreatic islets has been associated with diabetes mellitus. Although islet transplantation can be an alternative treatment, complications such as apoptosis, ischaemia and loss of viability have been reported. The use of decellularized organs as scaffolds in tissue engineering is of interest owing to the unique ultrastructure and composition of the extracellular matrix (ECM) believed to act on tissue regeneration. In this study, a cell culture system has been designed to study the effect of decellularized porcine bladder pieces on INS-1 cells, a cell line secreting insulin in response to glucose stimulation. Porcine bladders were decellularized using two techniques: a detergent-containing and a detergent-free methods. The resulting ECMs were characterized for the removal of both cells and dsDNA. INS-1 cells were not viable on ECM produced using detergent (i.e., sodium dodecyl sulfate). INS-1 cells were visualized following 7 days of culture on detergent-free decellularized bladders using a cell viability and metabolism assay (MTT) and cell proliferation quantified (CyQUANT™ NF Cell Proliferation Assay). Further, glucose-stimulated insulin secretion and immunostaining confirmed that cells were functional in response to glucose stimulation, as well as they expressed insulin and interacted with the detergent-free produced ECM, respectively.
Collapse
Affiliation(s)
- Vignesh Dhandapani
- Laboratoire de bio-ingénierie et de biophysique de l'Université de Sherbrooke, Department of Chemical and Biotechnological Engineering, Université de Sherbrooke, Sherbrooke, Canada
- Centre de recherche du CHUS, Faculté de médecine et des sciences de la santé, Sherbrooke, Canada
| | - Patrick Vermette
- Laboratoire de bio-ingénierie et de biophysique de l'Université de Sherbrooke, Department of Chemical and Biotechnological Engineering, Université de Sherbrooke, Sherbrooke, Canada
- Centre de recherche du CHUS, Faculté de médecine et des sciences de la santé, Sherbrooke, Canada
| |
Collapse
|
|
15
|
Doherty DT, Khambalia HA, van Dellen D, Jennings RE, Piper Hanley K. Unlocking the post-transplant microenvironment for successful islet function and survival. Front Endocrinol (Lausanne) 2023; 14:1250126. [PMID: 37711891 PMCID: PMC10497759 DOI: 10.3389/fendo.2023.1250126] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 08/07/2023] [Indexed: 09/16/2023] Open
Abstract
Islet transplantation (IT) offers the potential to restore euglycemia for patients with type 1 diabetes mellitus (T1DM). Despite improvements in islet isolation techniques and immunosuppressive regimes, outcomes remain suboptimal with UK five-year graft survivals (5YGS) of 55% and most patients still requiring exogenous insulin after multiple islet infusions. Native islets have a significant non-endocrine component with dense extra-cellular matrix (ECM), important for islet development, cell survival and function. Collagenase isolation necessarily disrupts this complex islet microenvironment, leaving islets devoid of a supporting framework and increasing vulnerability of transplanted islets. Following portal venous transplantation, a liver injury response is potentially induced, which typically results in inflammation and ECM deposition from liver specific myofibroblasts. The impact of this response may have important impact on islet survival and function. A fibroblast response and ECM deposition at the kidney capsule and eye chamber alongside other implantation sites have been shown to be beneficial for survival and function. Investigating the implantation site microenvironment and the interactions of transplanted islets with ECM proteins may reveal therapeutic interventions to improve IT and stem-cell derived beta-cell therapy.
Collapse
Affiliation(s)
- Daniel T. Doherty
- Faculty of Biology, Medicine & Health, University of Manchester, Manchester, United Kingdom
- Department of Renal & Pancreatic Transplantation, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Hussein A. Khambalia
- Faculty of Biology, Medicine & Health, University of Manchester, Manchester, United Kingdom
- Department of Renal & Pancreatic Transplantation, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - David van Dellen
- Faculty of Biology, Medicine & Health, University of Manchester, Manchester, United Kingdom
- Department of Renal & Pancreatic Transplantation, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Rachel E. Jennings
- Faculty of Biology, Medicine & Health, University of Manchester, Manchester, United Kingdom
- Department of Endocrinology, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Karen Piper Hanley
- Faculty of Biology, Medicine & Health, University of Manchester, Manchester, United Kingdom
| |
Collapse
|
|
16
|
Hayat H, Wang R, Sun A, Mallett CL, Nigam S, Redman N, Bunn D, Gjelaj E, Talebloo N, Alessio A, Moore A, Zinn K, Wei GW, Fan J, Wang P. Deep learning-enabled quantification of simultaneous PET/MRI for cell transplantation monitoring. iScience 2023; 26:107083. [PMID: 37416468 PMCID: PMC10319838 DOI: 10.1016/j.isci.2023.107083] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 02/10/2023] [Accepted: 06/06/2023] [Indexed: 07/08/2023] Open
Abstract
Current methods of in vivo imaging islet cell transplants for diabetes using magnetic resonance imaging (MRI) are limited by their low sensitivity. Simultaneous positron emission tomography (PET)/MRI has greater sensitivity and ability to visualize cell metabolism. However, this dual-modality tool currently faces two major challenges for monitoring cells. Primarily, the dynamic conditions of PET such as signal decay and spatiotemporal change in radioactivity prevent accurate quantification of the transplanted cell number. In addition, selection bias from different radiologists renders human error in segmentation. This calls for the development of artificial intelligence algorithms for the automated analysis of PET/MRI of cell transplantations. Here, we combined K-means++ for segmentation with a convolutional neural network to predict radioactivity in cell-transplanted mouse models. This study provides a tool combining machine learning with a deep learning algorithm for monitoring islet cell transplantation through PET/MRI. It also unlocks a dynamic approach to automated segmentation and quantification of radioactivity in PET/MRI.
Collapse
Affiliation(s)
- Hasaan Hayat
- Precision Health Program, Michigan State University, 766 Service Road, Rm. 2020, East Lansing, MI 48823, USA
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI, USA
- College of Human Medicine, Michigan State University, East Lansing, MI, USA
| | - Rui Wang
- Department of Mathematics, College of Natural Science, Michigan State University, East Lansing, MI, USA
| | - Aixia Sun
- Precision Health Program, Michigan State University, 766 Service Road, Rm. 2020, East Lansing, MI 48823, USA
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI, USA
| | - Christiane L. Mallett
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI, USA
- Institute for Quantitative Health Science and Engineering, Department of Biomedical Engineering, Michigan State University, East Lansing, MI, USA
| | - Saumya Nigam
- Precision Health Program, Michigan State University, 766 Service Road, Rm. 2020, East Lansing, MI 48823, USA
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI, USA
| | - Nathan Redman
- Institute for Quantitative Health Science and Engineering, Department of Biomedical Engineering, Michigan State University, East Lansing, MI, USA
- Department of Biomedical Engineering, College of Engineering, Michigan State University, East Lansing, MI, USA
| | - Demarcus Bunn
- Institute for Quantitative Health Science and Engineering, Department of Biomedical Engineering, Michigan State University, East Lansing, MI, USA
- Department of Biomedical Engineering, College of Engineering, Michigan State University, East Lansing, MI, USA
| | - Elvira Gjelaj
- Precision Health Program, Michigan State University, 766 Service Road, Rm. 2020, East Lansing, MI 48823, USA
- Lyman Briggs College, Michigan State University, East Lansing, MI, USA
| | - Nazanin Talebloo
- Precision Health Program, Michigan State University, 766 Service Road, Rm. 2020, East Lansing, MI 48823, USA
- Department of Chemistry, College of Natural Science, Michigan State University, East Lansing, MI, USA
| | - Adam Alessio
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI, USA
- Institute for Quantitative Health Science and Engineering, Department of Biomedical Engineering, Michigan State University, East Lansing, MI, USA
- Department of Biomedical Engineering, College of Engineering, Michigan State University, East Lansing, MI, USA
- Departments of Computational Mathematics, Science, and Engineering (CMSE), College of Natural Science, Michigan State University, East Lansing, MI, USA
| | - Anna Moore
- Precision Health Program, Michigan State University, 766 Service Road, Rm. 2020, East Lansing, MI 48823, USA
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI, USA
| | - Kurt Zinn
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI, USA
- Institute for Quantitative Health Science and Engineering, Department of Biomedical Engineering, Michigan State University, East Lansing, MI, USA
| | - Guo-Wei Wei
- Department of Mathematics, College of Natural Science, Michigan State University, East Lansing, MI, USA
- Departments of Computational Mathematics, Science, and Engineering (CMSE), College of Natural Science, Michigan State University, East Lansing, MI, USA
- Department of Electrical and Computer Engineering, College of Engineering, Michigan State University, East Lansing, MI, USA
| | - Jinda Fan
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI, USA
- Institute for Quantitative Health Science and Engineering, Department of Biomedical Engineering, Michigan State University, East Lansing, MI, USA
- Department of Chemistry, College of Natural Science, Michigan State University, East Lansing, MI, USA
| | - Ping Wang
- Precision Health Program, Michigan State University, 766 Service Road, Rm. 2020, East Lansing, MI 48823, USA
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI, USA
| |
Collapse
|
|
17
|
Hogrebe NJ, Ishahak M, Millman JR. Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes. Cell Stem Cell 2023; 30:530-548. [PMID: 37146579 PMCID: PMC10167558 DOI: 10.1016/j.stem.2023.04.002] [Citation(s) in RCA: 74] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/20/2023] [Accepted: 04/05/2023] [Indexed: 05/07/2023]
Abstract
The generation of islet-like endocrine clusters from human pluripotent stem cells (hPSCs) has the potential to provide an unlimited source of insulin-producing β cells for the treatment of diabetes. In order for this cell therapy to become widely adopted, highly functional and well-characterized stem cell-derived islets (SC-islets) need to be manufactured at scale. Furthermore, successful SC-islet replacement strategies should prevent significant cell loss immediately following transplantation and avoid long-term immune rejection. This review highlights the most recent advances in the generation and characterization of highly functional SC-islets as well as strategies to ensure graft viability and safety after transplantation.
