|
1
|
Fonseca LM, Krause N, Lebreton F, Berishvili E. Recreating the Endocrine Niche: Advances in Bioengineering the Pancreas. Artif Organs 2025; 49:541-555. [PMID: 39844747 DOI: 10.1111/aor.14950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 12/27/2024] [Accepted: 01/03/2025] [Indexed: 01/24/2025]
Abstract
Intrahepatic islet transplantation is a promising strategy for β-cell replacement therapy in the treatment of Type 1 Diabetes. However, several obstacles hinder the long-term efficacy of this therapy. A major challenge is the scarcity of donor organs. During the isolation process, islets are disconnected from their extracellular matrix (ECM) and vasculature, leading to significant loss due to anoikis and hypoxia. Additionally, inflammatory and rejection reactions further compromise islet survival and engraftment success. Extensive efforts are being made to improve the efficacy of islet transplantation. These strategies include promoting revascularization and ECM support through bioengineering techniques, exploring alternative sources of insulin-secreting cells, and providing immunomodulation for the graft. Despite these advancements, a significant gap remains in integrating these strategies into a cohesive approach that effectively replicates the native endocrine environment. Specifically, the lack of comprehensive methods to address both the structural and functional aspects of the endocrine niche limits reproducibility and clinical translation. Therefore, bioengineering an endocrine pancreas must aim to recreate the endocrine niche to achieve lifelong efficacy and insulin independence. This review discusses various strategies developed to produce the building blocks for generating a vascularized, immune-protected insulin-secreting construct, emphasizing the importance of the endocrine niche's composition and function.
Collapse
Affiliation(s)
- Laura Mar Fonseca
- Laboratory of Tissue Engineering and Organ Regeneration, Department of Surgery, University of Geneva, Geneva, Switzerland
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
- Faculty Diabetes Center, University of Geneva Medical Center, University of Geneva, Geneva, Switzerland
| | - Nicerine Krause
- Laboratory of Tissue Engineering and Organ Regeneration, Department of Surgery, University of Geneva, Geneva, Switzerland
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
- Faculty Diabetes Center, University of Geneva Medical Center, University of Geneva, Geneva, Switzerland
| | - Fanny Lebreton
- Laboratory of Tissue Engineering and Organ Regeneration, Department of Surgery, University of Geneva, Geneva, Switzerland
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
- Faculty Diabetes Center, University of Geneva Medical Center, University of Geneva, Geneva, Switzerland
| | - Ekaterine Berishvili
- Laboratory of Tissue Engineering and Organ Regeneration, Department of Surgery, University of Geneva, Geneva, Switzerland
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
- Faculty Diabetes Center, University of Geneva Medical Center, University of Geneva, Geneva, Switzerland
- Institute of Medical and Public Health Research, Ilia State University, Tbilisi, Georgia
| |
Collapse
|
|
2
|
Chen S, Wang W, Shen L, Liu H, Luo J, Ren Y, Cui S, Ye Y, Shi G, Cheng F, Su X, Dai L, Gou M, Deng H. A 3D-printed microdevice encapsulates vascularized islets composed of iPSC-derived β-like cells and microvascular fragments for type 1 diabetes treatment. Biomaterials 2025; 315:122947. [PMID: 39547136 DOI: 10.1016/j.biomaterials.2024.122947] [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: 05/23/2024] [Revised: 10/23/2024] [Accepted: 11/05/2024] [Indexed: 11/17/2024]
Abstract
Transplantation of insulin-secreting cells provides a promising method for re-establishing the autonomous blood glucose control ability of type 1 diabetes (T1D) patients, but the low survival of the transplanted cells hinder the therapeutic efficacy. In this study, we 3D-printed an encapsulation system containing β-like cells and microvascular fragments (MVF), to create a retrivable microdevice with vascularized islets in vivo for T1D therapy. The functional β-like cells were differentiated from the urine epithelial cell-derived induced pluripotent stem cells (UiPSCs). Single-cell RNA sequencing provided an integrative study and macroscopic developmental analyses of the entire process of differentiation, which revealed the developmental trajectory of differentiation in vitro follows the developmental pattern of embryonic pancreas in vivo. The MVF were isolated from the epididymal fat pad. The microdevice with a groove structure were rapidly fabricated by the digital light processing (DLP)-3D printing technology. The β-like cells and MVF were uniformly distributed in the device. After subcutaneous transplantation into C57BL/6 mice, the microdevice have less collagen accumulation and low immune cell infiltration. Moreover, the microdevice encapsulated vascularized islets reduced hyperglycemia in 33 % of the treated mice for up to 100 days without immunosuppressants, and the humanized C-peptide was also detected in the serum of the mice. In summary, we described the microdevice-protected vascularized islets for long-term treatment of T1D, with high safety and potential clinical transformative value, and may therefore provide a translatable solution to advance the research progress of β cell replacement therapy for T1D.
Collapse
Affiliation(s)
- Shuang Chen
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Wenshuang Wang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Lanlin Shen
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Haofan Liu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jing Luo
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yushuang Ren
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Susu Cui
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yixin Ye
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Gang Shi
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Fuyi Cheng
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xiaolan Su
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Lei Dai
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Maling Gou
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Hongxin Deng
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
| |
Collapse
|
|
3
|
Wang Y, McGarrigle J, Cook J, Rios P, Monica GL, Chen Y, Wei W, Oberholzer J. The future of islet transplantation beyond the BLA approval: challenges and opportunities. FRONTIERS IN TRANSPLANTATION 2025; 4:1522409. [PMID: 40124184 PMCID: PMC11925927 DOI: 10.3389/frtra.2025.1522409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 02/19/2025] [Indexed: 03/25/2025]
Abstract
This opinion paper explores the path forward for islet transplantation as a cell therapy for type 1 diabetes, following the Biologics License Application (BLA) approval. The authors review key challenges and opportunities that lie ahead. After a brief overview of the history of human islet transplantation, the paper examines the FDA's regulatory stance on isolated islet cells and the requirements for obtaining a BLA. The authors discuss the significance of this approval and the critical steps necessary to broaden patient access, such as scaling up production, clinical integration, reimbursement frameworks, post-marketing surveillance, and patient education initiatives. The paper highlights that the approval of LANTIDRA as an allogeneic cell transplant for uncontrolled type 1 diabetes marks the beginning of new chapters in improving islet transplantation. The authors emphasize essential areas for development, including advancements in islet manufacturing, optimization of transplant sites, islet encapsulation, exploration of unlimited cell sources, and gene editing technologies. In conclusion, the future of islet transplantation beyond the BLA approval presents challenges and opportunities. While significant regulatory milestones have been reached, hurdles remain. Innovations in stem cell-derived islets, cell encapsulation, and gene editing show promise in enhancing graft survival, expanding the availability of transplantable cells, and reducing the reliance on immunosuppressive drugs. These advancements could pave the way for more accessible, durable, and personalized diabetes treatments.
Collapse
Affiliation(s)
- Yong Wang
- Clinic of Visceral and Transplant Surgery, University Hospital Zurich, Zurich, Switzerland
- Faculty of Medicine, University of Zurich, Zürich, Switzerland
- CellTrans, Inc., Chicago, IL, United States
| | | | - Jenny Cook
- CellTrans, Inc., Chicago, IL, United States
| | - Peter Rios
- CellTrans, Inc., Chicago, IL, United States
| | | | - Yingying Chen
- Clinic of Visceral and Transplant Surgery, University Hospital Zurich, Zurich, Switzerland
- Faculty of Medicine, University of Zurich, Zürich, Switzerland
| | - Wei Wei
- Clinic of Visceral and Transplant Surgery, University Hospital Zurich, Zurich, Switzerland
- Faculty of Medicine, University of Zurich, Zürich, Switzerland
| | - Jose Oberholzer
- Clinic of Visceral and Transplant Surgery, University Hospital Zurich, Zurich, Switzerland
- Faculty of Medicine, University of Zurich, Zürich, Switzerland
- CellTrans, Inc., Chicago, IL, United States
| |
Collapse
|
|
4
|
Gonzalez GC, Li CM, Pasolini I, Pete SI, Verheyen C, Vignolo SM, De Toni T, Stock AA, Tomei AA. High-Yield Generation of Glucose-Responsive Pseudoislets From Murine Insulinoma Cells for In Vitro Studies and Longitudinal Monitoring of Graft Survival In Vivo. Cell Transplant 2025; 34:9636897251315123. [PMID: 39881520 PMCID: PMC11780636 DOI: 10.1177/09636897251315123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 12/14/2024] [Accepted: 01/06/2025] [Indexed: 01/31/2025] Open
Abstract
Compared to primary pancreatic islets, insulinoma cell-derived 3D pseudoislets offer a more accessible, consistent, renewable, and widely applicable model system for optimization and mechanistic studies in type 1 diabetes (T1D). Here, we report a simple and efficient method for generating 3D pseudoislets from MIN6 and NIT-1 murine insulinoma cells. These pseudoislets are homogeneous in size and morphology (~150 µm), exhibit functional glucose-stimulated insulin secretion (GSIS) up to 18 days (NIT-1) enabling long-term studies, are produced in high yield [>35,000 Islet Equivalence from 30 ml culture], and are suitable for both in vitro and in vivo studies, including for encapsulation studies. To enable non-invasive longitudinal monitoring of graft survival in vivo, we transduced NIT-1 cells with green fluorescent protein-luciferase and confirmed comparable morphology, viability, and GSIS to untransduced cells in vitro. After subcutaneous implantation, we show capability to monitor graft survival in immunodeficient mice, recurrence of autoimmunity in non-obese diabetic mice, and allorejection in C57BL/6 mice. Overall, this platform provides an accessible protocol for generating high yields of 3D pseudoislets and non-invasive longitudinal monitoring of graft survival in different models offer advantages over primary islets for optimization and mechanistic studies of β cell biology, drug discovery, T1D pathogenesis and prevention, and β cell transplantation.
Collapse
Affiliation(s)
- Grisell C. Gonzalez
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Chris M. Li
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Ilaria Pasolini
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Department of Biomedical Engineering, University of Miami, Miami, FL, USA
| | - Sophia I. Pete
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Department of Biomedical Engineering, University of Miami, Miami, FL, USA
| | - Connor Verheyen
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Department of Biomedical Engineering, University of Miami, Miami, FL, USA
| | - Sofia M. Vignolo
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Department of Biomedical Engineering, University of Miami, Miami, FL, USA
| | - Teresa De Toni
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Department of Biomedical Engineering, University of Miami, Miami, FL, USA
| | - Aaron A. Stock
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Department of Biomedical Engineering, University of Miami, Miami, FL, USA
| | - Alice A. Tomei
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA
- Department of Biomedical Engineering, University of Miami, Miami, FL, USA
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| |
Collapse
|
|
5
|
Altabas V, Bulum T. Current Challenges in Pancreas and Islet Transplantation: A Scoping Review. Biomedicines 2024; 12:2853. [PMID: 39767759 PMCID: PMC11673013 DOI: 10.3390/biomedicines12122853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 12/07/2024] [Accepted: 12/13/2024] [Indexed: 01/11/2025] Open
Abstract
Type 1 diabetes mellitus is an autoimmune condition characterized by the destruction of pancreatic β-cells, necessitating insulin therapy to prevent life-threatening complications such as diabetic ketoacidosis. Despite advancements in glucose monitoring and pharmacological treatments, managing this disease remains challenging, often leading to long-term complications and psychological burdens, including diabetes distress. Advanced treatment options, such as whole-pancreas transplantation and islet transplantation, aim to restore insulin production and improve glucose control in selected patients with diabetes. The risk of transplant rejection necessitates immunosuppressive therapy, which increases susceptibility to infections and other adverse effects. Additionally, surgical complications, including infection and bleeding, are significant concerns, particularly for whole-pancreas transplantation. Recently, stem cell-derived therapies for type 1 diabetes have emerged as a promising alternative, offering potential solutions to overcome the limitations of formerly established transplantation methods. The purpose of this scoping review was to: (1) summarize the current evidence on achieved insulin independence following various transplantation methods of insulin-producing cells in patients with type 1 diabetes; (2) compare insulin independence rates among whole-pancreas transplantation, islet cell transplantation, and stem cell transplantation; and (3) identify limitations, challenges and potential future directions associated with these techniques. We systematically searched three databases (PubMed, Scopus, and Web of Science) from inception to November 2024, focusing on English-language, peer-reviewed clinical studies. The search terms used were 'transplantation' AND 'type 1 diabetes' AND 'insulin independence'. Studies were included if they reported on achieved insulin independence, involved more than 10 patients with type 1 diabetes, and had a mean follow-up period of at least one year. Reviewers screened citations and extracted data on transplant type, study population size, follow-up duration, and insulin independence rates. We identified 1380 papers, and after removing duplicates, 705 papers remained for title and abstract screening. A total of 139 English-language papers were retrieved for full-text review, of which 48 studies were included in this review. The findings of this scoping review indicate a growing body of literature on transplantation therapy for type 1 diabetes. However, significant limitations and challenges, like insufficient rates of achieved insulin independence, risks related to immunosuppression, malignant diseases, and ethical issues remain with each of the established techniques, highlighting the need for innovative approaches such as stem cell-derived islet transplantation to promote β-cell regeneration and protection.
Collapse
Affiliation(s)
- Velimir Altabas
- Department of Endocrinology, Diabetes and Metabolic Diseases Mladen Sekso, Sestre Milosrdnice University Hospital Center, 10000 Zagreb, Croatia
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Tomislav Bulum
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
- Vuk Vrhovac University Clinic for Diabetes, Endocrinology and Metabolic Diseases, Merkur University Hospital, 10000 Zagreb, Croatia
| |
Collapse
|
|
6
|
Kundnani NR, Lolescu B, Dinu AR, Berceanu-Vaduva DM, Dumitrescu P, Tamaș TP, Sharma A, Popa MD. Biotechnology Revolution Shaping the Future of Diabetes Management. Biomolecules 2024; 14:1563. [PMID: 39766270 PMCID: PMC11674738 DOI: 10.3390/biom14121563] [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: 10/20/2024] [Revised: 11/28/2024] [Accepted: 12/05/2024] [Indexed: 01/11/2025] Open
Abstract
INTRODUCTION Diabetes mellitus (DM) has a millennia-long history, with early references dating back to ancient Egypt and India. However, it was not until the 20th century that the connection between diabetes and insulin was fully understood. The sequencing of insulin in the 1950s initiated the convergence of biotechnology and diabetes management, leading to the development of recombinant human insulin in 1982. This marked the start of peptide-based therapies in DM. Recombinant peptides for DM treatment: Numerous recombinant peptides have been developed since, starting with modified insulin molecules, with the aim of bettering DM management through fine-tuning the glycemic response to insulin. Peptide-based therapies in DM have expanded substantially beyond insulin to include agonists of Glucagon-like peptide-1 receptor and Glucose-dependent insulinotropic polypeptide receptor, glucagon receptor antagonists, and even peptides exerting multiple receptor agonist effects, for better metabolic control. Insulin pumps, continuous glucose monitoring, and automated insulin delivery systems: The development of modern delivery systems combined with real-time glucose monitoring has significantly advanced diabetes care. Insulin pumps evolved from early large devices to modern sensor-augmented pumps with automated shutoff features and hybrid closed-loop systems, requiring minimal user input. The second-generation systems have demonstrated superior outcomes, proving highly effective in diabetes management. Islet cell transplantation, organoids, and biological pancreas augmentation represent innovative approaches to diabetes management. Islet cell transplantation aims to restore insulin production by transplanting donor beta cells, though challenges persist regarding graft survival and the need for immunosuppression. Organoids are a promising platform for generating insulin-producing cells, although far from clinical use. Biological pancreas augmentation relies on therapies that promote beta-cell (re)generation, reduce stress, and induce immune tolerance. Further biotechnology-driven perspectives in DM will include metabolic control via biotechnology-enabled tools such as custom-designed insulin hybrid molecules, machine-learning algorithms to control peptide release, and engineering cells for optimal peptide production and secretion.
Collapse
Affiliation(s)
- Nilima Rajpal Kundnani
- Department of Cardiology—Internal Medicine and Ambulatory Care, Prevention and Cardiovascular Recovery, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (N.R.K.)
- Research Centre of Timisoara Institute of Cardiovascular Diseases, “Victor Babeșs” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Bogdan Lolescu
- Doctoral School Medicine-Pharmacy, “Victor Babeș” University of Medicine and Pharmacy from Timisoara, Eftimie Murgu Sq. No. 2, 300041 Timisoara, Romania
| | - Anca-Raluca Dinu
- Department XVI, Medical Recovery, “Victor Babeş” University of Medicine and Pharmacy, 300041 Timisoara, Romania
- Research Center for Assessment of Human Motion and Functionality and Disability, “Victor Babeșs” University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania
- “Pius Brinzeu” Emergency Clinical County Hospital, Bld Liviu Rebreanu, No. 156, 300723 Timisoara, Romania
| | - Delia Mira Berceanu-Vaduva
- Discipline of Microbiology, Department XIV Microbiology, University of Medicine and Pharmacy from Timisoara, Eftimie Murgu Sq. No. 2, 300041 Timisoara, Romania; (D.M.B.-V.)
| | - Patrick Dumitrescu
- Faculty of Medicine, University of Medicine and Pharmacy from Timisoara, Eftimie Murgu Sq. No. 2, 300041 Timisoara, Romania
| | - Tudor-Paul Tamaș
- Discipline of Physiology, Department III—Functional Sciences, University of Medicine and Pharmacy from Timisoara, Eftimie Murgu Sq. No. 2, 300041 Timisoara, Romania
| | - Abhinav Sharma
- Department of Cardiology—Internal Medicine and Ambulatory Care, Prevention and Cardiovascular Recovery, “Victor Babeș” University of Medicine and Pharmacy, 300041 Timisoara, Romania; (N.R.K.)
| | - Mihaela-Diana Popa
- Discipline of Microbiology, Department XIV Microbiology, University of Medicine and Pharmacy from Timisoara, Eftimie Murgu Sq. No. 2, 300041 Timisoara, Romania; (D.M.B.-V.)
| |
Collapse
|
|
7
|
Wang S, Du Y, Zhang B, Meng G, Liu Z, Liew SY, Liang R, Zhang Z, Cai X, Wu S, Gao W, Zhuang D, Zou J, Huang H, Wang M, Wang X, Wang X, Liang T, Liu T, Gu J, Liu N, Wei Y, Ding X, Pu Y, Zhan Y, Luo Y, Sun P, Xie S, Yang J, Weng Y, Zhou C, Wang Z, Wang S, Deng H, Shen Z. Transplantation of chemically induced pluripotent stem-cell-derived islets under abdominal anterior rectus sheath in a type 1 diabetes patient. Cell 2024; 187:6152-6164.e18. [PMID: 39326417 DOI: 10.1016/j.cell.2024.09.004] [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: 10/03/2023] [Revised: 06/25/2024] [Accepted: 09/04/2024] [Indexed: 09/28/2024]
Abstract
We report the 1-year results from one patient as the preliminary analysis of a first-in-human phase I clinical trial (ChiCTR2300072200) assessing the feasibility of autologous transplantation of chemically induced pluripotent stem-cell-derived islets (CiPSC islets) beneath the abdominal anterior rectus sheath for type 1 diabetes treatment. The patient achieved sustained insulin independence starting 75 days post-transplantation. The patient's time-in-target glycemic range increased from a baseline value of 43.18% to 96.21% by month 4 post-transplantation, accompanied by a decrease in glycated hemoglobin, an indicator of long-term systemic glucose levels at a non-diabetic level. Thereafter, the patient presented a state of stable glycemic control, with time-in-target glycemic range at >98% and glycated hemoglobin at around 5%. At 1 year, the clinical data met all study endpoints with no indication of transplant-related abnormalities. Promising results from this patient suggest that further clinical studies assessing CiPSC-islet transplantation in type 1 diabetes are warranted.
Collapse
Affiliation(s)
- Shusen Wang
- Research Institute of Transplant Medicine, Organ Transplant Center, Tianjin First Central Hospital, School of Medicine, Nankai University, NHC Key Laboratory for Critical Care Medicine, Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China.
| | - Yuanyuan Du
- School of Basic Medical Sciences, MOE Engineering Research Center of Regenerative Medicine, 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 100191, China; Hangzhou Reprogenix Bioscience, Hangzhou, China
| | - Boya Zhang
- Research Institute of Transplant Medicine, Organ Transplant Center, Tianjin First Central Hospital, School of Medicine, Nankai University, NHC Key Laboratory for Critical Care Medicine, Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China
| | - Gaofan Meng
- School of Basic Medical Sciences, MOE Engineering Research Center of Regenerative Medicine, 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 100191, China; Hangzhou Reprogenix Bioscience, Hangzhou, China
| | - Zewen Liu
- Research Institute of Transplant Medicine, Organ Transplant Center, Tianjin First Central Hospital, School of Medicine, Nankai University, NHC Key Laboratory for Critical Care Medicine, Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China
| | - Soon Yi Liew
- School of Basic Medical Sciences, MOE Engineering Research Center of Regenerative Medicine, 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 100191, China; Hangzhou Reprogenix Bioscience, Hangzhou, China
| | - Rui Liang
- Research Institute of Transplant Medicine, Organ Transplant Center, Tianjin First Central Hospital, School of Medicine, Nankai University, NHC Key Laboratory for Critical Care Medicine, Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China
| | - Zhengyuan Zhang
- School of Basic Medical Sciences, MOE Engineering Research Center of Regenerative Medicine, 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 100191, China
| | - Xiangheng Cai
- Research Institute of Transplant Medicine, Organ Transplant Center, Tianjin First Central Hospital, School of Medicine, Nankai University, NHC Key Laboratory for Critical Care Medicine, Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China
| | | | - Wei Gao
- Research Institute of Transplant Medicine, Organ Transplant Center, Tianjin First Central Hospital, School of Medicine, Nankai University, NHC Key Laboratory for Critical Care Medicine, Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China
| | | | - Jiaqi Zou
- Research Institute of Transplant Medicine, Organ Transplant Center, Tianjin First Central Hospital, School of Medicine, Nankai University, NHC Key Laboratory for Critical Care Medicine, Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China
| | - Hui Huang
- Hangzhou Reprogenix Bioscience, Hangzhou, China
| | - Mingyang Wang
- Department of Ultrasound, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China
| | | | - Xuelian Wang
- Research Institute of Transplant Medicine, Organ Transplant Center, Tianjin First Central Hospital, School of Medicine, Nankai University, NHC Key Laboratory for Critical Care Medicine, Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China
| | - Ting Liang
- Hangzhou Reprogenix Bioscience, Hangzhou, China
| | - Tengli Liu
- Research Institute of Transplant Medicine, Organ Transplant Center, Tianjin First Central Hospital, School of Medicine, Nankai University, NHC Key Laboratory for Critical Care Medicine, Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China
| | - Jiabin Gu
- Hangzhou Reprogenix Bioscience, Hangzhou, China
| | - Na Liu
- Research Institute of Transplant Medicine, Organ Transplant Center, Tianjin First Central Hospital, School of Medicine, Nankai University, NHC Key Laboratory for Critical Care Medicine, Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China
| | - Yanling Wei
- Hangzhou Reprogenix Bioscience, Hangzhou, China
| | - Xuejie Ding
- Research Institute of Transplant Medicine, Organ Transplant Center, Tianjin First Central Hospital, School of Medicine, Nankai University, NHC Key Laboratory for Critical Care Medicine, Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China
| | - Yue Pu
- Hangzhou Reprogenix Bioscience, Hangzhou, China
| | - Yixiang Zhan
- Research Institute of Transplant Medicine, Organ Transplant Center, Tianjin First Central Hospital, School of Medicine, Nankai University, NHC Key Laboratory for Critical Care Medicine, Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China
| | - Yu Luo
- Hangzhou Reprogenix Bioscience, Hangzhou, China
| | - Peng Sun
- Research Institute of Transplant Medicine, Organ Transplant Center, Tianjin First Central Hospital, School of Medicine, Nankai University, NHC Key Laboratory for Critical Care Medicine, Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China
| | - Shuangshuang Xie
- Radiology Department, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China
| | - Jiuxia Yang
- Research Institute of Transplant Medicine, Organ Transplant Center, Tianjin First Central Hospital, School of Medicine, Nankai University, NHC Key Laboratory for Critical Care Medicine, Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China
| | - Yiqi Weng
- Department of Anesthesiology, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China
| | - Chunlei Zhou
- Department of Medical Laboratory, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China
| | - Zhenglu Wang
- Research Institute of Transplant Medicine, Organ Transplant Center, Tianjin First Central Hospital, School of Medicine, Nankai University, NHC Key Laboratory for Critical Care Medicine, Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China
| | - Shuang Wang
- Department of Plastic and Burn, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China
| | - Hongkui Deng
- School of Basic Medical Sciences, MOE Engineering Research Center of Regenerative Medicine, 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 100191, China; China Changping Laboratory, Beijing 102206, China.
| | - Zhongyang Shen
- Research Institute of Transplant Medicine, Organ Transplant Center, Tianjin First Central Hospital, School of Medicine, Nankai University, NHC Key Laboratory for Critical Care Medicine, Key Laboratory of Transplant Medicine, Chinese Academy of Medical Sciences, Tianjin 300192, China.
| |
Collapse
|
|
8
|
Keymeulen B, De Groot K, Jacobs-Tulleneers-Thevissen D, Thompson DM, Bellin MD, Kroon EJ, Daniels M, Wang R, Jaiman M, Kieffer TJ, Foyt HL, Pipeleers D. Encapsulated stem cell-derived β cells exert glucose control in patients with type 1 diabetes. Nat Biotechnol 2024; 42:1507-1514. [PMID: 38012450 PMCID: PMC11471599 DOI: 10.1038/s41587-023-02055-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 11/05/2023] [Indexed: 11/29/2023]
Abstract
Clinical studies on the treatment of type 1 diabetes with device-encapsulated pancreatic precursor cells derived from human embryonic stem cells found that insulin output was insufficient for clinical benefit. We are conducting a phase 1/2, open-label, multicenter trial aimed at optimizing cell engraftment (ClinicalTrials.gov identifier: NCT03163511 ). Here we report interim, 1-year outcomes in one study group that received 2-3-fold higher cell doses in devices with an optimized membrane perforation pattern. β cell function was measured by meal-stimulated plasma C-peptide levels at 3-month intervals, and the effect on glucose control was assessed by continuous glucose monitoring (CGM) and insulin dosing. Of 10 patients with undetectable baseline C-peptide, three achieved levels ≥0.1 nmol l-1 from month 6 onwards that correlated with improved CGM measures and reduced insulin dosing, indicating a glucose-controlling effect. The patient with the highest C-peptide (0.23 nmol l-1) increased CGM time-in-range from 55% to 85% at month 12; β cell mass in sentinel devices in this patient at month 6 was 4% of the initial cell mass, indicating directions for improving efficacy.