Collapse
Affiliation(s)
- Nathaniel J Hogrebe
- Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, MSC 8127-057-08, 660 South Euclid Avenue, St. Louis, MO 63130, USA.
| | - Matthew Ishahak
- Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, MSC 8127-057-08, 660 South Euclid Avenue, St. Louis, MO 63130, USA
| | - Jeffrey R Millman
- Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, MSC 8127-057-08, 660 South Euclid Avenue, St. Louis, MO 63130, USA; Department of Biomedical Engineering, Washington University in St. Louis, 1 Brookings Drive, St. Louis, MO 63130, USA.
| |
Collapse
|
|
18
|
Jiang H, Jiang FX. Human pluripotent stem cell-derived β cells: Truly immature islet β cells for type 1 diabetes therapy? World J Stem Cells 2023; 15:182-195. [PMID: 37180999 PMCID: PMC10173812 DOI: 10.4252/wjsc.v15.i4.182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 01/30/2023] [Accepted: 03/20/2023] [Indexed: 04/26/2023] Open
Abstract
A century has passed since the Nobel Prize winning discovery of insulin, which still remains the mainstay treatment for type 1 diabetes mellitus (T1DM) to this day. True to the words of its discoverer Sir Frederick Banting, “insulin is not a cure for diabetes, it is a treatment”, millions of people with T1DM are dependent on daily insulin medications for life. Clinical donor islet transplantation has proven that T1DM is curable, however due to profound shortages of donor islets, it is not a mainstream treatment option for T1DM. Human pluripotent stem cell derived insulin-secreting cells, pervasively known as stem cell-derived β cells (SC-β cells), are a promising alternative source and have the potential to become a T1DM treatment through cell replacement therapy. Here we briefly review how islet β cells develop and mature in vivo and several types of reported SC-β cells produced using different ex vivo protocols in the last decade. Although some markers of maturation were expressed and glucose stimulated insulin secretion was shown, the SC-β cells have not been directly compared to their in vivo counterparts, generally have limited glucose response, and are not yet fully matured. Due to the presence of extra-pancreatic insulin-expressing cells, and ethical and technological issues, further clarification of the true nature of these SC-β cells is required.
Collapse
Affiliation(s)
- Helen Jiang
- Sir Charles Gairdner Hospital, University of Western Australia, Perth 6009, Australia
| | - Fang-Xu Jiang
- School of Biomedical Sciences, University of Western Australia, Perth 6009, Australia
- School of Health and Medical Sciences, Edith Cowan University, Perth 6027, Australia
| |
Collapse
|
|
19
|
Zhang Y, Lv Y, Wang Y, Chang TT, Rubinsky B. Pancreatic islets implanted in an irreversible electroporation generated extracellular matrix in the liver. Radiol Oncol 2023; 57:51-58. [PMID: 36653949 PMCID: PMC10039474 DOI: 10.2478/raon-2023-0006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Accepted: 11/24/2022] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND Pancreatic islet transplantation via infusion through the portal vein, has become an established clinical treatment for patients with type 1 diabetes. Because the engraftment efficiency is low, new approaches for pancreatic islets implantation are sought. The goal of this study is to explore the possibility that a non-thermal irreversible electroporation (NTIRE) decellularized matrix in the liver could be used as an engraftment site for pancreatic islets. MATERIALS AND METHODS Pancreatic islets or saline controls were injected at sites pre-treated with NTIRE in the livers of 7 rats, 16 hours after NTIRE treatment. Seven days after the NTIRE treatment, islet graft function was assessed by detecting insulin and glucagon in the liver with immunohistochemistry. RESULTS Pancreatic islets implanted into a NTIRE-treated volume of liver became incorporated into the liver parenchyma and produced insulin and glucagon in 2 of the 7 rat livers. Potential reasons for the failure to observe pancreatic islets in the remaining 5/7 rats may include local inflammatory reaction, graft rejection, low numbers of starting islets, timing of implantation. CONCLUSIONS This study shows that pancreatic islets can become incorporated and function in an NTIRE-generated extracellular matrix niche, albeit the success rate is low. Advances in the field could be achieved by developing a better understanding of the mechanisms of failure and ways to combat these mechanisms.
Collapse
Affiliation(s)
- Yanfang Zhang
- Department of Endocrinology, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, China
- Department of Mechanical Engineering and Department of Bioengineering, University of California, Berkeley Slovenia
| | - Yanpeng Lv
- Department of Mechanical Engineering and Department of Bioengineering, University of California, Berkeley Slovenia
- School of Electrical Engineering, Zhengzhou University, Zhengzhou, China
| | - Yunlong Wang
- Henan Bioengineering Research Center, Zhengzhou, China
| | - Tammy T Chang
- Department of Surgery, University of California, San Francisco, San Francisco, USA
| | - Boris Rubinsky
- Department of Mechanical Engineering and Department of Bioengineering, University of California, Berkeley Slovenia
| |
Collapse
|
|
20
|
Liang Z, Sun D, Lu S, Lei Z, Wang S, Luo Z, Zhan J, Wu S, Jiang Y, Lu Z, Sun S, Shi Y, Long H, Wei Y, Yu W, Wang Z, Yi LS, Zhang Y, Sun W, Fang X, Li Y, Lu S, Lv J, Sui W, Shen Z, Peng X, Du Y, Deng H. Implantation underneath the abdominal anterior rectus sheath enables effective and functional engraftment of stem-cell-derived islets. Nat Metab 2023; 5:29-40. [PMID: 36624157 DOI: 10.1038/s42255-022-00713-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 11/14/2022] [Indexed: 01/11/2023]
Abstract
Human pluripotent stem cell-derived islets (hPSC islets) are a promising alternative to primary human islets for the treatment of insulin-deficient diabetes. We previously demonstrated the feasibility of this approach in nonhuman primates; however, the therapeutic effects of hPSC islets can be limited by the maladaptive processes at the transplantation site. Here, we demonstrate successful implantation of hPSC-derived islets in a new transplantation site in the abdomen, the subanterior rectus sheath, in eight nonhuman primates (five male and three female). In this proof-of-principle study, we find that hPSC islets survive and gradually mature after transplantation, leading to improved glycemic control in diabetic primates. Notably, C-peptide secretion responds to meal challenge from 6 weeks post-transplantation (wpt), with stimulation indices comparable to those of native islets. The average post-prandial C-peptide level reaches approximately 2.0 ng ml-1 from 8 wpt, which is five times higher than the peak value we previously obtained after portal vein infusion of hPSC islets and was associated with a decrease of glycated hemoglobin levels by 44% at 12 wpt. Although additional studies in larger cohorts involving long-term follow-up of transplants are needed, our results indicate that the subanterior rectus sheath supports functional maturation and maintenance of hPSC islets, suggesting that it warrants further exploration as a transplantation target site in the context of for hPSC-based cell-replacement therapies.
Collapse
Affiliation(s)
- Zhen Liang
- MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
- Hangzhou Reprogenix Bioscience, Hangzhou, China
| | - Dong Sun
- MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | - Shuaiyao Lu
- State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Medical Primate Research Center, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China
| | | | - Shusen Wang
- Organ Transplant Center, NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Nankai University, Tianjin, China
| | - Zhifeng Luo
- The Second Department of Urology, Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Jinqin Zhan
- Ultrasonic Department, First Affiliated Hospital of Kunming Medical University, Kunming, China
| | | | - Yong Jiang
- Hangzhou Reprogenix Bioscience, Hangzhou, China
| | - Zhi Lu
- Hangzhou Reprogenix Bioscience, Hangzhou, China
| | - Shicheng Sun
- MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | | | - Haiting Long
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Yunnan, China
| | - Yanling Wei
- Hangzhou Reprogenix Bioscience, Hangzhou, China
| | - Wenhai Yu
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Yunnan, China
| | - Zhihui Wang
- Hangzhou Reprogenix Bioscience, Hangzhou, China
| | - Liew Soon Yi
- MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | - Yun Zhang
- Hangzhou Reprogenix Bioscience, Hangzhou, China
| | - Wenyong Sun
- Hangzhou Repugene Technology, Hangzhou, China
| | | | - Yanyan Li
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Yunnan, China
| | - Sufang Lu
- Hangzhou Reprogenix Bioscience, Hangzhou, China
| | - Jiayun Lv
- Hangzhou Repugene Technology, Hangzhou, China
| | - Weiguo Sui
- The Second Department of Urology, Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Zhongyang Shen
- Organ Transplant Center, NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Nankai University, Tianjin, China
| | - Xiaozhong Peng
- State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Medical Primate Research Center, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Yunnan, China.
| | - Yuanyuan Du
- MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
- Hangzhou Reprogenix Bioscience, Hangzhou, China.
| | - Hongkui Deng
- MOE Engineering Research Center of Regenerative Medicine, School of Basic Medical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center and the MOE Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
| |
Collapse
|
|
21
|
Kuang G, Zhang Q, Jia J, Yu Y. Freezing biological organisms for biomedical applications. SMART MEDICINE 2022; 1:e20220034. [PMID: 39188743 PMCID: PMC11235656 DOI: 10.1002/smmd.20220034] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 12/07/2022] [Indexed: 08/28/2024]
Abstract
Biological organisms play important roles in human health, either in a commensal or pathogenic manner. Harnessing inactivated organisms or living organisms is a promising way to treat diseases. As two types of freezing, cryoablation makes it simple to inactivate organisms that must be in a non-pathogenic state when needed, while cryopreservation is a facile way to address the problem of long-term storage challenged by living organism-based therapy. In this review, we present the latest studies of freezing biological organisms for biomedical applications. To begin with, the freezing strategies of cryoablation and cryopreservation, as well as their corresponding technical essentials, are illustrated. Besides, biomedical applications of freezing biological organisms are presented, including transplantation, tissue regeneration, anti-infection therapy, and anti-tumor therapy. The challenges and prospects of freezing living organisms for biomedical applications are well discussed. We believe that the freezing method will provide a potential direction for the standardization and commercialization of inactivated or living organism-based therapeutic systems, and promote the clinical application of organism-based therapy.
Collapse
Affiliation(s)
- Gaizhen Kuang
- Pharmaceutical Sciences LaboratoryÅbo Akademi UniversityTurkuFinland
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health)Wenzhou InstituteUniversity of Chinese Academy of SciencesWenzhouChina
| | - Qingfei Zhang
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health)Wenzhou InstituteUniversity of Chinese Academy of SciencesWenzhouChina
| | - Jinxuan Jia
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health)Wenzhou InstituteUniversity of Chinese Academy of SciencesWenzhouChina
| | - Yunru Yu
- Pharmaceutical Sciences LaboratoryÅbo Akademi UniversityTurkuFinland
| |
Collapse
|
|
22
|
Duman BO, Sariboyaci AE, Karaoz E. Bio-engineering of 3-D cell sheets for diabetic rats: Interaction between mesenchymal stem cells and beta cells in functional islet regeneration system. Tissue Cell 2022; 79:101919. [DOI: 10.1016/j.tice.2022.101919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 07/22/2022] [Accepted: 09/03/2022] [Indexed: 11/15/2022]
|
|
23
|
Nakafusa Y, Nitta N, Ishii K, Shirasu N, Iwamoto T, Nemoto T, Nakamura M, Goto M, Iwata H, Taniguchi M, Yasunami Y. Acceptance of Murine Islet Allografts Without Immunosuppression in Inguinal Subcutaneous White Adipose Tissue Pretreated With bFGF. Diabetes 2022; 71:1721-1734. [PMID: 35604856 DOI: 10.2337/db21-0684] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 04/24/2022] [Indexed: 11/13/2022]
Abstract
Prevention of immune rejection without immunosuppression is the ultimate goal of transplant immunobiology. One way to achieve this in cellular transplantation, such as with islet transplantation, is to create a favorable local environment at the transplant site. In the current study, we found that C57BL/6 mice with streptozotocin-induced diabetes remained normoglycemic for >1 year after transplantation of BALB/c islets without immunosuppression when the inguinal subcutaneous white adipose tissue (ISWAT) was the site of transplantation and when the site was pretreated with basic fibroblast growth factor. Mechanistically, mesenchymal stem cells (MSCs) expanded in the ISWAT after the treatment was found to produce transforming growth factor-β (TGF-β), and prevention of islet allograft rejection could be achieved by cotransplantation with syngeneic MSCs isolated from the ISWAT after the treatment, which was abolished by anti-TGF-β antibody treatment. Importantly, TGF-β-producing cells remained present at the site of cotransplantation up to the end of observation period at 240 days after transplantation. These findings indicate that prevention of islet allograft rejection without immunosuppression is feasible with the use of syngeneic TGF-β-producing MSCs expanded in the ISWAT after the treatment with bFGF, providing a novel strategy for prevention of islet allograft rejection without immunosuppression.