Collapse
Affiliation(s)
- Bart Keymeulen
- Diabetes Research Center, Vrije Universiteit Brussel and Universitair Ziekenhuis Brussel, Brussels, Belgium.
| | - Kaat De Groot
- Diabetes Research Center, Vrije Universiteit Brussel and Universitair Ziekenhuis Brussel, Brussels, Belgium
| | | | - David M Thompson
- Division of Endocrinology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Melena D Bellin
- Department of Pediatrics and Department of Surgery, University of Minnesota Medical Center, Minneapolis, MN, USA
| | | | | | | | | | - Timothy J Kieffer
- ViaCyte Inc., San Diego, CA, USA
- Department of Cellular and Physiological Sciences and Department of Surgery, University of British Columbia, Life Sciences Institute, Vancouver, British Columbia, Canada
| | | | - Daniel Pipeleers
- Diabetes Research Center, Vrije Universiteit Brussel and Universitair Ziekenhuis Brussel, Brussels, Belgium.
| |
Collapse
|
|
9
|
Annicchiarico A, Barile B, Buccoliero C, Nicchia GP, Brunetti G. Alternative therapeutic strategies in diabetes management. World J Diabetes 2024; 15:1142-1161. [PMID: 38983831 PMCID: PMC11229975 DOI: 10.4239/wjd.v15.i6.1142] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 02/17/2024] [Accepted: 04/12/2024] [Indexed: 06/11/2024] Open
Abstract
Diabetes is a heterogeneous metabolic disease characterized by elevated blood glucose levels resulting from the destruction or malfunction of pancreatic β cells, insulin resistance in peripheral tissues, or both, and results in a non-sufficient production of insulin. To adjust blood glucose levels, diabetic patients need exogenous insulin administration together with medical nutrition therapy and physical activity. With the aim of improving insulin availability in diabetic patients as well as ameliorating diabetes comorbidities, different strategies have been investigated. The first approaches included enhancing endogenous β cell activity or transplanting new islets. The protocol for this kind of intervention has recently been optimized, leading to standardized procedures. It is indicated for diabetic patients with severe hypoglycemia, complicated by impaired hypoglycemia awareness or exacerbated glycemic lability. Transplantation has been associated with improvement in all comorbidities associated with diabetes, quality of life, and survival. However, different trials are ongoing to further improve the beneficial effects of transplantation. Furthermore, to overcome some limitations associated with the availability of islets/pancreas, alternative therapeutic strategies are under evaluation, such as the use of mesenchymal stem cells (MSCs) or induced pluripotent stem cells for transplantation. The cotransplantation of MSCs with islets has been successful, thus providing protection against proinflammatory cytokines and hypoxia through different mechanisms, including exosome release. The use of induced pluripotent stem cells is recent and requires further investigation. The advantages of MSC implantation have also included the improvement of diabetes-related comorbidities, such as wound healing. Despite the number of advantages of the direct injection of MSCs, new strategies involving biomaterials and scaffolds have been developed to improve the efficacy of mesenchymal cell delivery with promising results. In conclusion, this paper offered an overview of new alternative strategies for diabetes management while highlighting some limitations that will need to be overcome by future approaches.
Collapse
Affiliation(s)
- Alessia Annicchiarico
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Bari 70125, Italy
| | - Barbara Barile
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Bari 70125, Italy
| | - Cinzia Buccoliero
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Bari 70125, Italy
| | - Grazia Paola Nicchia
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Bari 70125, Italy
| | - Giacomina Brunetti
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Bari 70125, Italy
| |
Collapse
|
|
10
|
Burke JA, Zhu Y, Zhang X, Rios PD, Joshi I, Lopez D, Nasir H, Roberts S, Rodriguez Q, McGarrigle J, Cook D, Oberholzer J, Luo X, Ameer GA. Phase-changing citrate macromolecule combats oxidative pancreatic islet damage, enables islet engraftment and function in the omentum. SCIENCE ADVANCES 2024; 10:eadk3081. [PMID: 38848367 PMCID: PMC11160476 DOI: 10.1126/sciadv.adk3081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 05/03/2024] [Indexed: 06/09/2024]
Abstract
Clinical outcomes for total-pancreatectomy followed by intraportal islet autotransplantation (TP-IAT) to treat chronic pancreatitis (CP) are suboptimal due to pancreas inflammation, oxidative stress during islet isolation, and harsh engraftment conditions in the liver's vasculature. We describe a thermoresponsive, antioxidant macromolecule poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) to protect islet redox status and function and to enable extrahepatic omentum islet engraftment. PPCN solution transitions from a liquid to a hydrogel at body temperature. Islets entrapped in PPCN and exposed to oxidative stress remain functional and support long-term euglycemia, in contrast to islets entrapped in a plasma-thrombin biologic scaffold. In the nonhuman primate (NHP) omentum, PPCN is well-tolerated and mostly resorbed without fibrosis at 3 months after implantation. In NHPs, autologous omentum islet transplantation using PPCN restores normoglycemia with minimal exogenous insulin requirements for >100 days. This preclinical study supports TP-IAT with PPCN in patients with CP and highlights antioxidant properties as a mechanism for islet function preservation.
Collapse
Affiliation(s)
- Jacqueline A. Burke
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
- Center for Advanced Regenerative Engineering, Northwestern University, Evanston, IL 60208, USA
| | - Yunxiao Zhu
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
- Center for Advanced Regenerative Engineering, Northwestern University, Evanston, IL 60208, USA
| | - Xiaomin Zhang
- Center for Advanced Regenerative Engineering, Northwestern University, Evanston, IL 60208, USA
- Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | | | - Ira Joshi
- CellTrans Inc., Chicago, IL 60612, USA
| | | | | | | | | | | | | | | | - Xunrong Luo
- Duke Transplant Center, Duke University School of Medicine, Durham, NC 27710, USA
| | - Guillermo A. Ameer
- Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
- Center for Advanced Regenerative Engineering, Northwestern University, Evanston, IL 60208, USA
- Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
- Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208 USA
- Simpson Querrey Institute, Northwestern University, Chicago, IL 60611, USA
- International Institute for Nanotechnology, Northwestern University, Evanston, IL 60208, USA
| |
Collapse
|
|
11
|
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: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [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
|
|
12
|
Qi B, Ding Y, Zhang Y, Kou L, Zhao YZ, Yao Q. Biomaterial-assisted strategies to improve islet graft revascularization and transplant outcomes. Biomater Sci 2024; 12:821-836. [PMID: 38168805 DOI: 10.1039/d3bm01295f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2024]
Abstract
Islet transplantation holds significant promise as a curative approach for type 1 diabetes (T1D). However, the transition of islet transplantation from the experimental phase to widespread clinical implementation has not occurred yet. One major hurdle in this field is the challenge of insufficient vascularization and subsequent early loss of transplanted islets, especially in non-intraportal transplantation sites. The establishment of a fully functional vascular system following transplantation is crucial for the survival and secretion function of islet grafts. This vascular network not only ensures the delivery of oxygen and nutrients, but also plays a critical role in insulin release and the timely removal of metabolic waste from the grafts. This review summarizes recent advances in effective strategies to improve graft revascularization and enhance islet survival. These advancements include the local release and regulation of angiogenic factors (e.g., vascular endothelial growth factor, VEGF), co-transplantation of vascular fragments, and pre-vascularization of the graft site. These innovative approaches pave the way for the development of effective islet transplantation therapies for individuals with T1D.
Collapse
Affiliation(s)
- Boyang Qi
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
| | - Yang Ding
- The Second School of Medicine, Wenzhou Medical University, Wenzhou, China
| | - Ying Zhang
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
| | - Longfa Kou
- The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Ying-Zheng Zhao
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
| | - Qing Yao
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
- Cixi Biomedical Research Institute, Wenzhou Medical University, Zhejiang, China
| |
Collapse
|
|
13
|
Hauser PV, Zhao L, Chang HM, Yanagawa N, Hamon M. In Vivo Vascularization Chamber for the Implantation of Embryonic Kidneys. Tissue Eng Part C Methods 2024; 30:63-72. [PMID: 38062758 DOI: 10.1089/ten.tec.2023.0225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2024] Open
Abstract
A major obstacle to the implantation of ex vivo engineered tissues is the incorporation of functional vascular supply to support the growth of new tissue and to minimize ischemic injury. Existing prevascularization systems, such as arteriovenous (AV) loop-based systems, require microsurgery, limiting their use to larger animals. We aimed to develop an implantable device that can be prevascularized to enable vascularization of tissues in small rodents, and test its application on the vascularization of embryonic kidneys. Implanting the chamber between the abdominal aorta and the inferior vena cava, we detected endothelial cells and vascular networks after 48 h of implantation. Loading the chamber with collagen I (C), Matrigel (M), or Matrigel + vascular endothelial growth factor) (MV) had a strong influence on vascularization speed: Chambers loaded with C took 7 days to vascularize, 4 days for chambers with M, and 2 days for chambers with MV. Implantation of E12.5 mouse embryonic kidneys into prevascularized chambers (C, MV) was followed with significant growth and ureteric branching over 22 days. In contrast, the growth of kidneys in non-prevascularized chambers was stunted. We concluded that our prevascularized chamber is a valuable tool for vascularizing implanted tissues and tissue-engineered constructs. Further optimization will be necessary to control the directional growth of vascular endothelial cells within the chamber and the vascularization grade. Impact Statement Vascularization of engineered tissue, or organoids, constructs is a major hurdle in tissue engineering. Failure of vascularization is associated with prolonged ischemia time and potential tissue damage due to hypoxic effects. The method presented, demonstrates the use of a novel chamber that allows rapid vascularization of native and engineered tissues. We hope that this technology helps to stimulate research in the field of tissue vascularization and enables researchers to generate larger engineered vascularized tissues.
Collapse
Affiliation(s)
- Peter Viktor Hauser
- Division of Research, Renal Regeneration Laboratory, VAGLAHS at Sepulveda, North Hills, California, USA
- Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA
| | - Lifu Zhao
- Division of Research, Renal Regeneration Laboratory, VAGLAHS at Sepulveda, North Hills, California, USA
| | - Hsiao-Min Chang
- Division of Research, Renal Regeneration Laboratory, VAGLAHS at Sepulveda, North Hills, California, USA
- Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA
| | - Norimoto Yanagawa
- Division of Research, Renal Regeneration Laboratory, VAGLAHS at Sepulveda, North Hills, California, USA
- Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA
| | - Morgan Hamon
- Division of Research, Renal Regeneration Laboratory, VAGLAHS at Sepulveda, North Hills, California, USA
- Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA
| |
Collapse
|
|
14
|
Ghoneim MA, Gabr MM, El-Halawani SM, Refaie AF. Current status of stem cell therapy for type 1 diabetes: a critique and a prospective consideration. Stem Cell Res Ther 2024; 15:23. [PMID: 38281991 PMCID: PMC10823744 DOI: 10.1186/s13287-024-03636-0] [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: 07/05/2023] [Accepted: 01/10/2024] [Indexed: 01/30/2024] Open
Abstract
Over the past decade, there had been progress in the development of cell therapy for insulin-dependent diabetes. Nevertheless, important hurdles that need to be overcome still remain. Protocols for the differentiation of pluripotent stem cells into pancreatic progenitors or fully differentiated β-cells have been developed. The resulting insulin-producing cells can control chemically induced diabetes in rodents and were the subject of several clinical trials. However, these cells are immunogenic and possibly teratogenic for their transplantation, and an immunoisolation device and/or immunosuppression is needed. A growing number of studies have utilized genetic manipulations to produce immune evasive cells. Evidence must be provided that in addition to the expected benefit, gene manipulations should not lead to any unforeseen complications. Mesenchymal stem/stromal cells (MSCs) can provide a viable alternative. MSCs are widely available from many tissues. They can form insulin-producing cells by directed differentiation. Experimentally, evidence has shown that the transplantation of allogenic insulin-producing cells derived from MSCs is associated with a muted allogeneic response that does not interfere with their functionality. This can be explained by the immunomodulatory functions of the MSC subpopulation that did not differentiate into insulin-producing cells. Recently, exosomes derived from naive MSCs have been used in the experimental domain to treat diabetes in rodents with varying degrees of success. Several mechanisms for their beneficial functions were proposed including a reduction in insulin resistance, the promotion of autophagy, and an increase in the T regulatory population. However, euglycemia was not achieved in any of these experiments. We suggest that exosomes derived from β-cells or insulin-producing cells (educated) can provide a better therapeutic effect than those derived from undifferentiated cells.
Collapse
|
|
15
|
Mei L, Yuwei Y, Weiping L, Zhiran X, Bingzheng F, Jibing C, Hongjun G. Strategy for Clinical Setting of Co-transplantation of Mesenchymal Stem Cells and Pancreatic Islets. Cell Transplant 2024; 33:9636897241259433. [PMID: 38877672 PMCID: PMC11179456 DOI: 10.1177/09636897241259433] [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: 02/21/2024] [Revised: 04/29/2024] [Accepted: 05/06/2024] [Indexed: 06/16/2024] Open
Abstract
Islet transplantation may be the most efficient therapeutic technique for patients with type 1 diabetes mellitus (T1DM). However, the clinical application of this method is faced with numerous limitations, including isolated islet apoptosis, recipient rejection, and graft vascular reconstruction. Mesenchymal stem cells (MSCs) possess anti-apoptotic, immunomodulatory, and angiogenic properties. Here, we review recent studies on co-culture and co-transplantation of islets with MSCs. We have summarized the methods of preparation of co-transplantation, especially the merits of co-culture, and the effects of co-transplantation. Accumulating experimental evidence shows that co-culture of islets with MSCs promotes islet survival, enhances islet secretory function, and prevascularizes islets through various pretransplant preparations. This review is expected to provide a reference for exploring the use of MSCs for clinical islet co-transplantation.