Collapse
Affiliation(s)
- Yuki Nakafusa
- Research Institute for Islet Biology, Fukuoka University Central Research Organization, Fukuoka, Japan
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Naoyoshi Nitta
- Research Institute for Islet Biology, Fukuoka University Central Research Organization, Fukuoka, Japan
| | - Kazunari Ishii
- Department of Microbiology and Immunology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Naoto Shirasu
- Department of Biochemistry, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Takahiro Iwamoto
- Research Institute for Islet Biology, Fukuoka University Central Research Organization, Fukuoka, Japan
- Department of Pharmacology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Takayuki Nemoto
- Department of Pharmacology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Masafumi Nakamura
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masafumi Goto
- Division of Transplantation and Regenerative Medicine, Tohoku University School of Medicine, Sendai, Japan
| | - Hiroo Iwata
- Frontiers of Innovative Research in Science and Technology (FIRST), Konan University, Kobe, Japan
| | - Masaru Taniguchi
- RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Japan
| | - Yohichi Yasunami
- Research Institute for Islet Biology, Fukuoka University Central Research Organization, Fukuoka, Japan
| |
Collapse
|
|
24
|
Huang HH, Stillman TJ, Branham LA, Williams SC. The Effects of Photobiomodulation Therapy on Porcine Islet Insulin Secretion. Photobiomodul Photomed Laser Surg 2022; 40:395-401. [DOI: 10.1089/photob.2022.0022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Han-Hung Huang
- Department of Physical Therapy, Angelo State University, Member, Texas Tech University System, San Angelo, Texas, USA
| | - Tori J. Stillman
- Department of Agriculture, and Angelo State University, Member, Texas Tech University System, San Angelo, Texas, USA
| | - Loree A. Branham
- Department of Agriculture, and Angelo State University, Member, Texas Tech University System, San Angelo, Texas, USA
| | - Scott C. Williams
- Department of Physics and Geosciences, Angelo State University, Member, Texas Tech University System, San Angelo, Texas, USA
| |
Collapse
|
|
25
|
Lei J, Coronel MM, Yolcu ES, Deng H, Grimany-Nuno O, Hunckler MD, Ulker V, Yang Z, Lee KM, Zhang A, Luo H, Peters CW, Zou Z, Chen T, Wang Z, McCoy CS, Rosales IA, Markmann JF, Shirwan H, García AJ. FasL microgels induce immune acceptance of islet allografts in nonhuman primates. SCIENCE ADVANCES 2022; 8:eabm9881. [PMID: 35559682 PMCID: PMC9106299 DOI: 10.1126/sciadv.abm9881] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 03/30/2022] [Indexed: 05/23/2023]
Abstract
Islet transplantation to treat insulin-dependent diabetes is greatly limited by the need for maintenance immunosuppression. We report a strategy through which cotransplantation of allogeneic islets and streptavidin (SA)-FasL-presenting microgels to the omentum under transient rapamycin monotherapy resulted in robust glycemic control, sustained C-peptide levels, and graft survival in diabetic nonhuman primates for >6 months. Surgical extraction of the graft resulted in prompt hyperglycemia. In contrast, animals receiving microgels without SA-FasL under the same rapamycin regimen rejected islet grafts acutely. Graft survival was associated with increased number of FoxP3+ cells in the graft site with no significant changes in T cell systemic frequencies or responses to donor and third-party antigens, indicating localized tolerance. Recipients of SA-FasL microgels exhibited normal liver and kidney metabolic function, demonstrating safety. This localized immunomodulatory strategy succeeded with unmodified islets and does not require long-term immunosuppression, showing translational potential in β cell replacement for treating type 1 diabetes.
Collapse
Affiliation(s)
- Ji Lei
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - María M. Coronel
- Woodruff School of Mechanical Engineering and Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA
| | - Esma S. Yolcu
- Departments of Child Health and Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO, USA
- Department of Microbiology and Immunology, Institute for Cellular Therapeutics, University of Louisville, Louisville, KY, USA
| | - Hongping Deng
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Orlando Grimany-Nuno
- Department of Microbiology and Immunology, Institute for Cellular Therapeutics, University of Louisville, Louisville, KY, USA
| | - Michael D. Hunckler
- Woodruff School of Mechanical Engineering and Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA
| | - Vahap Ulker
- Departments of Child Health and Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO, USA
| | - Zhihong Yang
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Kang M. Lee
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Alexander Zhang
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Hao Luo
- Department of General Surgery, General Hospital of Western Theater Command, Chengdu, China
| | - Cole W. Peters
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Zhongliang Zou
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Tao Chen
- Cellular Therapy Department, Xiang’an Hospital, Xiamen University Medical School, Xiamen, China
| | - Zhenjuan Wang
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Colleen S. McCoy
- Division of Comparative Medicine, Massachusetts Institute of Technology, Boston, MA, USA
| | - Ivy A. Rosales
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - James F. Markmann
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Haval Shirwan
- Departments of Child Health and Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO, USA
- Department of Microbiology and Immunology, Institute for Cellular Therapeutics, University of Louisville, Louisville, KY, USA
| | - Andrés J. García
- Woodruff School of Mechanical Engineering and Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA
| |
Collapse
|
|
26
|
Mazilescu LI, Parmentier C, Kalimuthu SN, Ganesh S, Kawamura M, Goto T, Noguchi Y, Selzner M, Reichman TW. Normothermic ex situ pancreas perfusion for the preservation of porcine pancreas grafts. Am J Transplant 2022; 22:1339-1349. [PMID: 35258859 PMCID: PMC9314088 DOI: 10.1111/ajt.17019] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 01/28/2022] [Accepted: 02/23/2022] [Indexed: 01/25/2023]
Abstract
Pancreas transplantation improves and extends the life of patients with insulin-dependent diabetes. Pancreata from extended criteria donors have been increasingly used due to the scarcity of available grafts. Normothermic ex situ pancreas perfusion (NESPP) can keep grafts metabolically active, potentially allowing for assessment and organ repair, and could improve outcomes of marginal grafts. A novel NESPP technique was developed and tested. Porcine pancreata were removed after a short period of warm ischemia and subjected to 6 h of NESPP. Perfusion parameters, potential graft assessment markers and graft injury were measured. Next, pancreata subjected to 3 h of NESPP were transplanted and animals were followed for up to 3 days. Graft function and injury post-transplantation were evaluated. Using this novel system of perfusion, pancreata were perfused for an extended period of time with minimal edema. Histology at the end of perfusion showed intact islet cells with only mild signs of tissue injury. NESPP transplanted grafts showed immediate function after transplantation, with glucose levels in normal range. NESPP maintains a physiologic environment and excellent graft function without causing significant graft injury. Porcine pancreas transplantation is feasible and allows for in vivo graft assessment of pancreas function and injury after NESPP.
Collapse
Affiliation(s)
- Laura I. Mazilescu
- Ajmera Transplant ProgramToronto General HospitalTorontoOntarioCanada,Division of NephrologyThe Hospital for Sick ChildrenTorontoOntarioCanada,Department of General, Visceral, and Transplantation SurgeryUniversity Hospital EssenEssenGermany,Division of General SurgeryToronto General HospitalUniversity Health NetworkTorontoOntarioCanada
| | | | - Sangeetha N. Kalimuthu
- Department of PathologyUniversity Health Network and University of TorontoTorontoOntarioCanada
| | - Sujani Ganesh
- Ajmera Transplant ProgramToronto General HospitalTorontoOntarioCanada
| | - Masataka Kawamura
- Ajmera Transplant ProgramToronto General HospitalTorontoOntarioCanada
| | - Toru Goto
- Ajmera Transplant ProgramToronto General HospitalTorontoOntarioCanada
| | - Yuki Noguchi
- Ajmera Transplant ProgramToronto General HospitalTorontoOntarioCanada
| | - Markus Selzner
- Ajmera Transplant ProgramToronto General HospitalTorontoOntarioCanada,Division of General SurgeryToronto General HospitalUniversity Health NetworkTorontoOntarioCanada
| | - Trevor W. Reichman
- Ajmera Transplant ProgramToronto General HospitalTorontoOntarioCanada,Division of General SurgeryToronto General HospitalUniversity Health NetworkTorontoOntarioCanada
| |
Collapse
|
|
27
|
Aghazadeh Y, Sarangi F, Poon F, Nkennor B, McGaugh EC, Nunes SS, Nostro MC. GP2-enriched pancreatic progenitors give rise to functional beta cells in vivo and eliminate the risk of teratoma formation. Stem Cell Reports 2022; 17:964-978. [PMID: 35364010 PMCID: PMC9023812 DOI: 10.1016/j.stemcr.2022.03.004] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 03/03/2022] [Accepted: 03/04/2022] [Indexed: 11/02/2022] Open
Abstract
Human pluripotent stem cell (hPSC)-derived pancreatic progenitors (PPs) can be differentiated into beta-like cells in vitro and in vivo and therefore have therapeutic potential for type 1 diabetes (T1D) treatment. However, the purity of PPs varies across different hPSC lines, differentiation protocols, and laboratories. The uncommitted cells may give rise to non-pancreatic endodermal, mesodermal, or ectodermal derivatives in vivo, hampering the safety of hPSC-derived PPs for clinical applications and their differentiation efficiency in research settings. Recently, proteomics and transcriptomics analyses identified glycoprotein 2 (GP2) as a PP-specific cell surface marker. The GP2-enriched PPs generate higher percentages of beta-like cells in vitro, but their potential in vivo remains to be elucidated. Here, we demonstrate that the GP2-enriched-PPs give rise to all pancreatic cells in vivo, including functional beta-like cells. Remarkably, GP2 enrichment eliminates the risk of teratomas, which establishes GP2 sorting as an effective method for PP purification and safe pancreatic differentiation.