Collapse
Affiliation(s)
- Liang Mei
- Graduate School, Guangxi University of Chinese Medicine, Nanning, China
| | - Yang Yuwei
- Ruikang Hospital affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - Liang Weiping
- Ruikang Hospital affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - Xu Zhiran
- Ruikang Hospital affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - Feng Bingzheng
- Ruikang Hospital affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - Chen Jibing
- Ruikang Hospital affiliated to Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Clinical Research Center for Kidney Diseases of Integrated Traditional Chinese and Western Medicine, Nanning, China
| | - Gao Hongjun
- Ruikang Hospital affiliated to Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Clinical Research Center for Kidney Diseases of Integrated Traditional Chinese and Western Medicine, Nanning, China
| |
Collapse
|
|
16
|
Li Y, He C, Liu R, Xiao Z, Sun B. Stem cells therapy for diabetes: from past to future. Cytotherapy 2023; 25:1125-1138. [PMID: 37256240 DOI: 10.1016/j.jcyt.2023.04.012] [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: 01/26/2023] [Revised: 04/05/2023] [Accepted: 04/24/2023] [Indexed: 06/01/2023]
Abstract
Diabetes mellitus is a chronic disease of carbohydrate metabolism characterized by uncontrolled hyperglycemia due to the body's impaired ability to produce or respond to insulin. Oral or injectable exogenous insulin and its analogs cannot mimic endogenous insulin secreted by healthy individuals, and pancreatic and islet transplants face a severe shortage of sources and transplant complications, all of which limit the widespread use of traditional strategies in diabetes treatment. We are now in the era of stem cells and their potential in ameliorating human disease. At the same time, the rapid development of gene editing and cell-encapsulation technologies has added to the wings of stem cell therapy. However, there are still many unanswered questions before stem cell therapy can be applied clinically to patients with diabetes. In this review, we discuss the progress of strategies to obtain insulin-producing cells from different types of stem cells, the application of gene editing in stem cell therapy for diabetes, as well as summarize the current advanced cell encapsulation technologies in diabetes therapy and look forward to the future development of stem cell therapy in diabetes.
Collapse
Affiliation(s)
- Yumin Li
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China
| | - Cong He
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China; Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital,The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Rui Liu
- Department of Genetic Engineering, College of Natural Science, University of Suwon, Kyunggi-Do, Republic of Korea
| | - Zhongdang Xiao
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China.
| | - Bo Sun
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China.
| |
Collapse
|
|
17
|
Czarnecka Z, Dadheech N, Razavy H, Pawlick R, Shapiro AMJ. The Current Status of Allogenic Islet Cell Transplantation. Cells 2023; 12:2423. [PMID: 37887267 PMCID: PMC10605704 DOI: 10.3390/cells12202423] [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: 09/12/2023] [Revised: 10/05/2023] [Accepted: 10/06/2023] [Indexed: 10/28/2023] Open
Abstract
Type 1 Diabetes (T1D) is an autoimmune destruction of pancreatic beta cells. The development of the Edmonton Protocol for islet transplantation in 2000 revolutionized T1D treatment and offered a glimpse at a cure for the disease. In 2022, the 20-year follow-up findings of islet cell transplantation demonstrated the long-term safety of islet cell transplantation despite chronic immunosuppression. The Edmonton Protocol, however, remains limited by two obstacles: scarce organ donor availability and risks associated with chronic immunosuppression. To overcome these challenges, the search has begun for an alternative cell source. In 2006, pluripotency genomic factors, coined "Yamanaka Factors," were discovered, which reprogram mature somatic cells back to their embryonic, pluripotent form (iPSC). iPSCs can then be differentiated into specialized cell types, including islet cells. This discovery has opened a gateway to a personalized medicine approach to treating diabetes, circumventing the issues of donor supply and immunosuppression. In this review, we present a brief history of allogenic islet cell transplantation from the early days of pancreatic remnant transplantation to present work on encapsulating stem cell-derived cells. We review data on long-term outcomes and the ongoing challenges of allogenic islet cell and stem cell-derived islet cell transplant.
Collapse
Affiliation(s)
- Zofia Czarnecka
- Department of Surgery, University of Alberta, Edmonton, AB T6G 2RW3, Canada; (N.D.); (H.R.); (R.P.); (A.M.J.S.)
| | | | | | | | | |
Collapse
|
|
18
|
Bealer E, Crumley K, Clough D, King J, Behrend M, Annulis C, Li F, Soleimanpour S, Shea LD. Extrahepatic transplantation of 3D cultured stem cell-derived islet organoids on microporous scaffolds. Biomater Sci 2023; 11:3645-3655. [PMID: 37017294 PMCID: PMC10192035 DOI: 10.1039/d3bm00217a] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/05/2023]
Abstract
Stem cell differentiation methods have been developed to produce cells capable of insulin secretion which are showing promise in clinical trials for treatment of type-1 diabetes. Nevertheless, opportunities remain to improve cell maturation and function. Three-dimensional (3D) culture has demonstrated improved differentiation and metabolic function in organoid systems, with biomaterial scaffolds employed to direct cell assembly and facilitate cell-cell contacts. Herein, we investigate 3D culture of human stem cell-derived islet organoids, with 3D culture initiated at the pancreatic progenitor, endocrine progenitor, or immature β-cell stage. Clusters formed by reaggregation of immature β-cells could be readily seeded into the microporous poly(lactide-co-glycolide) scaffold, with control over cell number. Culture of islet organoids on scaffolds at the early to mid-stage beta cell progenitors had improved in vitro glucose stimulated insulin secretion relative to organoids formed at the pancreatic progenitor stage. Reaggregated islet organoids were transplanted into the peritoneal fat of streptozotocin-induced diabetic mice, which resulted in reduced blood glucose levels and the presence of systemic human C-peptide. In conclusion, 3D cell culture supports development of islet organoids as indicated by insulin secretion in vitro and supports transplantation to extrahepatic sites that leads to a reduction of hyperglycemia in vivo.
Collapse
Affiliation(s)
- Elizabeth Bealer
- Department of Biomedical Engineering, University of Michigan, 1119 Carl A. Gerstacker Building, 2200 Bonisteel Boulevard, Ann Arbor, MI 48109, USA.
| | - Kelly Crumley
- Department of Biomedical Engineering, University of Michigan, 1119 Carl A. Gerstacker Building, 2200 Bonisteel Boulevard, Ann Arbor, MI 48109, USA.
| | - Daniel Clough
- Department of Biomedical Engineering, University of Michigan, 1119 Carl A. Gerstacker Building, 2200 Bonisteel Boulevard, Ann Arbor, MI 48109, USA.
| | - Jessica King
- Department of Biomedical Engineering, University of Michigan, 1119 Carl A. Gerstacker Building, 2200 Bonisteel Boulevard, Ann Arbor, MI 48109, USA.
| | - Maya Behrend
- Department of Biomedical Engineering, University of Michigan, 1119 Carl A. Gerstacker Building, 2200 Bonisteel Boulevard, Ann Arbor, MI 48109, USA.
| | - Connor Annulis
- Department of Biomedical Engineering, University of Michigan, 1119 Carl A. Gerstacker Building, 2200 Bonisteel Boulevard, Ann Arbor, MI 48109, USA.
| | - Feiran Li
- Department of Biomedical Engineering, University of Michigan, 1119 Carl A. Gerstacker Building, 2200 Bonisteel Boulevard, Ann Arbor, MI 48109, USA.
| | - Scott Soleimanpour
- Department of Internal Medicine and Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, MI, USA
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
- Medicine Service, Endocrinology and Metabolism Section, VA Ann Arbor Health Care System, Ann Arbor, MI, USA
| | - Lonnie D Shea
- Department of Biomedical Engineering, University of Michigan, 1119 Carl A. Gerstacker Building, 2200 Bonisteel Boulevard, Ann Arbor, MI 48109, USA.
- Department of Surgery, University of Michigan, USA
| |
Collapse
|
|
19
|
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: 61] [Impact Index Per Article: 30.5] [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
|
|
20
|
Deng H, Zhang A, Pang DRR, Xi Y, Yang Z, Matheson R, Li G, Luo H, Lee KM, Fu Q, Zou Z, Chen T, Wang Z, Rosales IA, Peters CW, Yang J, Coronel MM, Yolcu ES, Shirwan H, García AJ, Markmann JF, Lei J. Bioengineered omental transplant site promotes pancreatic islet allografts survival in non-human primates. Cell Rep Med 2023; 4:100959. [PMID: 36863336 PMCID: PMC10040375 DOI: 10.1016/j.xcrm.2023.100959] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 12/04/2022] [Accepted: 02/07/2023] [Indexed: 03/04/2023]
Abstract
The transplanting islets to the liver approach suffers from an immediate posttransplant loss of islets of more than 50%, progressive graft dysfunction over time, and precludes recovery of grafts should there be serious complications such as the development of teratomas with grafts that are stem cell-derived islets (SC-islets). The omentum features an attractive extrahepatic alternative site for clinical islet transplantation. We explore an approach in which allogeneic islets are transplanted onto the omentum, which is bioengineered with a plasma-thrombin biodegradable matrix in three diabetic non-human primates (NHPs). Within 1 week posttransplant, each transplanted NHP achieves normoglycemia and insulin independence and remains stable until termination of the experiment. Success was achieved in each case with islets recovered from a single NHP donor. Histology demonstrates robust revascularization and reinnervation of the graft. This preclinical study can inform the development of strategies for β cell replacement including the use of SC-islets or other types of novel cells in clinical settings.
Collapse
Affiliation(s)
- Hongping Deng
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Alexander Zhang
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Dillon Ren Rong Pang
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Yinsheng Xi
- School of Clinical Medicine, Southern Medical University, Foshan 528300, China
| | - Zhihong Yang
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Rudy Matheson
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Guoping Li
- Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Hao Luo
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Kang M Lee
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Qiang Fu
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Zhongliang Zou
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Tao Chen
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Zhenjuan Wang
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Ivy A Rosales
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Cole W Peters
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Jibing Yang
- Center for Comparative Medicine, Massachusetts General Hospital, Boston, MA 02114, 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
| | - Haval Shirwan
- Departments of Child Health and Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO, USA
| | - Andrés J García
- Woodruff School of Mechanical Engineering and Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA
| | - James F Markmann
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Ji Lei
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
| |
Collapse
|
|
21
|
Verhoeff K, Marfil-Garza BA, Dajani K, Bigam DL, Anderson B, Kin T, Lam A, O'Gorman D, Senior PA, Shapiro AMJ. C-peptide Targets and Patient-centered Outcomes of Relevance to Cellular Transplantation for Diabetes. Transplantation 2023; 107:774-781. [PMID: 36253897 DOI: 10.1097/tp.0000000000004328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND C-peptide levels are a key measure of beta-cell mass following islet transplantation, but threshold values required to achieve clinically relevant patient-centered outcomes are not yet established. METHODS We conducted a cross-sectional retrospective cohort study evaluating patients undergoing islet transplantation at a single center from 1999 to 2018. Cohorts included patients achieving insulin independence without hypoglycemia, those with insulin dependence without hypoglycemia, and those with recurrent symptomatic hypoglycemia. Primary outcome was fasting C-peptide levels at 6 to 12 mo postfirst transplant; secondary outcomes included stimulated C-peptide levels and BETA-2 scores. Fasting and stimulated C-peptide and BETA-2 cutoff values for determination of hypoglycemic freedom and insulin independence were evaluated using receiver operating characteristic curves. RESULTS We analyzed 192 patients, with 122 (63.5%) being insulin independent without hypoglycemia, 61 (31.8%) being insulin dependent without hypoglycemia, and 9 (4.7%) experiencing recurrent symptomatic hypoglycemia. Patients with insulin independence had a median (interquartile range) fasting C-peptide level of 0.66 nmol/L (0.34 nmol/L), compared with 0.49 nmol/L (0.25 nmol/L) for those being insulin dependent without hypoglycemia and 0.07 nmol/L (0.05 nmol/L) for patients experiencing hypoglycemia ( P < 0.001). Optimal fasting C-peptide cutoffs for insulin independence and hypoglycemia were ≥0.50 nmol/L and ≥0.12 nmol/L, respectively. Cutoffs for insulin independence and freedom of hypoglycemia using stimulated C-peptide were ≥1.2 nmol/L and ≥0.68 nmol/L, respectively, whereas optimal cutoff BETA-2 scores were ≥16.4 and ≥5.2. CONCLUSIONS We define C-peptide levels and BETA-2 scores associated with patient-centered outcomes. Characterizing these values will enable evaluation of ongoing clinical trials with islet or stem cell therapies.
Collapse
Affiliation(s)
- Kevin Verhoeff
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
| | - Braulio A Marfil-Garza
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
- National Institute of Medical Sciences and Nutrition Salvador Zubiran, Mexico City, Mexico
- CHRISTUS-LatAm Hub-Excellence and Innovation Center, Monterrey, Mexico
| | - Khaled Dajani
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
| | - David L Bigam
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
| | - Blaire Anderson
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
| | - Tatsuya Kin
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
| | - Anna Lam
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
- Department of Medicine, Division of Endocrinology, University of Alberta, Edmonton, AB, Canada
- Alberta Diabetes Institute, Edmonton, AB, Canada
| | - Doug O'Gorman
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
| | - Peter A Senior
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
- Department of Medicine, Division of Endocrinology, University of Alberta, Edmonton, AB, Canada
- Alberta Diabetes Institute, Edmonton, AB, Canada
| | - A M James Shapiro
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
- Alberta Diabetes Institute, Edmonton, AB, Canada
| |
Collapse
|
|
22
|
Naqvi RA, Naqvi A. Co-transplantation with mesenchymal stem cells and endothelial cells improvise islet engraftment and survival in STZ treated hyperglycemic mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.24.525444. [PMID: 36747732 PMCID: PMC9900768 DOI: 10.1101/2023.01.24.525444] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Though intra-portal islet transplantation demonstrated as best suited strategy for the reversal of hyperglycemia without the threat of iatrogenic hyperglycemia in type 1 diabetes (T1D) in patients, the inferior quality of post-transplantation (tx) vascularization needs to be addressed for the maximization of post-tx islet survival. Therefore, in this study, we have first generated MSCs and endothelial progenitor cells (EPC) from mice bone marrow by in house optimized protocol and then 3-D co-cultured them with mice islets. Secretion of in the culture supernatant suggested the pro-angiogenic nature of 3D cultured mice islets. After 5 days post-tx of these pro-angiogenic islets in the omental pouch of syngeneic mice led to: 1) restoration of normoglycemia, 2) secretion of mouse C-peptide and 3) induction of angiogenic factors after 3 days of post-tx. The induction of angiogenic factors was done by RT-qPCR of omental biopsies. Importantly, pro-angiogenic islet recipient mice also demonstrated the clearance of glucose within 75 min, reflecting their efficient function and engraftment. Our results highlights needs of 3-D co-culture islets for superior quality post-tx islet vasculature and better engraftment â€" crux to improvise the challenges associated with post-tx islet vascularization and functions.
Collapse
|
|
23
|
Nijns JR, De Mesmaeker I, Suenens KG, Stangé GM, De Groot K, Marques de Lima M, Kraus MRC, Keymeulen B, Waelput W, Jacobs-Tulleneers Thevissen D, Pipeleers DG. Comparison of Omentum and Subcutis as Implant Sites for Device-Encapsulated Human iPSC-Derived Pancreatic Endoderm in Nude Rats. Cell Transplant 2023; 32:9636897231167323. [PMID: 37129266 PMCID: PMC10150423 DOI: 10.1177/09636897231167323] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/03/2023] Open
Abstract
Subcutaneous implants of device-encapsulated stem cell-derived pancreatic endoderm (PE) can establish a functional beta cell mass (FBM) with metabolic control in immune-compromised mice. In a study with human-induced pluripotent stem cell-PE, this outcome was favored by a preformed pouch which allowed lesion-free insertion of devices in a pre-vascularized site. This was not reproduced in nude rats, known to exhibit a higher innate reactivity than mice and therefore relevant as preclinical model: a dense fibrotic capsule formed around subcutis (SC) implants with virtually no FBM formation. Placement in omentum (OM) of nude rats provided a less fibrous, better vascularized environment than SC. It resulted in less donor cell loss (56% recovery at post-transplant-PT week 3 versus 16% in SC) allowing FBM-formation. At PT week 30, 6/13 OM-recipients exhibited glucose-induced plasma hu-C-peptide to 0.1-0.4 ng/ml, versus 0/8 in SC-recipients. These levels are more than 10-fold lower than in a state of metabolic control. This shortcoming is not caused by inadequate glucose responsiveness of the beta cells but by their insufficient number. The size of the formed beta cell mass (0.4 ± 0.2 µl) was lower than that reported in mice receiving the same cell product subcutaneously; the difference is attributed to a lower expansion of pancreatic progenitor cells and to their lower degree of differentiation to beta cells. This study in the nude rat model demonstrates that OM provides a better environment for formation of beta cells in device-encapsulated PE-implants than SC. It also identified targets for increasing their dose-efficacy.
Collapse
Affiliation(s)
- Jolien R Nijns
- Diabetes Research Center, Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - Ines De Mesmaeker
- Diabetes Research Center, Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - Krista G Suenens
- Diabetes Research Center, Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - Geert M Stangé
- Diabetes Research Center, Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - Kaat De Groot
- Diabetes Research Center, Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | | | - Marine R C Kraus
- Nestlé Institute of Health Sciences (NIHS), Nestec SA, Lausanne, Switzerland
| | - Bart Keymeulen
- Diabetes Research Center, Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - Wim Waelput
- Department of Pathology, Universitair Ziekenhuis Brussel (UZB), Brussels, Belgium
| | | | - Daniel G Pipeleers
- Diabetes Research Center, Vrije Universiteit Brussel (VUB), Brussels, Belgium
| |
Collapse
|
|
24
|
Berney T, Wassmer CH, Lebreton F, Bellofatto K, Fonseca LM, Bignard J, Hanna R, Peloso A, Berishvili E. From islet of Langerhans transplantation to the bioartificial pancreas. Presse Med 2022; 51:104139. [PMID: 36202182 DOI: 10.1016/j.lpm.2022.104139] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Accepted: 09/29/2022] [Indexed: 11/09/2022] Open
Abstract
Type 1 diabetes is a disease resulting from autoimmune destruction of the insulin-producing beta cells in the pancreas. When type 1 diabetes develops into severe secondary complications, in particular end-stage nephropathy, or life-threatening severe hypoglycemia, the best therapeutic approach is pancreas transplantation, or more recently transplantation of the pancreatic islets of Langerhans. Islet transplantation is a cell therapy procedure, that is minimally invasive and has a low morbidity, but does not display the same rate of functional success as the more invasive pancreas transplantation because of suboptimal engraftment and survival. Another issue is that pancreas or islet transplantation (collectively known as beta cell replacement therapy) is limited by the shortage of organ donors and by the need for lifelong immunosuppression to prevent immune rejection and recurrence of autoimmunity. A bioartificial pancreas is a construct made of functional, insulin-producing tissue, embedded in an anti-inflammatory, immunomodulatory microenvironment and encapsulated in a perm-selective membrane allowing glucose sensing and insulin release, but isolating from attacks by cells of the immune system. A successful bioartificial pancreas would address the issues of engraftment, survival and rejection. Inclusion of unlimited sources of insulin-producing cells, such as xenogeneic porcine islets or stem cell-derived beta cells would further solve the problem of organ shortage. This article reviews the current status of clinical islet transplantation, the strategies aiming at developing a bioartificial pancreas, the clinical trials conducted in the field and the perspectives for further progress.
Collapse
Affiliation(s)
- Thierry Berney
- Cell Isolation and Transplantation Center, Department of Surgery, University of Geneva School of Medicine, Geneva, Switzerland; Division of Transplantation, Department of Surgery, University of Geneva Hospitals, Geneva, Switzerland; Faculty Diabetes Center, University of Geneva School of Medicine, Geneva, Switzerland; Department of Surgery, School of Medicine and Natural Sciences, Ilia State University, Tbilisi, Georgia
| | - Charles H Wassmer
- Cell Isolation and Transplantation Center, Department of Surgery, University of Geneva School of Medicine, Geneva, Switzerland; Division of Transplantation, Department of Surgery, University of Geneva Hospitals, Geneva, Switzerland
| | - Fanny Lebreton
- Cell Isolation and Transplantation Center, Department of Surgery, University of Geneva School of Medicine, Geneva, Switzerland
| | - Kevin Bellofatto
- Cell Isolation and Transplantation Center, Department of Surgery, University of Geneva School of Medicine, Geneva, Switzerland
| | - Laura Mar Fonseca
- Cell Isolation and Transplantation Center, Department of Surgery, University of Geneva School of Medicine, Geneva, Switzerland; Division of Transplantation, Department of Surgery, University of Geneva Hospitals, Geneva, Switzerland
| | - Juliette Bignard
- Cell Isolation and Transplantation Center, Department of Surgery, University of Geneva School of Medicine, Geneva, Switzerland
| | - Reine Hanna
- Cell Isolation and Transplantation Center, Department of Surgery, University of Geneva School of Medicine, Geneva, Switzerland
| | - Andrea Peloso
- Division of Transplantation, Department of Surgery, University of Geneva Hospitals, Geneva, Switzerland
| | - Ekaterine Berishvili
- Cell Isolation and Transplantation Center, Department of Surgery, University of Geneva School of Medicine, Geneva, Switzerland; Faculty Diabetes Center, University of Geneva School of Medicine, Geneva, Switzerland; Institute of Medical and Public Health Research, Ilia State University, Tbilisi, Georgia.
| |
Collapse
|
|
25
|
Verhoeff K, Marfil-Garza BA, Sandha G, Cooper D, Dajani K, Bigam DL, Anderson B, Kin T, Lam A, O'Gorman D, Senior PA, Ricordi C, Shapiro AMJ. Outcomes Following Extrahepatic and Intraportal Pancreatic Islet Transplantation: A Comparative Cohort Study. Transplantation 2022; 106:2224-2231. [PMID: 35676866 DOI: 10.1097/tp.0000000000004180] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
BACKGROUND Preliminary studies show promise for extrahepatic islet transplantation (ITx). However, clinical comparisons with intraportal ITx outcomes remain limited. METHODS This single-center cohort study evaluates patients receiving extrahepatic or intraportal ITx between 1999 and 2018. Primary outcome was stimulated C-peptide level. Secondary outcomes were fasting plasma glucose, BETA-2 scores, and fasting C-peptide level. Multivariable logistic modeling evaluated factors independently associated with a composite variable of early graft failure and primary nonfunction within 60 d of ITx. RESULTS Of 264 patients, 9 (3.5%) received extrahepatic ITx (gastric submucosal = 2, subcutaneous = 3, omental = 4). Group demographics were similar at baseline (age, body mass index, diabetes duration, and glycemic control). At 1-3 mo post-first infusion, patients receiving extrahepatic ITx had significantly lower stimulated C-peptide (0.05 nmol/L versus 1.2 nmol/L, P < 0.001), higher fasting plasma glucose (9.3 mmol/L versus 7.3 mmol/L, P < 0.001), and lower BETA-2 scores (0 versus 11.6, P < 0.001) and SUITO indices (1.5 versus 39.6, P < 0.001) compared with those receiving intraportal ITx. Subjects receiving extrahepatic grafts failed to produce median C-peptide ≥0.2 nmol/L within the first 60 d after transplant. Subsequent intraportal infusion following extrahepatic transplants achieved equivalent outcomes compared with patients receiving intraportal transplant alone. Extrahepatic ITx was independently associated with early graft failure/primary non-function (odds ratio 1.709, confidence interval 73.8-39 616.0, P < 0.001), whereas no other factors were independently predictive. CONCLUSIONS Using current techniques, intraportal islet infusion remains the gold standard for clinical ITx, with superior engraftment, graft function, and glycemic outcomes compared with extrahepatic transplantation of human islets.
Collapse
Affiliation(s)
- Kevin Verhoeff
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
| | - Braulio A Marfil-Garza
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
- National Institute of Medical Sciences and Nutrition Salvador Zubiran, Mexico City, Mexico
- CHRISTUS-LatAm Hub - Excellence and Innovation Center, Monterrey, Mexico
| | - Gurpal Sandha
- Department of Medicine, Division of Gastroenterology, University of Alberta, Edmonton, AB, Canada
| | | | - Khaled Dajani
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
| | - David L Bigam
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
| | - Blaire Anderson
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
| | - Tatsuya Kin
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
| | - Anna Lam
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
- Department of Medicine, Division of Endocrinology, University of Alberta, Edmonton, AB, Canada
| | - Doug O'Gorman
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
| | - Peter A Senior
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
- Department of Medicine, Division of Endocrinology, University of Alberta, Edmonton, AB, Canada
| | - Camillo Ricordi
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL
| | - A M James Shapiro
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
| |
Collapse
|
|
26
|
Jeyagaran A, Lu CE, Zbinden A, Birkenfeld AL, Brucker SY, Layland SL. Type 1 diabetes and engineering enhanced islet transplantation. Adv Drug Deliv Rev 2022; 189:114481. [PMID: 36002043 PMCID: PMC9531713 DOI: 10.1016/j.addr.2022.114481] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 08/01/2022] [Accepted: 08/02/2022] [Indexed: 01/24/2023]
Abstract
The development of new therapeutic approaches to treat type 1 diabetes mellitus (T1D) relies on the precise understanding and deciphering of insulin-secreting β-cell biology, as well as the mechanisms responsible for their autoimmune destruction. β-cell or islet transplantation is viewed as a potential long-term therapy for the millions of patients with diabetes. To advance the field of insulin-secreting cell transplantation, two main research areas are currently investigated by the scientific community: (1) the identification of the developmental pathways that drive the differentiation of stem cells into insulin-producing cells, providing an inexhaustible source of cells; and (2) transplantation strategies and engineered transplants to provide protection and enhance the functionality of transplanted cells. In this review, we discuss the biology of pancreatic β-cells, pathology of T1D and current state of β-cell differentiation. We give a comprehensive view and discuss the different possibilities to engineer enhanced insulin-secreting cell/islet transplantation from a translational perspective.
Collapse
Affiliation(s)
- Abiramy Jeyagaran
- Institute of Biomedical Engineering, Department for Medical Technologies and Regenerative Medicine, Eberhard Karls University Tübingen, 72076 Tübingen, Germany; NMI Natural and Medical Sciences Institute at the University Tübingen, 72770 Reutlingen, Germany
| | - Chuan-En Lu
- Institute of Biomedical Engineering, Department for Medical Technologies and Regenerative Medicine, Eberhard Karls University Tübingen, 72076 Tübingen, Germany
| | - Aline Zbinden
- Department of Immunology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Andreas L Birkenfeld
- Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, German Center for Diabetes Research (DZD e.V.), Munich, Germany
| | - Sara Y Brucker
- Department of Women's Health, Eberhard Karls University, 72076 Tübingen, Germany
| | - Shannon L Layland
- Institute of Biomedical Engineering, Department for Medical Technologies and Regenerative Medicine, Eberhard Karls University Tübingen, 72076 Tübingen, Germany; Department of Women's Health, Eberhard Karls University, 72076 Tübingen, Germany.
| |
Collapse
|
|
27
|
Decellularized Pancreatic Tail as Matrix for Pancreatic Islet Transplantation into the Greater Omentum in Rats. J Funct Biomater 2022; 13:jfb13040171. [PMID: 36278640 PMCID: PMC9589982 DOI: 10.3390/jfb13040171] [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: 08/31/2022] [Revised: 09/27/2022] [Accepted: 09/28/2022] [Indexed: 11/29/2022] Open
Abstract
Infusing pancreatic islets into the portal vein currently represents the preferred approach for islet transplantation, despite considerable loss of islet mass almost immediately after implantation. Therefore, approaches that obviate direct intravascular placement are urgently needed. A promising candidate for extrahepatic placement is the omentum. We aimed to develop an extracellular matrix skeleton from the native pancreas that could provide a microenvironment for islet survival in an omental flap. To that end, we compared different decellularization approaches, including perfusion through the pancreatic duct, gastric artery, portal vein, and a novel method through the splenic vein. Decellularized skeletons were compared for size, residual DNA content, protein composition, histology, electron microscopy, and MR imaging after repopulation with isolated islets. Compared to the other approaches, pancreatic perfusion via the splenic vein provided smaller extracellular matrix skeletons, which facilitated transplantation into the omentum, without compromising other requirements, such as the complete depletion of cellular components and the preservation of pancreatic extracellular proteins. Repeated MR imaging of iron-oxide-labeled pancreatic islets showed that islets maintained their position in vivo for 49 days. Advanced environmental scanning electron microscopy demonstrated that islets remained integrated with the pancreatic skeleton. This novel approach represents a proof-of-concept for long-term transplantation experiments.