Collapse
Affiliation(s)
- Yasaman Aghazadeh
- McEwen Stem Cell Institute, University Health Network, 101 College Street MaRS, PMCRT 3-916, Toronto, ON M5G 1L7, Canada; Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada
| | - Farida Sarangi
- McEwen Stem Cell Institute, University Health Network, 101 College Street MaRS, PMCRT 3-916, Toronto, ON M5G 1L7, Canada
| | - Frankie Poon
- McEwen Stem Cell Institute, University Health Network, 101 College Street MaRS, PMCRT 3-916, Toronto, ON M5G 1L7, Canada; Deparment of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Blessing Nkennor
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Biological Sciences, University of Toronto, Scarborough, ON M1C 1A4, Canada
| | - Emily C McGaugh
- McEwen Stem Cell Institute, University Health Network, 101 College Street MaRS, PMCRT 3-916, Toronto, ON M5G 1L7, Canada; Deparment of Physiology, University of Toronto, Toronto, ON M5S 1A8, 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; Heart & Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, ON M5S 3H2, Canada; Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - M Cristina Nostro
- McEwen Stem Cell Institute, University Health Network, 101 College Street MaRS, PMCRT 3-916, Toronto, ON M5G 1L7, Canada; Deparment of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
| |
Collapse
|
|
28
|
Sthijns MMJPE, Rademakers T, Oosterveer J, Geuens T, van Blitterswijk CA, LaPointe VLS. The response of three-dimensional pancreatic alpha and beta cell co-cultures to oxidative stress. PLoS One 2022; 17:e0257578. [PMID: 35290395 PMCID: PMC8923503 DOI: 10.1371/journal.pone.0257578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 02/17/2022] [Indexed: 11/19/2022] Open
Abstract
The pancreatic islets of Langerhans have low endogenous antioxidant levels and are thus especially sensitive to oxidative stress, which is known to influence cell survival and behaviour. As bioengineered islets are gaining interest for therapeutic purposes, it is important to understand how their composition can be optimized to diminish oxidative stress. We investigated how the ratio of the two main islet cell types (alpha and beta cells) and their culture in three-dimensional aggregates could protect against oxidative stress. Monolayer and aggregate cultures were established by seeding the alphaTC1 (alpha) and INS1E (beta) cell lines in varying ratios, and hydrogen peroxide was applied to induce oxidative stress. Viability, oxidative stress, and the level of the antioxidant glutathione were measured. Both aggregation and an increasing prevalence of INS1E cells in the co-cultures conferred greater resistance to cell death induced by oxidative stress. Increasing the prevalence of INS1E cells also decreased the number of alphaTC1 cells experiencing oxidative stress in the monolayer culture. In 3D aggregates, culturing the alphaTC1 and INS1E cells in a ratio of 50:50 prevented oxidative stress in both cell types. Together, the results of this study lead to new insight into how modulating the composition and dimensionality of a co-culture can influence the oxidative stress levels experienced by the cells.
Collapse
Affiliation(s)
- Mireille M. J. P. E. Sthijns
- Department of Cell Biology–Inspired Tissue Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Maastricht, The Netherlands
| | - Timo Rademakers
- Department of Cell Biology–Inspired Tissue Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Maastricht, The Netherlands
| | - Jolien Oosterveer
- Department of Cell Biology–Inspired Tissue Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Maastricht, The Netherlands
| | - Thomas Geuens
- Department of Cell Biology–Inspired Tissue Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Maastricht, The Netherlands
| | - Clemens A. van Blitterswijk
- Department of Cell Biology–Inspired Tissue Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Maastricht, The Netherlands
| | - Vanessa L. S. LaPointe
- Department of Cell Biology–Inspired Tissue Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Maastricht, The Netherlands
- * E-mail:
| |
Collapse
|
|
29
|
Kuppan P, Kelly S, Seeberger K, Castro C, Rosko M, Pepper AR, Korbutt GS. Bioabsorption of Subcutaneous Nanofibrous Scaffolds Influences the Engraftment and Function of Neonatal Porcine Islets. Polymers (Basel) 2022; 14:polym14061120. [PMID: 35335450 PMCID: PMC8954444 DOI: 10.3390/polym14061120] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 03/08/2022] [Accepted: 03/09/2022] [Indexed: 02/07/2023] Open
Abstract
The subcutaneous space is currently being pursued as an alternative transplant site for ß-cell replacement therapies due to its retrievability, minimally invasive procedure and potential for graft imaging. However, implantation of ß-cells into an unmodified subcutaneous niche fails to reverse diabetes due to a lack of adequate blood supply. Herein, poly (ε-caprolactone) (PCL) and poly (lactic-co-glycolic acid) (PLGA) polymers were used to make scaffolds and were functionalized with peptides (RGD (Arginine-glycine-aspartate), VEGF (Vascular endothelial growth factor), laminin) or gelatin to augment engraftment. PCL, PCL + RGD + VEGF (PCL + R + V), PCL + RGD + Laminin (PCL + R + L), PLGA and PLGA + Gelatin (PLGA + G) scaffolds were implanted into the subcutaneous space of immunodeficient Rag mice. After four weeks, neonatal porcine islets (NPIs) were transplanted within the lumen of the scaffolds or under the kidney capsule (KC). Graft function was evaluated by blood glucose, serum porcine insulin, glucose tolerance tests, graft cellular insulin content and histologically. PLGA and PLGA + G scaffold recipients achieved significantly superior euglycemia rates (86% and 100%, respectively) compared to PCL scaffold recipients (0% euglycemic) (* p < 0.05, ** p < 0.01, respectively). PLGA scaffolds exhibited superior glucose tolerance (* p < 0.05) and serum porcine insulin secretion (* p < 0.05) compared to PCL scaffolds. Functionalized PLGA + G scaffold recipients exhibited higher total cellular insulin contents compared to PLGA-only recipients (* p < 0.05). This study demonstrates that the bioabsorption of PLGA-based fibrous scaffolds is a key factor that facilitates the function of NPIs transplanted subcutaneously in diabetic mice.
Collapse
Affiliation(s)
- Purushothaman Kuppan
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada; (P.K.); (S.K.); (K.S.); (C.C.); (M.R.)
- Department of Surgery, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - Sandra Kelly
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada; (P.K.); (S.K.); (K.S.); (C.C.); (M.R.)
- Department of Surgery, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - Karen Seeberger
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada; (P.K.); (S.K.); (K.S.); (C.C.); (M.R.)
- Department of Surgery, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - Chelsea Castro
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada; (P.K.); (S.K.); (K.S.); (C.C.); (M.R.)
- Department of Surgery, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - Mandy Rosko
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada; (P.K.); (S.K.); (K.S.); (C.C.); (M.R.)
- Department of Surgery, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - Andrew R. Pepper
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada; (P.K.); (S.K.); (K.S.); (C.C.); (M.R.)
- Department of Surgery, University of Alberta, Edmonton, AB T6G 2E1, Canada
- Correspondence: (A.R.P.); (G.S.K.)
| | - Gregory S. Korbutt
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada; (P.K.); (S.K.); (K.S.); (C.C.); (M.R.)
- Department of Surgery, University of Alberta, Edmonton, AB T6G 2E1, Canada
- Correspondence: (A.R.P.); (G.S.K.)
| |
Collapse
|
|
30
|
Cefalu WT, Andersen DK, Arreaza-Rubín G, Pin CL, Sato S, Verchere CB, Woo M, Rosenblum ND. Heterogeneity of Diabetes: β-Cells, Phenotypes, and Precision Medicine: Proceedings of an International Symposium of the Canadian Institutes of Health Research's Institute of Nutrition, Metabolism and Diabetes and the U.S. National Institutes of Health's National Institute of Diabetes and Digestive and Kidney Diseases. Diabetes Care 2022; 45:3-22. [PMID: 34782355 PMCID: PMC8753760 DOI: 10.2337/dci21-0051] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 09/23/2021] [Indexed: 02/03/2023]
Abstract
One hundred years have passed since the discovery of insulin-an achievement that transformed diabetes from a fatal illness into a manageable chronic condition. The decades since that momentous achievement have brought ever more rapid innovation and advancement in diabetes research and clinical care. To celebrate the important work of the past century and help to chart a course for its continuation into the next, the Canadian Institutes of Health Research's Institute of Nutrition, Metabolism and Diabetes and the U.S. National Institutes of Health's National Institute of Diabetes and Digestive and Kidney Diseases recently held a joint international symposium, bringing together a cohort of researchers with diverse interests and backgrounds from both countries and beyond to discuss their collective quest to better understand the heterogeneity of diabetes and thus gain insights to inform new directions in diabetes treatment and prevention. This article summarizes the proceedings of that symposium, which spanned cutting-edge research into various aspects of islet biology, the heterogeneity of diabetic phenotypes, and the current state of and future prospects for precision medicine in diabetes.
Collapse
Affiliation(s)
- William T. Cefalu
- Division of Diabetes, Endocrinology and Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - Dana K. Andersen
- Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - Guillermo Arreaza-Rubín
- Division of Diabetes, Endocrinology and Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - Christopher L. Pin
- Departments of Physiology and Pharmacology, Paediatrics, and Oncology, University of Western Ontario, and Genetics and Development Division, Children’s Health Research Institute, Lawson Health Research Institute, London, Ontario, Canada
| | - Sheryl Sato
- Division of Diabetes, Endocrinology and Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - C. Bruce Verchere
- Departments of Surgery and Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
- BC Children’s Hospital, Vancouver, British Columbia, Canada
- UBC Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada
| | - Minna Woo
- Departments of Medicine and Immunology, University of Toronto, Toronto, Ontario, Canada
- Division of Endocrinology and Metabolism, University Health Network and Sinai Health System, Toronto, Ontario, Canada
- Toronto General Hospital Research Institute, Toronto, Ontario, Canada
| | - Norman D. Rosenblum
- Canadian Institutes of Health Research Institute of Nutrition, Metabolism and Diabetes, Toronto, Ontario, Canada
- Division of Nephrology, Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada
- Program in Stem Cell and Developmental Biology, Research Institute, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada
| |
Collapse
|
|
31
|
Cefalu WT, Andersen DK, Arreaza-Rubín G, Pin CL, Sato S, Verchere CB, Woo M, Rosenblum ND. Heterogeneity of Diabetes: β-Cells, Phenotypes, and Precision Medicine: Proceedings of an International Symposium of the Canadian Institutes of Health Research's Institute of Nutrition, Metabolism and Diabetes and the U.S. National Institutes of Health's National Institute of Diabetes and Digestive and Kidney Diseases. Can J Diabetes 2021; 45:697-713. [PMID: 34794897 DOI: 10.1016/j.jcjd.2021.09.126] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 09/23/2021] [Indexed: 10/19/2022]
Abstract
One hundred years have passed since the discovery of insulin-an achievement that transformed diabetes from a fatal illness into a manageable chronic condition. The decades since that momentous achievement have brought ever more rapid innovation and advancement in diabetes research and clinical care. To celebrate the important work of the past century and help to chart a course for its continuation into the next, the Canadian Institutes of Health Research's Institute of Nutrition, Metabolism and Diabetes and the U.S. National Institutes of Health's National Institute of Diabetes and Digestive and Kidney Diseases recently held a joint international symposium, bringing together a cohort of researchers with diverse interests and backgrounds from both countries and beyond to discuss their collective quest to better understand the heterogeneity of diabetes and thus gain insights to inform new directions in diabetes treatment and prevention. This article summarizes the proceedings of that symposium, which spanned cutting-edge research into various aspects of islet biology, the heterogeneity of diabetic phenotypes, and the current state of and future prospects for precision medicine in diabetes.