Collapse
|
|
28
|
Pretransplant HOMA-β Is Predictive of Insulin Independence in 7 Patients With Chronic Pancreatitis Undergoing Islet Autotransplantation. Transplant Direct 2022; 8:e1367. [PMID: 36204182 PMCID: PMC9529061 DOI: 10.1097/txd.0000000000001367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 06/24/2022] [Accepted: 07/13/2022] [Indexed: 11/26/2022] Open
Abstract
Islet and β-cell function is intrinsic to glucose homeostasis. Pancreatectomy and islet autotransplantation (PIAT) for chronic pancreatitis (CP) treatment is a useful model for assessing islet function in the absence of immune-suppression and to perform extensive presurgical metabolic evaluations not possible from deceased donors. We recently showed that in CP-PIAT patients, preoperative islet identity loss presented with postoperative glycemic loss. Here, we examine presurgical islet function using Homeostatic Model Assessment-Beta Cell Function (%) (HOMA-β) and glycemic variables and compared them with postsurgical insulin independence and their predicted alignment with Secretory Unit of Islet Transplant Objects (SUITO) and beta cell score after transplantation (BETA-2) scores.
Collapse
|
|
29
|
Bolla AM, Montefusco L, Pastore I, Lunati ME, Ben Nasr M, Fiorina P. Benefits and Hurdles of Pancreatic β-Cell Replacement. Stem Cells Transl Med 2022; 11:1029-1039. [PMID: 36073717 PMCID: PMC9585952 DOI: 10.1093/stcltm/szac058] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 07/02/2022] [Indexed: 11/13/2022] Open
Abstract
Insulin represents a life-saving treatment in patients with type 1 diabetes, and technological advancements have improved glucose control in an increasing number of patients. Despite this, adequate control is often still difficult to achieve and insulin remains a therapy and not a cure for the disease. β-cell replacement strategies can potentially restore pancreas endocrine function and aim to maintain normoglycemia; both pancreas and islet transplantation have greatly progressed over the last decades and, in subjects with extreme glycemic variability and diabetes complications, represent a concrete and effective treatment option. Some issues still limit the adoption of this approach on a larger scale. One is represented by the strict selection criteria for the recipient who can benefit from a transplant and maintain the lifelong immunosuppression necessary to avoid organ rejection. Second, with regard to islet transplantation, up to 40% of islets can be lost during hepatic engraftment. Recent studies showed very preliminarily but promising results to overcome these hurdles: the ability to induce β-cell maturation from stem cells may represent a solution to the organ shortage, and the creation of semi-permeable membranes that envelope or package cells in either micro- or macro- encapsulation strategies, together with engineering cells to be hypo-immunogenic, pave the way for developing strategies without immunosuppression. The aim of this review is to describe the state of the art in β-cell replacement with a focus on its efficacy and clinical benefits, on the actual limitations and still unmet needs, and on the latest findings and future directions.
Collapse
Affiliation(s)
| | - Laura Montefusco
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | - Ida Pastore
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | | | - Moufida Ben Nasr
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy.,Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Paolo Fiorina
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy.,International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy.,Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| |
Collapse
|
|
30
|
Pignatelli C, Campo F, Neroni A, Piemonti L, Citro A. Bioengineering the Vascularized Endocrine Pancreas: A Fine-Tuned Interplay Between Vascularization, Extracellular-Matrix-Based Scaffold Architecture, and Insulin-Producing Cells. Transpl Int 2022; 35:10555. [PMID: 36090775 PMCID: PMC9452644 DOI: 10.3389/ti.2022.10555] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 08/11/2022] [Indexed: 11/23/2022]
Abstract
Intrahepatic islet transplantation is a promising β-cell replacement strategy for the treatment of type 1 diabetes. Instant blood-mediated inflammatory reactions, acute inflammatory storm, and graft revascularization delay limit islet engraftment in the peri-transplant phase, hampering the success rate of the procedure. Growing evidence has demonstrated that islet engraftment efficiency may take advantage of several bioengineering approaches aimed to recreate both vascular and endocrine compartments either ex vivo or in vivo. To this end, endocrine pancreas bioengineering is an emerging field in β-cell replacement, which might provide endocrine cells with all the building blocks (vascularization, ECM composition, or micro/macro-architecture) useful for their successful engraftment and function in vivo. Studies on reshaping either the endocrine cellular composition or the islet microenvironment have been largely performed, focusing on a single building block element, without, however, grasping that their synergistic effect is indispensable for correct endocrine function. Herein, the review focuses on the minimum building blocks that an ideal vascularized endocrine scaffold should have to resemble the endocrine niche architecture, composition, and function to foster functional connections between the vascular and endocrine compartments. Additionally, this review highlights the possibility of designing bioengineered scaffolds integrating alternative endocrine sources to overcome donor organ shortages and the possibility of combining novel immune-preserving strategies for long-term graft function.
Collapse
Affiliation(s)
- Cataldo Pignatelli
- San Raffaele Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Francesco Campo
- San Raffaele Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Università Vita-Salute San Raffaele, Milan, Italy
| | - Alessia Neroni
- San Raffaele Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Università Vita-Salute San Raffaele, Milan, Italy
| | - Lorenzo Piemonti
- San Raffaele Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Università Vita-Salute San Raffaele, Milan, Italy
| | - Antonio Citro
- San Raffaele Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| |
Collapse
|
|
31
|
Berney T, Andres A, Bellin MD, de Koning EJP, Johnson PRV, Kay TWH, Lundgren T, Rickels MR, Scholz H, Stock PG, White S. A Worldwide Survey of Activities and Practices in Clinical Islet of Langerhans Transplantation. Transpl Int 2022; 35:10507. [PMID: 36033644 PMCID: PMC9402897 DOI: 10.3389/ti.2022.10507] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Accepted: 05/30/2022] [Indexed: 11/19/2022]
Abstract
A global online survey was administered to 69 islet transplantation programs, covering 84 centers and 5 networks. The survey addressed questions on program organization and activity in the 2000–2020 period, including impact on activity of national health care coverage policies. We obtained full data from 55 institutions or networks worldwide and basic activity data from 6 centers. Additional data were obtained from alternative sources. A total of 94 institutions and 5 networks was identified as having performed islet allotransplantation. 4,365 islet allotransplants (2,608 in Europe, 1,475 in North America, 135 in Asia, 119 in Oceania, 28 in South America) were reported in 2,170 patients in the survey period. From 15 centers active at the start of the study period, the number of simultaneously active islet centers peaked at 54, to progressively decrease to 26 having performed islet allotransplants in 2020. Notably, only 16 centers/networks have done >100 islet allotransplants in the survey period. Types of transplants performed differed notably between North America and the rest of the world, in particular with respect to the near-absence of simultaneous islet-kidney transplantation. Absence of heath care coverage has significantly hampered transplant activity in the past years and the COVID-19 pandemic in 2020.
Collapse
Affiliation(s)
- Thierry Berney
- Division of Transplantation, Department of Surgery, University of Geneva Hospitals, Geneva, Switzerland,*Correspondence: Thierry Berney,
| | - Axel Andres
- Division of Transplantation, Department of Surgery, University of Geneva Hospitals, Geneva, Switzerland
| | - Melena D. Bellin
- Departments of Pediatrics and Surgery, University of Minnesota Medical Center, Minneapolis, MN, United States
| | | | - Paul R. V. Johnson
- Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - Thomas W. H. Kay
- Department of Medicine, St. Vincent’s Hospital, St. Vincent’s Institute of Medical Research, University of Melbourne, Melbourne, VIC, Australia
| | - Torbjörn Lundgren
- Department of Transplantation Surgery, Karolinska University Hospital, Stockholm, Sweden
| | - Michael R. Rickels
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
| | - Hanne Scholz
- Department of Transplant Medicine, Institute for Surgical Research, Oslo University Hospital, Oslo, Norway
| | - Peter G. Stock
- Division of Transplantation, Department of Surgery, University of California at San Francisco, San Francisco, CA, United States
| | - Steve White
- Department of HPB and Transplant Surgery, The Freeman Hospital, Newcastle Upon Tyne, United Kingdom
| | | |
Collapse
|
|
32
|
Tun SBB, Chua M, Tan GSW, Leibiger I, Ali Y, Barathi VA, Berggren PO. Local Dexamethasone Administration Delays Allogeneic Islet Graft Rejection in the Anterior Chamber of the Eye of Non-Human Primates. Cell Transplant 2022; 31:9636897221098038. [PMID: 35603580 PMCID: PMC9125106 DOI: 10.1177/09636897221098038] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Pancreatic islet transplantation into the anterior chamber of the eye (ACE) has been shown to improve glycemic control and metabolic parameters of diabetes in both murine and primate models. This novel transplantation site also allows the delivery of therapeutic agents, such as immunosuppressive drugs, locally to prevent islet graft rejection and circumvent unwanted systemic side effects. Local intravitreal administration of micronized dexamethasone implant was performed prior to allogeneic islet transplantation into the ACEs of non-human primates. Two study groups were observed namely allogeneic graft without immunosuppression (n = 4 eyes) and allogeneic graft with local immunosuppression (n = 8 eyes). Survival of islet grafts and dexamethasone concentration in the ACE were assessed in parallel for 24 weeks. Allogeneic islet grafts with local dexamethasone treatment showed significantly better survival than those with no immunosuppression (median survival time- 15 weeks vs 3 weeks, log-rank test p<0.0001). Around 73% of the grafts still survived at week 10 with a single local dexamethasone implant, where the control group showed no graft survival. Dexamethasone treated islet grafts revealed a good functional response to high glucose stimulation despite there was a transient suppression of insulin secretion from week 8 to 12. Our findings show a significant improvement of allografts survival in the ACE with local dexamethasone treatment. These results highlight the feasibility of local administration of pharmacological compounds in the ACE to improve islet graft survival and function. By eliminating the need for systemic immunosuppression, these findings may impact clinical islet transplantation in the treatment of diabetes, and the ACE may serve as a novel therapeutic islet transplantation site with high potential for local pharmacological intervention.
Collapse
Affiliation(s)
- Sai Bo Bo Tun
- Translational Pre-Clinical Model Platform, Singapore Eye Research Institute, Singapore
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden
| | - Minni Chua
- Translational Pre-Clinical Model Platform, Singapore Eye Research Institute, Singapore
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
| | - Gavin Siew Wei Tan
- Translational Pre-Clinical Model Platform, Singapore Eye Research Institute, Singapore
- Ophthalmology and Visual Sciences Academic Clinical Program, DUKE-NUS Medical School, Singapore
| | - Ingo Leibiger
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden
| | - Yusuf Ali
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
| | - Veluchamy Amutha Barathi
- Translational Pre-Clinical Model Platform, Singapore Eye Research Institute, Singapore
- Ophthalmology and Visual Sciences Academic Clinical Program, DUKE-NUS Medical School, Singapore
- Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Per-Olof Berggren
- Translational Pre-Clinical Model Platform, Singapore Eye Research Institute, Singapore
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| |
Collapse
|
|
33
|
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: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [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
|
|
34
|
Chen S, Luo J, Shen L, Liu X, Wang W, Xu J, Ren Y, Ye Y, Shi G, Cheng F, Cheng L, Su X, Dai L, Gou M, Deng H. 3D Printing Mini-Capsule Device for Islet Delivery to Treat Type 1 Diabetes. ACS APPLIED MATERIALS & INTERFACES 2022; 14:23139-23151. [PMID: 35544723 DOI: 10.1021/acsami.2c02487] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Transplantation of encapsulated islets has been shown to hold a promising potential treatment for type 1 diabetes (T1D). However, there are several obstacles to overcome, such as immune rejection by the host of the grafts, sustainability of islet function, and retrievability or replacement of the encapsulated system, hinder their clinical applications. In this study, mini-capsule devices containing islets were fabricated by using digital light processing (DLP) 3D printing. To ensure a high survival rate and low immunogenicity of the fabricated islets, 20s was selected as the most suitable printing condition. Meanwhile, the mini-capsule devices with a groove structure were fabricated to prevent islet cells leakage. Subcutaneous transplantations of encapsulated islets in immunocompetent C57BL/6 mice indicated significant improvement in the symptoms of streptozotocin-induced hyperglycemia without any immunosuppression treatment for at least 15 weeks. In vivo intraperitoneal glucose tolerance tests (IPGTT) performed at different time points demonstrated therapeutically relevant glycemic ameliorate of the device. The implants retrieved after 15 weeks still contained viable and adequate numbers of islet cells. The results of this study indicate that the proposed mini-capsule device can deliver sufficient islet cell mass, prevent islet cells leakage, and maintain long-term cell survival while allowing easy retrieval. Furthermore, the proposed encapsulated islets may help with T1D cellular treatment by overcoming the obstacles of islet transplantation.
Collapse
Affiliation(s)
- Shuang Chen
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Jing Luo
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Lanlin Shen
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Xuan Liu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Wenshuang Wang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Jia Xu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yushuang Ren
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yixin Ye
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Gang Shi
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Fuyi Cheng
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Lin Cheng
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Xiaolan Su
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Lei Dai
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Maling Gou
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Hongxin Deng
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| |
Collapse
|
|
35
|
Van Hulle F, De Groot K, Hilbrands R, Van de Velde U, Suenens K, Stangé G, De Mesmaeker I, De Paep DL, Ling Z, Roep B, Gillard P, Pipeleers D, Keymeulen B, Jacobs-Tulleneers-Thevissen D. Function and composition of pancreatic islet cell implants in omentum of type 1 diabetes patients. Am J Transplant 2022; 22:927-936. [PMID: 34735732 DOI: 10.1111/ajt.16884] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 10/10/2021] [Accepted: 10/30/2021] [Indexed: 01/25/2023]
Abstract
Intraportal (IP) islet cell transplants can restore metabolic control in type 1 diabetes patients, but limitations raise the need for establishing a functional beta cell mass (FBM) in a confined extrahepatic site. This study reports on function and composition of omental (OM) implants after placement of islet cell grafts with similar beta cell mass as in our IP-protocol (2-5.106 beta cells/kg body weight) on a scaffold. Four of seven C-peptide-negative recipients achieved low beta cell function (hyperglycemic clamp [HGC] 2-8 percent of controls) until laparoscopy, 2-6 months later, for OM-biopsy and concomitant IP-transplant with similar beta cell dose. This IP-transplant increased HGC-values to 15-40 percent. OM-biopsies reflected the composition of initial grafts, exhibiting varying proportions of endocrine-cell-enriched clusters with more beta than alpha cells and leucocyte pole, non-endocrine cytokeratin-positive clusters surrounded by leucocytes, and scaffold remnants with foreign body reaction. OM-implants on a polyglactin-thrombin-fibrinogen-scaffold presented larger endocrine clusters with infiltrating endothelial cells and corresponded to the higher HGC-values. No activation of cellular immunity to GAD/IA2 was measured post-OM-transplant. Establishment of a metabolically adequate FBM in omentum may require a higher beta cell number in grafts but also elimination of their immunogenic non-endocrine components as well as local conditioning that favors endocrine cell engraftment and function.
Collapse
Affiliation(s)
- Freya Van Hulle
- Diabetes Research Center, Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - Kaat De Groot
- Diabetes Research Center, Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - Robert Hilbrands
- Diabetes Research Center, Vrije Universiteit Brussel (VUB), Brussels, Belgium.,Diabetes Clinic, Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
| | - Ursule Van de Velde
- Diabetes Research Center, Vrije Universiteit Brussel (VUB), Brussels, Belgium.,Diabetes Clinic, Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
| | - Krista Suenens
- Diabetes Research Center, Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - Geert Stangé
- Diabetes Research Center, Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - Ines De Mesmaeker
- Diabetes Research Center, Vrije Universiteit Brussel (VUB), Brussels, Belgium.,Beta Cell Bank, Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
| | - Diedert L De Paep
- Diabetes Research Center, Vrije Universiteit Brussel (VUB), Brussels, Belgium.,Beta Cell Bank, Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium.,Department of Surgery, Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
| | - Zhidong Ling
- Diabetes Research Center, Vrije Universiteit Brussel (VUB), Brussels, Belgium.,Beta Cell Bank, Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
| | - Bart Roep
- Department Internal Medicine, Leiden University Medical Center - LUMC, Leiden, The Netherlands
| | - Pieter Gillard
- Department of Endocrinology, University Hospitals Leuven, Leuven, Belgium
| | - Daniel Pipeleers
- Diabetes Research Center, Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - Bart Keymeulen
- Diabetes Research Center, Vrije Universiteit Brussel (VUB), Brussels, Belgium.,Diabetes Clinic, Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
| | - Daniel Jacobs-Tulleneers-Thevissen
- Diabetes Research Center, Vrije Universiteit Brussel (VUB), Brussels, Belgium.,Department of Surgery, Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
| |
Collapse
|
|
36
|
Lei J, Zhang A, Deng H, Yang Z, Peters CW, Lee KM, Wang Z, Rosales IA, Rickert C, Markmann JF. Intrapleural transplantation of allogeneic pancreatic islets achieves glycemic control in a diabetic non-human primate. Am J Transplant 2022; 22:966-972. [PMID: 34704352 PMCID: PMC8897220 DOI: 10.1111/ajt.16875] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 10/03/2021] [Accepted: 10/18/2021] [Indexed: 01/25/2023]
Abstract
Clinical islet transplantation has relied almost exclusively on intraportal administration of pancreatic islets, as it has been the only consistent approach to achieve robust graft function in human recipients. However, this approach suffers from significant loss of islet mass from a potent immediate blood-mediated inflammatory response (IBMIR) and a hypoxic environment. To avoid these negative aspects of the portal site, we explored an alternative approach in which allogeneic islets were transplanted into the intrapleural space of a non-human primate (NHP), treated with an immunosuppression regimen previously reported to secure routine survival and tolerance to allogeneic islets in NHP. Robust glycemic control and graft survival were achieved for the planned study period of >90 days. Our observations suggest the intrapleural space provides an attractive locale for islet transplantation due to its higher oxygen tension, ability to accommodate large transplant tissue volumes, and a lack of IBMIR-mediated islet damage. Our preliminary results reveal the promise of the intrapleural space as an alternative site for clinical islet transplantation in the treatment of type 1 diabetes.
Collapse
Affiliation(s)
- Ji Lei
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA,To whom correspondence should be addressed: Ji Lei, MD, MBA, 185 Cambridge Street, Rm3836, Massachusetts General Hospital, Boston, MA 02114. Phone: 617-643-5327, FAX: 617-643-7464,
| | - Alexander Zhang
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Hongping Deng
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Zhihong Yang
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Cole W. Peters
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Kang M. Lee
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Zhenjuan Wang
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Ivy A. Rosales
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Charles Rickert
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - James F. Markmann
- Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| |
Collapse
|
|
37
|
Enhanced Differentiation Capacity and Transplantation Efficacy of Insulin-Producing Cell Clusters from Human iPSCs Using Permeable Nanofibrous Microwell-Arrayed Membrane for Diabetes Treatment. Pharmaceutics 2022; 14:pharmaceutics14020400. [PMID: 35214135 PMCID: PMC8879814 DOI: 10.3390/pharmaceutics14020400] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 02/08/2022] [Accepted: 02/09/2022] [Indexed: 11/17/2022] Open
Abstract
Although pancreatic islet transplantation is a potentially curative treatment for insulin-dependent diabetes, a shortage of donor sources, low differentiation capacity, and transplantation efficacy are major hurdles to overcome before becoming a standard therapy. Stem cell-derived insulin-producing cells (IPCs) are a potential approach to overcoming these limitations. To improve the differentiation capacity of the IPCs, cell cluster formation is crucial to mimic the 3D structure of the islet. This study developed a biodegradable polycaprolactone (PCL) electrospun nanofibrous (NF) microwell-arrayed membrane permeable to soluble factors. Based on the numerical analysis and experimental diffusion test, the NF microwell could provide sufficient nutrients, unlike an impermeable PDMS (polydimethylsiloxane) microwell. The IPC clusters in the NF microwells showed higher gene expression of insulin and PDX1 and insulin secretion than the PDMS microwells. The IPC clusters in the NF microwell-arrayed membrane could be directly transplanted. Transplanted IPC clusters in the microwells survived well and expressed PDX1 and insulin. Additionally, human c-peptide was identified in the blood plasma at two months after transplantation of the membranes. The NF microwell-arrayed membrane can be a new platform promoting IPC differentiation capacity and realizing an in situ transplantation technique for diabetic patients.
Collapse
|
|
38
|
Saudek F, Hladiková Z, Hagerf B, Nemetova L, Girman P, Kriz J, Marada T, Habart D, Berkova Z, Leontovyc I, Fronek J. Transplantation of Pancreatic Islets Into the Omentum Using a Biocompatible Plasma-Thrombin Gel: First Experience at the Institute for Clinical and Experimental Medicine in Prague. Transplant Proc 2022; 54:806-810. [DOI: 10.1016/j.transproceed.2021.11.037] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 11/02/2021] [Accepted: 11/18/2021] [Indexed: 01/08/2023]
|
|
39
|
Walker S, Appari M, Forbes S. Considerations and challenges of islet transplantation and future therapies on the horizon. Am J Physiol Endocrinol Metab 2022; 322:E109-E117. [PMID: 34927459 DOI: 10.1152/ajpendo.00310.2021] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Islet transplantation is a treatment for selected adults with type 1 diabetes and severe hypoglycemia. Islets from two or more donor pancreases, a scarce resource, are usually required to impact glycemic control, but the treatment falls short of a cure. Islets are avascular when transplanted into the hypoxic liver environment and subjected to inflammatory insults, immune attack, and toxicity from systemic immunosuppression. The Collaborative Islet Transplant Registry, with outcome data on over 1,000 islet transplant recipients, has demonstrated that larger islet numbers transplanted and older age of recipients are associated with better outcomes. Induction with T-cell depleting agents and the TNF-α inhibitor etanercept and maintenance systemic immunosuppression with mTOR inhibitors in combination with calcineurin inhibitors also appear advantageous, but concerns remain over immunosuppressive toxicity. We discuss strategies and therapeutics that address specific challenges of islet transplantation, many of which are at the preclinical stage of development. On the horizon are adjuvant cell therapies with mesenchymal stromal cells and regulatory T cells that have been used in preclinical models and in humans in other contexts; such a strategy may enable reductions in immunosuppression in the early peri-transplant period when the islets are vulnerable to apoptosis. Human embryonic stem cell-derived islets are in early-phase clinical trials and hold the promise of an inexhaustible supply of insulin-producing cells; effective encapsulation of such cells or, silencing of the human leukocyte antigen (HLA) complex would eliminate the need for immunosuppression, enabling this therapy to be used in all those with type 1 diabetes.
Collapse
Affiliation(s)
- Sophie Walker
- BHF Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Mahesh Appari
- BHF Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Shareen Forbes
- BHF Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
- Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom
- Islet Transplant Program, University of Alberta, Edmonton, Alberta, Canada
| |
Collapse
|
|
40
|
Quizon MJ, García AJ. Engineering β Cell Replacement Therapies for Type 1 Diabetes: Biomaterial Advances and Considerations for Macroscale Constructs. ANNUAL REVIEW OF PATHOLOGY 2022; 17:485-513. [PMID: 34813353 DOI: 10.1146/annurev-pathol-042320-094846] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
While significant progress has been made in treatments for type 1 diabetes (T1D) based on exogenous insulin, transplantation of insulin-producing cells (islets or stem cell-derived β cells) remains a promising curative strategy. The current paradigm for T1D cell therapy is clinical islet transplantation (CIT)-the infusion of islets into the liver-although this therapeutic modality comes with its own limitations that deteriorate islet health. Biomaterials can be leveraged to actively address the limitations of CIT, including undesired host inflammatory and immune responses, lack of vascularization, hypoxia, and the absence of native islet extracellular matrix cues. Moreover, in efforts toward a clinically translatable T1D cell therapy, much research now focuses on developing biomaterial platforms at the macroscale, at which implanted platforms can be easily retrieved and monitored. In this review, we discuss how biomaterials have recently been harnessed for macroscale T1D β cell replacement therapies.
Collapse
Affiliation(s)
- Michelle J Quizon
- George W. Woodruff School of Mechanical Engineering and Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332, USA; ,
| | - Andrés J García
- George W. Woodruff School of Mechanical Engineering and Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332, USA; ,
| |
Collapse
|
|
41
|
Rios P, Baidal D, Lemos J, Camhi SS, Infante M, Padilla N, Gil AMA, Fuenmayor V, Ambut J, Qasmi FA, Mantero AM, Cayetano SM, Ruiz P, Ricordi C, Alejandro R. Long-term Persistence of Allosensitization After Islet Allograft Failure. Transplantation 2021; 105:2490-2498. [PMID: 33481552 PMCID: PMC8289921 DOI: 10.1097/tp.0000000000003635] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Allosensitization has been reported after discontinuation of immunosuppression following graft failure in islet transplantation (ITx) recipients, though duration of its persistence is unknown. METHODS We evaluated 35 patients with type 1 diabetes who received ITx, including 17 who developed graft failure (ITx alone, n = 13; ITx plus bone marrow-derived hematopoietic stem cells, n = 4) and 18 with persistent graft function. Panel-reactive antibody (PRA) was measured yearly for the duration of graft function within 1 y after graft failure at enrollment and yearly thereafter. RESULTS In ITx alone graft failure patients, 61% (8/13) were PRA-positive at 6 y postgraft failure, and 46% (6/13) developed donor-specific anti-HLA antibodies (DSA to 2 ± 1 donors) during follow-up. The degree of sensitization was variable (cPRA ranging between 22% and 100% after graft failure). Allosensitization persisted for 7-15 y. Three subjects (3/13) were not allosensitized. In ITx plus bone marrow-derived hematopoietic stem cell recipients, cPRA-positivity (88%-98%) and DSA positivity persisted for 15 y in 75% (3/4) of subjects. CONCLUSIONS Allosensitization was minimal while subjects remained on immunosuppression, but after discontinuation of immunosuppressive therapy, the majority of subjects (77%) became allosensitized with persistence of PRA positivity for up to 15 y. Persistence of allosensitization in this patient population is of clinical importance as it may result in longer transplant waiting list times for identification of a suitable donor in the case of requiring a subsequent transplant.