Collapse
Affiliation(s)
- William T Cefalu
- Division of Diabetes, Endocrinology and Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States.
| | - Dana K Andersen
- Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States
| | - Guillermo Arreaza-Rubín
- Division of Diabetes, Endocrinology and Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States
| | - Christopher L Pin
- Departments of Physiology and Pharmacology, Paediatrics, and Oncology, University of Western Ontario, and Genetics and Development Division, Children's Health Research Institute, Lawson Health Research Institute, London, Ontario, Canada
| | - Sheryl Sato
- Division of Diabetes, Endocrinology and Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States
| | - C Bruce Verchere
- Departments of Surgery and Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada; BC Children's Hospital, Vancouver, British Columbia, Canada; UBC Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada
| | - Minna Woo
- Departments of Medicine and Immunology, University of Toronto, Toronto, Ontario, Canada; Division of Endocrinology and Metabolism, University Health Network and Sinai Health System, Toronto, Ontario, Canada; Toronto General Hospital Research Institute, Toronto, Ontario, Canada
| | - Norman D Rosenblum
- Canadian Institutes of Health Research's Institute of Nutrition, Metabolism and Diabetes, Toronto, Ontario, Canada; Division of Nephrology, Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada; Program in Stem Cell and Developmental Biology, Research Institute, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada
| |
Collapse
|
|
32
|
Exendin-4-Conjugated Manganese Magnetism-Engineered Iron Oxide Nanoparticles as a Potential Magnetic Resonance Imaging Contrast Agent for Tracking Transplanted β-Cells. NANOMATERIALS 2021; 11:nano11113145. [PMID: 34835906 PMCID: PMC8625548 DOI: 10.3390/nano11113145] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 11/18/2021] [Accepted: 11/19/2021] [Indexed: 11/16/2022]
Abstract
To specifically detect and trace transplanted islet β-cells by magnetic resonance imaging (MRI), we conjugated manganese magnetism-engineered iron oxide nanoparticles (MnMEIO NPs) with exendin-4 (Ex4) which specifically binds glucagon-like peptide-1 receptors on the surface of β-cells. The size distribution of MnMEIO and MnMEIO-Ex4 NPs were 67.8 ± 1.3 and 70.2 ± 2.3 nm and zeta potential 33.3 ± 0.5 and 0.6 ± 0.1 mV, respectively. MnMEIO and MnMEIO-Ex4 NPs with iron content ≤ 40 μg/mL did not affect MIN6 β-cell viability and insulin secretion. Positive iron staining was found in MIN6 β-cells loaded with MnMEIO-Ex4 NPs but not in those with MnMEIO NPs. A transmission electron microscope confirmed MnMEIO-Ex4 NPs were distributed in the cytoplasm of MIN6. In vitro MR images revealed a loss of signal intensity in MIN6 β-cells labeled with MnMEIO-Ex4 NPs but not with MnMEIO NPs. After transplantation of islets labeled with MnMEIO-Ex4, the graft under kidney capsule could be visualized on MRI as persistent hypointense areas up to 17 weeks. Moreover, histology of the islet graft showed positive staining for insulin, glucagon and iron. Our results indicate MnMEIO-Ex4 NPs are safe and effective for the detection and long-term monitoring of transplanted β-cells by MRI.
Collapse
|
|
33
|
Cefalu WT, Andersen DK, Arreaza-Rubín G, Pin CL, Sato S, Verchere CB, Woo M, Rosenblum ND. Heterogeneity of Diabetes: β-Cells, Phenotypes, and Precision Medicine: Proceedings of an International Symposium of the Canadian Institutes of Health Research's Institute of Nutrition, Metabolism and Diabetes and the U.S. National Institutes of Health's National Institute of Diabetes and Digestive and Kidney Diseases. Diabetes 2021; 71:db210777. [PMID: 34782351 PMCID: PMC8763877 DOI: 10.2337/db21-0777] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 09/23/2021] [Indexed: 11/13/2022]
Abstract
One hundred years have passed since the discovery of insulin-an achievement that transformed diabetes from a fatal illness into a manageable chronic condition. The decades since that momentous achievement have brought ever more rapid innovation and advancement in diabetes research and clinical care. To celebrate the important work of the past century and help to chart a course for its continuation into the next, the Canadian Institutes of Health Research's Institute of Nutrition, Metabolism and Diabetes and the U.S. National Institutes of Health's National Institute of Diabetes and Digestive and Kidney Diseases recently held a joint international symposium, bringing together a cohort of researchers with diverse interests and backgrounds from both countries and beyond to discuss their collective quest to better understand the heterogeneity of diabetes and thus gain insights to inform new directions in diabetes treatment and prevention. This article summarizes the proceedings of that symposium, which spanned cutting-edge research into various aspects of islet biology, the heterogeneity of diabetic phenotypes, and the current state of and future prospects for precision medicine in diabetes.
Collapse
Affiliation(s)
- William T Cefalu
- Division of Diabetes, Endocrinology and Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - Dana K Andersen
- Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - Guillermo Arreaza-Rubín
- Division of Diabetes, Endocrinology and Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - Christopher L Pin
- Departments of Physiology and Pharmacology, Paediatrics, and Oncology, University of Western Ontario, and Genetics and Development Division, Children's Health Research Institute, Lawson Health Research Institute, London, Ontario, Canada
| | - Sheryl Sato
- Division of Diabetes, Endocrinology and Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - C Bruce Verchere
- Departments of Surgery and Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
- BC Children's Hospital, Vancouver, British Columbia, Canada
- UBC Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada
| | - Minna Woo
- Departments of Medicine and Immunology, University of Toronto, Toronto, Ontario, Canada
- Division of Endocrinology and Metabolism, University Health Network and Sinai Health System, Toronto, Ontario, Canada
- Toronto General Hospital Research Institute, Toronto, Ontario, Canada
| | | |
Collapse
|
|
34
|
Szymanska M, Mahmood D, Yap TE, Cordeiro MF. Recent Advancements in the Medical Treatment of Diabetic Retinal Disease. Int J Mol Sci 2021; 22:ijms22179441. [PMID: 34502350 PMCID: PMC8430918 DOI: 10.3390/ijms22179441] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 08/24/2021] [Accepted: 08/25/2021] [Indexed: 02/06/2023] Open
Abstract
Diabetic retinal disease remains one of the most common complications of diabetes mellitus (DM) and a leading cause of preventable blindness. The mainstay of management involves glycemic control, intravitreal, and laser therapy. However, intravitreal therapy commonly requires frequent hospital visits and some patients fail to achieve a significant improvement in vision. Novel and long-acting therapies targeting a range of pathways are warranted, while evidence to support optimal combinations of treatments is currently insufficient. Improved understanding of the molecular pathways involved in pathogenesis is driving the development of therapeutic agents not only targeting visible microvascular disease and metabolic derangements, but also inflammation and accelerated retinal neurodegeneration. This review summarizes the current and emerging treatments of diabetic retinal diseases and provides an insight into the future of managing this important condition.
Collapse
Affiliation(s)
- Maja Szymanska
- The Imperial College Ophthalmic Research Group (ICORG), Imperial College London, London NW1 5QH, UK; (M.S.); (D.M.); (T.E.Y.)
| | - Daanyaal Mahmood
- The Imperial College Ophthalmic Research Group (ICORG), Imperial College London, London NW1 5QH, UK; (M.S.); (D.M.); (T.E.Y.)
| | - Timothy E. Yap
- The Imperial College Ophthalmic Research Group (ICORG), Imperial College London, London NW1 5QH, UK; (M.S.); (D.M.); (T.E.Y.)
| | - Maria F. Cordeiro
- The Imperial College Ophthalmic Research Group (ICORG), Imperial College London, London NW1 5QH, UK; (M.S.); (D.M.); (T.E.Y.)
- The Western Eye Hospital, Imperial College Healthcare NHS Trust (ICHNT), London NW1 5QH, UK
- Glaucoma and Retinal Neurodegeneration Group, Department of Visual Neuroscience, UCL Institute of Ophthalmology, London EC1V 9EL, UK
- Correspondence:
| |
Collapse
|
|
35
|
Hayat H, Nukala A, Nyamira A, Fan J, Wang P. A concise review: the synergy between artificial intelligence and biomedical nanomaterials that empowers nanomedicine. Biomed Mater 2021; 16:052001. [PMID: 34280907 DOI: 10.1088/1748-605x/ac15b2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Accepted: 07/19/2021] [Indexed: 12/17/2022]
Abstract
Nanomedicine has recently experienced unprecedented growth and development. However, the complexity of operations at the nanoscale introduces a layer of difficulty in the clinical translation of nanodrugs and biomedical nanotechnology. This problem is further exacerbated when engineering and optimizing nanomaterials for biomedical purposes. To navigate this issue, artificial intelligence (AI) algorithms have been applied for data analysis and inference, allowing for a more applicable understanding of the complex interaction amongst the abundant variables in a system involving the synthesis or use of nanomedicine. Here, we report on the current relationship and implications of nanomedicine and AI. Particularly, we explore AI as a tool for enabling nanomedicine in the context of nanodrug screening and development, brain-machine interfaces and nanotoxicology. We also report on the current state and future direction of nanomedicine and AI in cancer, diabetes, and neurological disorder therapy.
Collapse
Affiliation(s)
- Hasaan Hayat
- Precision Health Program,, Michigan State University, East Lansing, MI, United States of America
- Lyman Briggs College, Michigan State University, East Lansing, MI, United States of America
| | - Arijit Nukala
- Precision Health Program,, Michigan State University, East Lansing, MI, United States of America
- Department of Biomedical Engineering, School of Medicine, Johns Hopkins University, Baltimore, MD, United States of America
| | - Anthony Nyamira
- Lyman Briggs College, Michigan State University, East Lansing, MI, United States of America
| | - Jinda Fan
- Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, United States of America
| | - Ping Wang
- Precision Health Program,, Michigan State University, East Lansing, MI, United States of America
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI, United States of America
| |
Collapse
|
|
36
|
Lu C, Han L, Wang J, Wan J, Song G, Rao J. Engineering of magnetic nanoparticles as magnetic particle imaging tracers. Chem Soc Rev 2021; 50:8102-8146. [PMID: 34047311 DOI: 10.1039/d0cs00260g] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Magnetic particle imaging (MPI) has recently emerged as a promising non-invasive imaging technique because of its signal linearly propotional to the tracer mass, ability to generate positive contrast, low tissue background, unlimited tissue penetration depth, and lack of ionizing radiation. The sensitivity and resolution of MPI are highly dependent on the properties of magnetic nanoparticles (MNPs), and extensive research efforts have been focused on the design and synthesis of tracers. This review examines parameters that dictate the performance of MNPs, including size, shape, composition, surface property, crystallinity, the surrounding environment, and aggregation state to provide guidance for engineering MPI tracers with better performance. Finally, we discuss applications of MPI imaging and its challenges and perspectives in clinical translation.
Collapse
Affiliation(s)
- Chang Lu
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. China.
| | - Linbo Han
- College of Health Science and Environmental Engineering, Shenzhen Technology University, Shenzhen 518118, P. R. China
| | - Joanna Wang
- Molecular Imaging Program at Stanford, Department of Radiology, Stanford University School of Medicine, 1201 Welch Road, Stanford, California 94305-5484, USA.
| | - Jiacheng Wan
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. China.
| | - Guosheng Song
- State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. China.
| | - Jianghong Rao
- Molecular Imaging Program at Stanford, Department of Radiology, Stanford University School of Medicine, 1201 Welch Road, Stanford, California 94305-5484, USA.
| |
Collapse
|
|
37
|
Strategies for Vascularizing Pancreatic Islets and Stem Cell–Derived Islet Organoids. CURRENT TRANSPLANTATION REPORTS 2021. [DOI: 10.1007/s40472-021-00334-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
|
|
38
|
Fernandez SA, Danielczak L, Gauvin-Rossignol G, Hasilo C, Bégin-Drolet A, Ruel J, Paraskevas S, Leask RL, Hoesli CA. An in vitro Perfused Macroencapsulation Device to Study Hemocompatibility and Survival of Islet-Like Cell Clusters. Front Bioeng Biotechnol 2021; 9:674125. [PMID: 34124024 PMCID: PMC8193939 DOI: 10.3389/fbioe.2021.674125] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 04/30/2021] [Indexed: 11/23/2022] Open
Abstract
Transplantation of hydrogel-encapsulated pancreatic islets is a promising long-term treatment for type 1 diabetes that restores blood glucose regulation while providing graft immunoprotection. Most human-scale islet encapsulation devices that rely solely on diffusion fail to provide sufficient surface area to meet islet oxygen demands. Perfused macroencapsulation devices use blood flow to mitigate oxygen limitations but increase the complexity of blood-device interactions. Here we describe a human-scale in vitro perfusion system to study hemocompatibility and performance of islet-like cell clusters (ILCs) in alginate hydrogel. A cylindrical perfusion device was designed for multi-day culture without leakage, contamination, or flow occlusion. Rat blood perfusion was assessed for prothrombin time and international normalized ratio and demonstrated no significant change in clotting time. Ex vivo perfusion performed with rats showed patency of the device for over 100 min using Doppler ultrasound imaging. PET-CT imaging of the device successfully visualized metabolically active mouse insulinoma 6 ILCs. ILCs cultured for 7 days under static conditions exhibited abnormal morphology and increased activated caspase-3 staining when compared with the perfused device. These findings reinforce the need for convective transport in macroencapsulation strategies and offer a robust and versatile in vitro system to better inform preclinical design.
Collapse
Affiliation(s)
| | - Lisa Danielczak
- Department of Chemical Engineering, McGill University, Montréal, QC, Canada
| | | | - Craig Hasilo
- Department of Surgery, McGill University Health Centre, Montréal, QC, Canada
| | - André Bégin-Drolet
- Department of Mechanical Engineering, Laval University, Québec City, QC, Canada
| | - Jean Ruel
- Department of Mechanical Engineering, Laval University, Québec City, QC, Canada
| | - Steven Paraskevas
- Department of Surgery, McGill University Health Centre, Montréal, QC, Canada
| | - Richard L Leask
- Department of Chemical Engineering, McGill University, Montréal, QC, Canada.,Department of Biomedical Engineering, McGill University, Montréal, QC, Canada
| | - Corinne A Hoesli
- Department of Chemical Engineering, McGill University, Montréal, QC, Canada.,Department of Biomedical Engineering, McGill University, Montréal, QC, Canada
| |
Collapse
|
|
39
|
SIX2 Regulates Human β Cell Differentiation from Stem Cells and Functional Maturation In Vitro. Cell Rep 2021; 31:107687. [PMID: 32460030 PMCID: PMC7304247 DOI: 10.1016/j.celrep.2020.107687] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 03/24/2020] [Accepted: 05/04/2020] [Indexed: 12/30/2022] Open
Abstract
Generation of insulin-secreting β cells in vitro is a promising approach for diabetes cell therapy. Human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) are differentiated to β cells (SC-β cells) and mature to undergo glucose-stimulated insulin secretion, but molecular regulation of this defining β cell phenotype is unknown. Here, we show that maturation of SC-β cells is regulated by the transcription factor SIX2. Knockdown (KD) or knockout (KO) of SIX2 in SC-β cells drastically limits glucose-stimulated insulin secretion in both static and dynamic assays, along with the upstream processes of cytoplasmic calcium flux and mitochondrial respiration. Furthermore, SIX2 regulates the expression of genes associated with these key β cell processes, and its expression is restricted to endocrine cells. Our results demonstrate that expression of SIX2 influences the generation of human SC-β cells in vitro. Velazco-Cruz et al. characterize the role of SIX2 in stem cell differentiation to β cells. SIX2 expression is restricted to late-stage endocrine cells. Generation of β cells does not require SIX2, but lack of SIX2 impairs maturation, as assessed by glucose-stimulated insulin secretion, calcium flux, mitochondrial respiration, and gene expression.
Collapse
|
|
40
|
Encapsulation Strategies for Pancreatic Islet Transplantation without Immune Suppression. CURRENT STEM CELL REPORTS 2021. [DOI: 10.1007/s40778-021-00190-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
|
|
41
|
Duy Nguyen BT, Nguyen Thi HY, Nguyen Thi BP, Kang DK, Kim JF. The Roles of Membrane Technology in Artificial Organs: Current Challenges and Perspectives. MEMBRANES 2021; 11:239. [PMID: 33800659 PMCID: PMC8065507 DOI: 10.3390/membranes11040239] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/20/2021] [Accepted: 03/20/2021] [Indexed: 02/07/2023]
Abstract
The recent outbreak of the COVID-19 pandemic in 2020 reasserted the necessity of artificial lung membrane technology to treat patients with acute lung failure. In addition, the aging world population inevitably leads to higher demand for better artificial organ (AO) devices. Membrane technology is the central component in many of the AO devices including lung, kidney, liver and pancreas. Although AO technology has improved significantly in the past few decades, the quality of life of organ failure patients is still poor and the technology must be improved further. Most of the current AO literature focuses on the treatment and the clinical use of AO, while the research on the membrane development aspect of AO is relatively scarce. One of the speculated reasons is the wide interdisciplinary spectrum of AO technology, ranging from biotechnology to polymer chemistry and process engineering. In this review, in order to facilitate the membrane aspects of the AO research, the roles of membrane technology in the AO devices, along with the current challenges, are summarized. This review shows that there is a clear need for better membranes in terms of biocompatibility, permselectivity, module design, and process configuration.
Collapse
Affiliation(s)
- Bao Tran Duy Nguyen
- Department of Energy and Chemical Engineering, Incheon National University, Incheon 22012, Korea; (B.T.D.N.); (H.Y.N.T.); (B.P.N.T.)
| | - Hai Yen Nguyen Thi
- Department of Energy and Chemical Engineering, Incheon National University, Incheon 22012, Korea; (B.T.D.N.); (H.Y.N.T.); (B.P.N.T.)
| | - Bich Phuong Nguyen Thi
- Department of Energy and Chemical Engineering, Incheon National University, Incheon 22012, Korea; (B.T.D.N.); (H.Y.N.T.); (B.P.N.T.)
| | - Dong-Ku Kang
- Department of Chemistry, Incheon National University, Incheon 22012, Korea
| | - Jeong F. Kim
- Department of Energy and Chemical Engineering, Incheon National University, Incheon 22012, Korea; (B.T.D.N.); (H.Y.N.T.); (B.P.N.T.)
- Innovation Center for Chemical Engineering, Incheon National University, Incheon 22012, Korea
| |
Collapse
|
|
42
|
Ng NHJ, Neo CWY, Ding SSL, Teo AKK. Insights from single cell studies of human pancreatic islets and stem cell-derived islet cells to guide functional beta cell maturation in vitro. VITAMINS AND HORMONES 2021; 116:193-233. [PMID: 33752818 DOI: 10.1016/bs.vh.2021.02.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
There is now a sizeable number of single cell transcriptomics studies performed on human and rodent pancreatic islets that have shed light on the unique gene signatures and level of heterogeneity within each individual islet cell type. Following closely from these studies, there is also rapidly-growing activity on characterizing islet-like cells derived from in vitro differentiation of human pluripotent stem cells (hPSCs) at the single cell level. The overall consensus across the studies so far suggests that the first few stages of differentiation are largely uniform, whereas during pancreatic endocrine commitment, cell trajectories start to diverge, resulting in multiple end-stage pancreatic cells that include progenitor-like, endocrine and non-endocrine cells. Comprehensive transcriptional profiling is important for understanding how and why islet cells, especially the insulin-secreting beta cells, exist in subpopulations that differ in maturity, proliferation rate, sensitivity to stress, and insulin secretion function. For hPSC-derived beta cells to be used confidently for cell therapy, optimal differentiation and thorough characterization is required. The key questions to address are-What is the trajectory of differentiation? Is heterogeneity a natural occurrence or is it a consequence of imperfect differentiation protocols? Can lessons be drawn from the extensive single cell transcriptomic data to help guide maturation of beta cells in vitro? This book chapter seeks to address some of these questions, and facilitate ongoing efforts in improving the beta cell differentiation pipeline or enriching for desired beta cell populations following differentiation, to make way for better mechanistic studies and future clinical translation.
Collapse
Affiliation(s)
- Natasha Hui Jin Ng
- Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology (IMCB), A*STAR, Proteos, Singapore, Singapore
| | - Claire Wen Ying Neo
- Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology (IMCB), A*STAR, Proteos, Singapore, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Shirley Suet Lee Ding
- Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology (IMCB), A*STAR, Proteos, Singapore, Singapore
| | - Adrian Kee Keong Teo
- Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology (IMCB), A*STAR, Proteos, Singapore, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
| |
Collapse
|
|
43
|
Hayat H, Sun A, Hayat H, Liu S, Talebloo N, Pinger C, Bishop JO, Gudi M, Dwan BF, Ma X, Zhao Y, Moore A, Wang P. Artificial Intelligence Analysis of Magnetic Particle Imaging for Islet Transplantation in a Mouse Model. Mol Imaging Biol 2021; 23:18-29. [PMID: 32833112 PMCID: PMC7785569 DOI: 10.1007/s11307-020-01533-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 08/06/2020] [Accepted: 08/12/2020] [Indexed: 12/13/2022]
Abstract
PURPOSE Current approaches to quantification of magnetic particle imaging (MPI) for cell-based therapy are thwarted by the lack of reliable, standardized methods of segmenting the signal from background in images. This calls for the development of artificial intelligence (AI) systems for MPI analysis. PROCEDURES We utilize a canonical algorithm in the domain of unsupervised machine learning, known as K-means++, to segment the regions of interest (ROI) of images and perform iron quantification analysis using a standard curve model. We generated in vitro, in vivo, and ex vivo data using islets and mouse models and applied the AI algorithm to gain insight into segmentation and iron prediction on these MPI data. In vitro models included imaging the VivoTrax-labeled islets in varying numbers. In vivo mouse models were generated through transplantation of increasing numbers of the labeled islets under the kidney capsule of mice. Ex vivo data were obtained from the MPI images of excised kidney grafts. RESULTS The K-means++ algorithms segmented the ROI of in vitro phantoms with minimal noise. A linear correlation between the islet numbers and the increasing prediction of total iron value (TIV) in the islets was observed. Segmentation results of the ROI of the in vivo MPI scans showed that with increasing number of transplanted islets, the signal intensity increased with linear trend. Upon segmenting the ROI of ex vivo data, a linear trend was observed in which increasing intensity of the ROI yielded increasing TIV of the islets. Through statistical evaluation of the algorithm performance via intraclass correlation coefficient validation, we observed excellent performance of K-means++-based model on segmentation and quantification analysis of MPI data. CONCLUSIONS We have demonstrated the ability of the K-means++-based model to provide a standardized method of segmentation and quantification of MPI scans in an islet transplantation mouse model.
Collapse
Affiliation(s)
- Hasaan Hayat
- Precision Health Program, Michigan State University, 766 Service Road, Rm. 2020, East Lansing, MI, 48823, USA
- Lyman Briggs College, Michigan State University, East Lansing, MI, USA
| | - Aixia Sun
- Precision Health Program, Michigan State University, 766 Service Road, Rm. 2020, East Lansing, MI, 48823, USA
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI, USA
| | - Hanaan Hayat
- Lyman Briggs College, Michigan State University, East Lansing, MI, USA
- Institute for Quantitative Health Science and Engineering, Department of Biomedical Engineering, Michigan State University, East Lansing, MI, USA
| | - Sihai Liu
- Precision Health Program, Michigan State University, 766 Service Road, Rm. 2020, East Lansing, MI, 48823, USA
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI, USA
- Department of Orthopedics, Beijing Charity Hospital, Capital Medical University, Beijing, China
| | - Nazanin Talebloo
- Precision Health Program, Michigan State University, 766 Service Road, Rm. 2020, East Lansing, MI, 48823, USA
- Department of Chemistry, College of Natural Science, Michigan State University, East Lansing, MI, USA
| | - Cody Pinger
- Institute for Quantitative Health Science and Engineering, Department of Biomedical Engineering, Michigan State University, East Lansing, MI, USA
| | - Jack Owen Bishop
- Precision Health Program, Michigan State University, 766 Service Road, Rm. 2020, East Lansing, MI, 48823, USA
- Department of Neuroscience, College of Natural Science, Michigan State University, East Lansing, MI, USA
| | - Mithil Gudi
- Precision Health Program, Michigan State University, 766 Service Road, Rm. 2020, East Lansing, MI, 48823, USA
- Lyman Briggs College, Michigan State University, East Lansing, MI, USA
| | - Bennett Francis Dwan
- Precision Health Program, Michigan State University, 766 Service Road, Rm. 2020, East Lansing, MI, 48823, USA
- College of Natural Science, Michigan State University, East Lansing, MI, USA
| | - Xiaohong Ma
- Precision Health Program, Michigan State University, 766 Service Road, Rm. 2020, East Lansing, MI, 48823, USA
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI, USA
- Department of Radiology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yanfeng Zhao
- Precision Health Program, Michigan State University, 766 Service Road, Rm. 2020, East Lansing, MI, 48823, USA
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI, USA
- Department of Radiology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Anna Moore
- Precision Health Program, Michigan State University, 766 Service Road, Rm. 2020, East Lansing, MI, 48823, USA
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI, USA
| | - Ping Wang
- Precision Health Program, Michigan State University, 766 Service Road, Rm. 2020, East Lansing, MI, 48823, USA.
- Department of Radiology, College of Human Medicine, Michigan State University, East Lansing, MI, USA.
| |
Collapse
|
|
44
|
Chung WY, Pollard CA, Kumar R, Drogemuller CJ, Naziruddin B, Stover C, Issa E, Isherwood J, Cooke J, Levy MF, Coates PTH, Garcea G, Dennison AR. A comparison of the inflammatory response following autologous compared with allogenic islet cell transplantation. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:98. [PMID: 33569400 PMCID: PMC7867892 DOI: 10.21037/atm-20-3519] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Background The initial response to islet transplantation and the subsequent acute inflammation is responsible for significant attrition of islets following both autologous and allogenic procedures. This multicentre study compares this inflammatory response using cytokine profiles and complement activation. Methods Inflammatory cytokine and complement pathway activity were examined in two cohorts of patients undergoing total pancreatectomy followed either by autologous (n=11) or allogenic (n=6) islet transplantation. Two patients who underwent total pancreatectomy alone (n=2) served as controls. Results The peak of cytokine production occurred immediately following induction of anaesthesia and during surgery. There was found to be a greater elevation of the following cytokines: TNF-alpha (P<0.01), MCP-1 (P=0.0013), MIP-1α (P=0.001), MIP-1β (P=0.00020), IP-10 (P=0.001), IL-8 (P=0.004), IL-1α (P=0.001), IL-1ra (0.0018), IL-10 (P=0.001), GM-CSF (P=0.001), G-CSF (P=0.0198), and Eotaxin (P=0.01) in the allogenic group compared to autografts and controls. Complement activation and consumption was observed in all three pathways, and there were no significant differences in between the groups although following allogenic transplantation ∆IL-10 and ∆VEGF levels were significantly elevated those patients who became insulin-independent compared with those who were insulin-dependent. Conclusions The cytokine profiles following islet transplantation suggests a significantly greater acute inflammatory response following allogenic islet transplantation compared with auto-transplantation although a significant, non-specific inflammatory response occurs following both forms of islet transplantation.
Collapse
Affiliation(s)
- Wen Yuan Chung
- Department of Hepatobiliary and Pancreatic Surgery, Leicester General Hospital, Leicester, UK
| | - Cristina A Pollard
- Department of Hepatobiliary and Pancreatic Surgery, Leicester General Hospital, Leicester, UK
| | - Rohan Kumar
- Department of Hepatobiliary and Pancreatic Surgery, Leicester General Hospital, Leicester, UK
| | | | | | - Cordula Stover
- Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK
| | - Eyad Issa
- Department of Hepatobiliary and Pancreatic Surgery, Leicester General Hospital, Leicester, UK
| | - John Isherwood
- Department of Hepatobiliary and Pancreatic Surgery, Leicester General Hospital, Leicester, UK
| | - Jill Cooke
- Department of Hepatobiliary and Pancreatic Surgery, Leicester General Hospital, Leicester, UK
| | - Marlon F Levy
- Baylor Research Institute, Dallas & Fort Worth, TX, USA
| | - P Toby H Coates
- Australian Islet Consortium, Royal Adelaide Hospital, South Australia, Australia
| | - Giuseppe Garcea
- Department of Hepatobiliary and Pancreatic Surgery, Leicester General Hospital, Leicester, UK
| | - Ashley R Dennison
- Department of Hepatobiliary and Pancreatic Surgery, Leicester General Hospital, Leicester, UK
| |
Collapse
|
|
45
|
Han EX, Wang J, Kural M, Jiang B, Leiby KL, Chowdhury N, Tellides G, Kibbey RG, Lawson JH, Niklason LE. Development of a Bioartificial Vascular Pancreas. J Tissue Eng 2021; 12:20417314211027714. [PMID: 34262686 PMCID: PMC8243137 DOI: 10.1177/20417314211027714] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Accepted: 06/08/2021] [Indexed: 12/16/2022] Open
Abstract
Transplantation of pancreatic islets has been shown to be effective, in some patients, for the long-term treatment of type 1 diabetes. However, transplantation of islets into either the portal vein or the subcutaneous space can be limited by insufficient oxygen transfer, leading to islet loss. Furthermore, oxygen diffusion limitations can be magnified when islet numbers are increased dramatically, as in translating from rodent studies to human-scale treatments. To address these limitations, an islet transplantation approach using an acellular vascular graft as a vascular scaffold has been developed, termed the BioVascular Pancreas (BVP). To create the BVP, islets are seeded as an outer coating on the surface of an acellular vascular graft, using fibrin as a hydrogel carrier. The BVP can then be anastomosed as an arterial (or arteriovenous) graft, which allows fully oxygenated arterial blood with a pO2 of roughly 100 mmHg to flow through the graft lumen and thereby supply oxygen to the islets. In silico simulations and in vitro bioreactor experiments show that the BVP design provides adequate survivability for islets and helps avoid islet hypoxia. When implanted as end-to-end abdominal aorta grafts in nude rats, BVPs were able to restore near-normoglycemia durably for 90 days and developed robust microvascular infiltration from the host. Furthermore, pilot implantations in pigs were performed, which demonstrated the scalability of the technology. Given the potential benefits provided by the BVP, this tissue design may eventually serve as a solution for transplantation of pancreatic islets to treat or cure type 1 diabetes.
Collapse
Affiliation(s)
- Edward X Han
- Department of Biomedical Engineering,
Yale School of Engineering and Applied Science, New Haven, CT, USA
| | - Juan Wang
- Vascular Biology and Therapeutics
Program, Yale School of Medicine, New Haven, CT, USA
- Department of Anesthesiology, Yale
School of Medicine, New Haven, CT, USA
| | - Mehmet Kural
- Vascular Biology and Therapeutics
Program, Yale School of Medicine, New Haven, CT, USA
- Department of Anesthesiology, Yale
School of Medicine, New Haven, CT, USA
| | - Bo Jiang
- Department of Surgery, Yale School of
Medicine, New Haven, CT, USA
- Department of Vascular Surgery, The
First Hospital of China Medical University, Shenyang, China
| | - Katherine L Leiby
- Department of Biomedical Engineering,
Yale School of Engineering and Applied Science, New Haven, CT, USA
| | - Nazar Chowdhury
- Molecular, Cellular, and Developmental
Biology, Yale University, New Haven, CT, USA
| | - George Tellides
- Vascular Biology and Therapeutics
Program, Yale School of Medicine, New Haven, CT, USA
- Department of Surgery, Yale School of
Medicine, New Haven, CT, USA
- Veterans Affairs Connecticut Healthcare
System, West Haven, CT, USA
| | - Richard G Kibbey
- Department of Internal Medicine
(Endocrinology), Yale University, New Haven, CT, USA
- Department of Cellular & Molecular
Physiology, Yale School of Medicine, New Haven, CT, USA
| | - Jeffrey H Lawson
- Department of Surgery, Duke
University, Durham, NC, USA
- Humacyte Inc., Durham, NC, USA
| | - Laura E Niklason
- Department of Biomedical Engineering,
Yale School of Engineering and Applied Science, New Haven, CT, USA
- Vascular Biology and Therapeutics
Program, Yale School of Medicine, New Haven, CT, USA
- Department of Anesthesiology, Yale
School of Medicine, New Haven, CT, USA
- Humacyte Inc., Durham, NC, USA
| |
Collapse
|
|
46
|
Huang Q, Huang Y, Liu J. Mesenchymal Stem Cells: An Excellent Candidate for the Treatment of Diabetes Mellitus. Int J Endocrinol 2021; 2021:9938658. [PMID: 34135959 PMCID: PMC8178013 DOI: 10.1155/2021/9938658] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 05/19/2021] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are adult stem cells (ASCs) known for repairing damaged cells, exerting anti-inflammatory responses and producing immunoregulatory effects that can be significantly induced into insulin-producing cells (IPCs), providing an inexhaustible supply of functional β cells for cell replacement therapy and disease modeling for diabetes. MSC therapy may be the most promising strategy for diabetes mellitus because of these significant merits. In this paper, we focused on MSC therapy for diabetes.
Collapse
Affiliation(s)
- Qiulan Huang
- Department of Endocrinology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Yanting Huang
- Department of Endocrinology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Jianping Liu
- Department of Endocrinology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| |
Collapse
|
|
47
|
Clough DW, King JL, Li F, Shea LD. Integration of Islet/Beta-Cell Transplants with Host Tissue Using Biomaterial Platforms. Endocrinology 2020; 161:bqaa156. [PMID: 32894299 PMCID: PMC8253249 DOI: 10.1210/endocr/bqaa156] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 08/27/2020] [Indexed: 12/30/2022]
Abstract
Cell-based therapies are emerging for type I diabetes mellitus (T1D), an autoimmune disease characterized by the destruction of insulin-producing pancreatic β-cells, as a means to provide long-term restoration of glycemic control. Biomaterial scaffolds provide an opportunity to enhance the manufacturing and transplantation of islets or stem cell-derived β-cells. In contrast to encapsulation strategies that prevent host contact with the graft, recent approaches aim to integrate the transplant with the host to facilitate glucose sensing and insulin distribution, while also needing to modulate the immune response. Scaffolds can provide a supportive niche for cells either during the manufacturing process or following transplantation at extrahepatic sites. Scaffolds are being functionalized to deliver oxygen, angiogenic, anti-inflammatory, or trophic factors, and may facilitate cotransplantation of cells that can enhance engraftment or modulate immune responses. This local engineering of the transplant environment can complement systemic approaches for maximizing β-cell function or modulating immune responses leading to rejection. This review discusses the various scaffold platforms and design parameters that have been identified for the manufacture of human pluripotent stem cell-derived β-cells, and the transplantation of islets/β-cells to maintain normal blood glucose levels.
Collapse
Affiliation(s)
- Daniel W Clough
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan
| | - Jessica L King
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan
| | - Feiran Li
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan
| | - Lonnie D Shea
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan
| |
Collapse
|
|
48
|
Razavi M, Primavera R, Kevadiya BD, Wang J, Ullah M, Buchwald P, Thakor AS. Controlled Nutrient Delivery to Pancreatic Islets Using Polydopamine-Coated Mesoporous Silica Nanoparticles. NANO LETTERS 2020; 20:7220-7229. [PMID: 32909757 PMCID: PMC8121116 DOI: 10.1021/acs.nanolett.0c02576] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/09/2023]
Abstract
In the present study, we created a nanoscale platform that can deliver nutrients to pancreatic islets in a controlled manner. Our platform consists of a mesoporous silica nanoparticle (MSNP), which can be loaded with glutamine (G: an essential amino acid required for islet survival and function). To control the release of G, MSNPs were coated with a polydopamine (PD) layer. With the optimal parameters (0.5 mg/mL and 0.5 h), MSNPs were coated with a layer of PD, which resulted in a delay of G release from MSNPs over 14 d (57.4 ± 4.7% release). Following syngeneic renal subcapsule islet transplantation in diabetic mice, PDG-MSNPs improved the engraftment of islets (i.e., enhanced revascularization and reduced inflammation) as well as their function, resulting in re-establishment of glycemic control. Collectively, our data show that PDG-MSNPs can support transplanted islets by providing them with a controlled and sustained supply of nutrients.
Collapse
Affiliation(s)
- Mehdi Razavi
- Interventional Regenerative Medicine and Imaging Laboratory, Stanford University School of Medicine, Palo Alto, California 94304, United States; Biionix (Bionic Materials, Implants & Interfaces) Cluster, Department of Internal Medicine, College of Medicine and Department of Materials Science & Engineering, University of Central Florida, Orlando, Florida 32827, United States
| | - Rosita Primavera
- Interventional Regenerative Medicine and Imaging Laboratory, Stanford University School of Medicine, Palo Alto, California 94304, United States
| | - Bhavesh D Kevadiya
- Interventional Regenerative Medicine and Imaging Laboratory, Stanford University School of Medicine, Palo Alto, California 94304, United States
| | - Jing Wang
- Interventional Regenerative Medicine and Imaging Laboratory, Stanford University School of Medicine, Palo Alto, California 94304, United States
| | - Mujib Ullah
- Interventional Regenerative Medicine and Imaging Laboratory, Stanford University School of Medicine, Palo Alto, California 94304, United States
| | - Peter Buchwald
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, Florida 33136, United States
| | - Avnesh S Thakor
- Interventional Regenerative Medicine and Imaging Laboratory, Stanford University School of Medicine, Palo Alto, California 94304, United States
| |
Collapse
|
|
49
|
The MEK Inhibitor Trametinib Suppresses Major Histocompatibility Antigen-mismatched Rejection Following Pancreatic Islet Transplantation. Transplant Direct 2020; 6:e591. [PMID: 32851124 PMCID: PMC7423917 DOI: 10.1097/txd.0000000000001045] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 06/19/2020] [Accepted: 07/04/2020] [Indexed: 11/26/2022] Open
Abstract
Background. Potential adverse effects, such as functional impairment of islets, render conventional immunosuppressive drugs unsuitable for use in islet transplantation. In addition, as a single therapy, they cannot prolong islet allograft survival. Here, we investigated the utility of the mitogen-activated protein kinase inhibitor trametinib and asked whether it ameliorates acute rejection of transplanted islets without the need for conventional immunosuppressants. Methods. Islets from fully major histocompatibility complex-mismatched BALB/c mice were transplanted into streptozotocin-induced diabetic C57BL/6 mice via the portal vein. These mice received trametinib or vehicle (orally) for 28 days. Isolated islets from BALB/c mice were incubated in vitro with different concentrations of trametinib to determine viability and function. Results. Trametinib (0.1 and 0.3 mg/kg) prolonged graft survival significantly (P = 0.0007 and P = 0.005, respectively) when compared with vehicle. Histologic analyses revealed that cellular infiltration of the graft by lymphocytes was inhibited significantly on day 7 (P < 0.05). In addition, trametinib suppressed functional differentiation of naive CD4+ T cells in recipients. Expression of mRNA encoding inflammatory cytokines interleukin (IL)-2, tumor necrosis factor α, and interferon γ in recipients treated with trametinib was also inhibited (P < 0.001, P < 0.05, and P < 0.01, respectively). Trametinib also increased production of IL-4 and IL-10 (P < 0.05 and P = 0.20, respectively). In vitro, islets incubated with different concentrations of trametinib exhibited no harmful effects with respect to viability and function. Conclusions. Trametinib delayed islet graft rejection by inhibiting functional differentiation of naive CD4+ T cells and regulating inflammatory cytokines. Trametinib might be a promising candidate for maintenance immunosuppressive therapy after allogeneic islet transplantation.
Collapse
|
|
50
|
Yamane K, Anazawa T, Tada S, Fujimoto N, Inoguchi K, Emoto N, Nagai K, Masui T, Okajima H, Takaori K, Sumi S, Uemoto S. Mitomycin C treatment improves pancreatic islet graft longevity in intraportal islet transplantation by suppressing proinflammatory response. Sci Rep 2020; 10:12086. [PMID: 32694579 PMCID: PMC7374693 DOI: 10.1038/s41598-020-69009-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Accepted: 07/06/2020] [Indexed: 12/14/2022] Open
Abstract
The in vitro culture period prior to cell transplantation (i.e. pancreatic islet transplantation) enables cell modification and is thus advantageous. However, the islet preconditioning method has not been fully explored. Here we present a simple approach for islet preconditioning that uses the antibiotic mitomycin C (MMC), which has antitumor activity, to reduce islet immunogenicity and prevent proinflammatory events in an intraportal islet transplantation model. Freshly isolated mice islets were treated for 30 min with 10 μg/mL MMC or not, cultured for 20 h and transplanted into the livers of syngeneic or allogeneic diabetic mouse recipients. In the allogeneic model, MMC preconditioning significantly prolonged graft survival without requiring immunosuppressants. In vitro, MMC treatment suppressed the expression of proinflammatory cytokines in islet allografts, while immunohistochemical studies revealed the suppression of inflammatory cell infiltration into MMC-treated allografts relative to untreated allografts. Furthermore, MMC preconditioning significantly suppressed the mRNA expression of proinflammatory cytokines into the transplant site and induced the differentiation of regulatory T cells with the ability to suppress CD4+ T cell-mediated immune responses. In conclusion, islet preconditioning with MMC prolonged graft survival in an intraportal islet transplantation model by suppressing proinflammatory events and inducing potentially regulatory lymphocytes.
Collapse
Affiliation(s)
- Kei Yamane
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, 6068507, Japan
| | - Takayuki Anazawa
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, 6068507, Japan.
| | - Seiichiro Tada
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, 6068507, Japan
| | - Nanae Fujimoto
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, 6068507, Japan
| | - Kenta Inoguchi
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, 6068507, Japan
| | - Norio Emoto
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, 6068507, Japan
| | - Kazuyuki Nagai
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, 6068507, Japan
| | - Toshihiko Masui
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, 6068507, Japan
| | - Hideaki Okajima
- Department of Paediatric Surgery, Kanazawa Medical University, Kanazawa, 9200293, Japan
| | - Kyoichi Takaori
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, 6068507, Japan
| | - Shoichiro Sumi
- Laboratory of Organ and Tissue Reconstruction, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, 6068507, Japan
| | - Shinji Uemoto
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, 6068507, Japan
| |
Collapse
|