Collapse
Affiliation(s)
- Paola Rios
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL
| | - David Baidal
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL
| | - Joana Lemos
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL
| | - Stephanie S. Camhi
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL
| | - Marco Infante
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL
| | - Nathalia Padilla
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL
| | - Ana M. Alvarez Gil
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL
| | - Virginia Fuenmayor
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL
| | - Jonathan Ambut
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL
| | - Fatima A. Qasmi
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL
| | - Alejandro M. Mantero
- Division of Biostatistics, Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL
| | - Shari Messinger Cayetano
- Division of Biostatistics, Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL
| | - Phillip Ruiz
- Department of Surgery and Pathology, University of Miami Miller School of Medicine, University of Miami Miller School of Medicine, Miami, FL
| | - Camillo Ricordi
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL
- Division of Cellular Transplantation, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL
| | - Rodolfo Alejandro
- Diabetes Research Institute (DRI) and Clinical Cell Transplant Program, University of Miami Miller School of Medicine, Miami, FL
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL
| |
Collapse
|
|
42
|
Di Piazza E, Pandolfi E, Cacciotti I, Del Fattore A, Tozzi AE, Secinaro A, Borro L. Bioprinting Technology in Skin, Heart, Pancreas and Cartilage Tissues: Progress and Challenges in Clinical Practice. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:ijerph182010806. [PMID: 34682564 PMCID: PMC8535210 DOI: 10.3390/ijerph182010806] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 09/29/2021] [Accepted: 10/08/2021] [Indexed: 12/16/2022]
Abstract
Bioprinting is an emerging additive manufacturing technique which shows an outstanding potential for shaping customized functional substitutes for tissue engineering. Its introduction into the clinical space in order to replace injured organs could ideally overcome the limitations faced with allografts. Presently, even though there have been years of prolific research in the field, there is a wide gap to bridge in order to bring bioprinting from "bench to bedside". This is due to the fact that bioprinted designs have not yet reached the complexity required for clinical use, nor have clear GMP (good manufacturing practices) rules or precise regulatory guidelines been established. This review provides an overview of some of the most recent and remarkable achievements for skin, heart, pancreas and cartilage bioprinting breakthroughs while highlighting the critical shortcomings for each tissue type which is keeping this technique from becoming widespread reality.
Collapse
Affiliation(s)
- Eleonora Di Piazza
- Multifactorial and Complex Disease Research Area, Preventive and Predictive Medicine Unit, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy; (E.D.P.); (A.E.T.)
| | - Elisabetta Pandolfi
- Multifactorial and Complex Disease Research Area, Preventive and Predictive Medicine Unit, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy; (E.D.P.); (A.E.T.)
- Correspondence:
| | - Ilaria Cacciotti
- Engineering Department, Niccolò Cusano University of Rome, INSTM RU, 00166 Rome, Italy;
| | - Andrea Del Fattore
- Genetics and Rare Diseases Research Area, Bone Physiopathology Research Unit, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy;
| | - Alberto Eugenio Tozzi
- Multifactorial and Complex Disease Research Area, Preventive and Predictive Medicine Unit, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy; (E.D.P.); (A.E.T.)
| | - Aurelio Secinaro
- Clinical Management and Technological Innovations Area, Department of Imaging, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy; (A.S.); (L.B.)
| | - Luca Borro
- Clinical Management and Technological Innovations Area, Department of Imaging, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy; (A.S.); (L.B.)
| |
Collapse
|
|
43
|
Wang LH, Ernst AU, An D, Datta AK, Epel B, Kotecha M, Ma M. A bioinspired scaffold for rapid oxygenation of cell encapsulation systems. Nat Commun 2021; 12:5846. [PMID: 34615868 PMCID: PMC8494927 DOI: 10.1038/s41467-021-26126-w] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 09/18/2021] [Indexed: 01/13/2023] Open
Abstract
Inadequate oxygenation is a major challenge in cell encapsulation, a therapy which holds potential to treat many diseases including type I diabetes. In such systems, cellular oxygen (O2) delivery is limited to slow passive diffusion from transplantation sites through the poorly O2-soluble encapsulating matrix, usually a hydrogel. This constrains the maximum permitted distance between the encapsulated cells and host site to within a few hundred micrometers to ensure cellular function. Inspired by the natural gas-phase tracheal O2 delivery system of insects, we present herein the design of a biomimetic scaffold featuring internal continuous air channels endowed with 10,000-fold higher O2 diffusivity than hydrogels. We incorporate the scaffold into a bulk hydrogel containing cells, which facilitates rapid O2 transport through the whole system to cells several millimeters away from the device-host boundary. A computational model, validated by in vitro analysis, predicts that cells and islets maintain high viability even in a thick (6.6 mm) device. Finally, the therapeutic potential of the device is demonstrated through the correction of diabetes in immunocompetent mice using rat islets for over 6 months.
Collapse
Affiliation(s)
- Long-Hai Wang
- Biological and Environmental Engineering, Cornell University, Ithaca, NY, USA
| | | | - Duo An
- Biological and Environmental Engineering, Cornell University, Ithaca, NY, USA
| | - Ashim Kumar Datta
- Biological and Environmental Engineering, Cornell University, Ithaca, NY, USA
| | - Boris Epel
- Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL, USA
| | | | - Minglin Ma
- Biological and Environmental Engineering, Cornell University, Ithaca, NY, USA.
| |
Collapse
|
|
44
|
Krentz NAJ, Shea LD, Huising MO, Shaw JAM. Restoring normal islet mass and function in type 1 diabetes through regenerative medicine and tissue engineering. Lancet Diabetes Endocrinol 2021; 9:708-724. [PMID: 34480875 PMCID: PMC10881068 DOI: 10.1016/s2213-8587(21)00170-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 05/17/2021] [Accepted: 06/08/2021] [Indexed: 02/09/2023]
Abstract
Type 1 diabetes is characterised by autoimmune-mediated destruction of pancreatic β-cell mass. With the advent of insulin therapy a century ago, type 1 diabetes changed from a progressive, fatal disease to one that requires lifelong complex self-management. Replacing the lost β-cell mass through transplantation has proven successful, but limited donor supply and need for lifelong immunosuppression restricts widespread use. In this Review, we highlight incremental advances over the past 20 years and remaining challenges in regenerative medicine approaches to restoring β-cell mass and function in type 1 diabetes. We begin by summarising the role of endocrine islets in glucose homoeostasis and how this is altered in disease. We then discuss the potential regenerative capacity of the remaining islet cells and the utility of stem cell-derived β-like cells to restore β-cell function. We conclude with tissue engineering approaches that might improve the engraftment, function, and survival of β-cell replacement therapies.
Collapse
Affiliation(s)
- Nicole A J Krentz
- Division of Endocrinology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
| | - Lonnie D Shea
- Departments of Biomedical Engineering, Chemical Engineering, and Surgery, College of Engineering and School of Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Mark O Huising
- Department of Neurobiology, Physiology and Behavior, College of Biological Sciences, University of California, Davis, Davis, CA, USA; Department of Physiology and Membrane Biology, School of Medicine, University of California, Davis, Davis, CA, USA
| | - James A M Shaw
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK; Institute of Transplantation, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
| |
Collapse
|
|
45
|
Mishra V, Nayak P, Sharma M, Albutti A, Alwashmi ASS, Aljasir MA, Alsowayeh N, Tambuwala MM. Emerging Treatment Strategies for Diabetes Mellitus and Associated Complications: An Update. Pharmaceutics 2021; 13:1568. [PMID: 34683861 PMCID: PMC8538773 DOI: 10.3390/pharmaceutics13101568] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 09/10/2021] [Accepted: 09/13/2021] [Indexed: 12/13/2022] Open
Abstract
The occurrence of diabetes mellitus (DM) is increasing rapidly at an accelerating rate worldwide. The status of diabetes has changed over the last three generations; whereas before it was deemed a minor disease of older people but currently it is now one of the leading causes of morbidity and mortality among middle-aged and young people. High blood glucose-mediated functional loss, insulin sensitivity, and insulin deficiency lead to chronic disorders such as Type 1 and Type 2 DM. Traditional treatments of DM, such as insulin sensitization and insulin secretion cause undesirable side effects, leading to patient incompliance and lack of treatment. Nanotechnology in diabetes studies has encouraged the development of new modalities for measuring glucose and supplying insulin that hold the potential to improve the quality of life of diabetics. Other therapies, such as β-cells regeneration and gene therapy, in addition to insulin and oral hypoglycemic drugs, are currently used to control diabetes. The present review highlights the nanocarrier-based drug delivery systems and emerging treatment strategies of DM.
Collapse
Affiliation(s)
- Vijay Mishra
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara 144411, Punjab, India;
| | - Pallavi Nayak
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara 144411, Punjab, India;
- Faculty of Pharmaceutical Sciences, PCTE Group of Institutes, Ludhiana 142021, Punjab, India
| | - Mayank Sharma
- SVKM’s NMIMS School of Pharmacy & Technology Management, Shirpur 425405, Maharashtra, India;
| | - Aqel Albutti
- Department of Medical Biotechnology, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia
| | - Ameen S. S. Alwashmi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia; (A.S.S.A.); (M.A.A.)
| | - Mohammad Abdullah Aljasir
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia; (A.S.S.A.); (M.A.A.)
| | - Noorah Alsowayeh
- Biology Department, College of Education, Majmaah University, Majmaah 11932, Saudi Arabia;
| | - Murtaza M. Tambuwala
- School of Pharmacy and Pharmaceutical Sciences, Ulster University, Coleraine BT52 1SA, UK;
| |
Collapse
|
|
46
|
Damyar K, Farahmand V, Whaley D, Alexander M, Lakey JRT. An overview of current advancements in pancreatic islet transplantation into the omentum. Islets 2021; 13:115-120. [PMID: 34402725 PMCID: PMC8528405 DOI: 10.1080/19382014.2021.1954459] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 07/07/2021] [Indexed: 12/14/2022] Open
Abstract
Pancreatic islet transplantation to restore insulin production in Type 1 Diabetes Mellitus patients is commonly performed by infusion of islets into the hepatic portal system. However, the risk of portal vein thrombosis or elevation of portal pressure after transplantation introduces challenges to this procedure. Thus, alternative sites have been investigated, among which the omentum represents an ideal candidate. The surgical site is easily accessible, and the tissue is highly vascularized with a large surface area for metabolic exchange. Furthermore, the ability of the omentum to host large volumes of islets represents an intriguing if not ideal site for encapsulated islet transplantation. Research on the safety and efficacy of the omentum as a transplant site focuses on the utilization of biologic scaffolds or encapsulation of islets in a biocompatible semi-permeable membrane. Currently, more clinical trials are required to better characterize the safety and efficacy of islet transplantation into the omentum.
Collapse
Affiliation(s)
- Kimia Damyar
- Department of Surgery, University of California Irvine, Orange, CA, USA
| | - Vesta Farahmand
- Department of Surgery, University of California Irvine, Orange, CA, USA
| | - David Whaley
- Department of Surgery, University of California Irvine, Orange, CA, USA
| | - Michael Alexander
- Department of Surgery, University of California Irvine, Orange, CA, USA
| | - Jonathan R. T. Lakey
- Department of Surgery, University of California Irvine, Orange, CA, USA
- Department of Biomedical Engineering, University of California Irvine, Irvine, CA, USA
| |
Collapse
|
|
47
|
Ghasemi A, Akbari E, Imani R. An Overview of Engineered Hydrogel-Based Biomaterials for Improved β-Cell Survival and Insulin Secretion. Front Bioeng Biotechnol 2021; 9:662084. [PMID: 34513805 PMCID: PMC8427138 DOI: 10.3389/fbioe.2021.662084] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 07/16/2021] [Indexed: 12/28/2022] Open
Abstract
Islet transplantation provides a promising strategy in treating type 1 diabetes as an autoimmune disease, in which damaged β-cells are replaced with new islets in a minimally invasive procedure. Although islet transplantation avoids the complications associated with whole pancreas transplantations, its clinical applications maintain significant drawbacks, including long-term immunosuppression, a lack of compatible donors, and blood-mediated inflammatory responses. Biomaterial-assisted islet transplantation is an emerging technology that embeds desired cells into biomaterials, which are then directly transplanted into the patient, overcoming the aforementioned challenges. Among various biomaterials, hydrogels are the preferred biomaterial of choice in these transplants due to their ECM-like structure and tunable properties. This review aims to present a comprehensive overview of hydrogel-based biomaterials that are engineered for encapsulation of insulin-secreting cells, focusing on new hydrogel design and modification strategies to improve β-cell viability, decrease inflammatory responses, and enhance insulin secretion. We will discuss the current status of clinical studies using therapeutic bioengineering hydrogels in insulin release and prospective approaches.
Collapse
Affiliation(s)
| | | | - Rana Imani
- Department of Biomedical Engineering, Amirkabir University of Technology (Tehran Polytechnic), Tehran, Iran
| |
Collapse
|
|
48
|
Liang JP, Accolla RP, Soundirarajan M, Emerson A, Coronel MM, Stabler CL. Engineering a macroporous oxygen-generating scaffold for enhancing islet cell transplantation within an extrahepatic site. Acta Biomater 2021; 130:268-280. [PMID: 34087442 DOI: 10.1016/j.actbio.2021.05.028] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 05/14/2021] [Accepted: 05/20/2021] [Indexed: 01/04/2023]
Abstract
Insufficient oxygenation is a serious issue arising within cell-based implants, as the hypoxic period between implantation and vascularization of the graft is largely unavoidable. In situ oxygen supplementation at the implant site should significantly mitigate hypoxia-induced cell death and dysfunction, as well as improve transplant efficacy, particularly for highly metabolically active cells such as pancreatic islets. One promising approach is the use of an oxygen generating material created through the encapsulation of calcium peroxide within polydimethylsiloxane (PDMS), termed OxySite. In this study, OxySite microbeads were incorporated within a macroporous PDMS scaffold to create a single, streamlined, oxygen generating macroporous scaffold. The resulting OxySite scaffold generated sufficient local oxygenation for up to 20 days, with nontoxic levels of reaction intermediates or by-products. The benefit of local oxygen release on transplant efficacy was investigated in a diabetic Lewis rat syngeneic transplantation model using a clinically relevant islet dosage (10,000 IEQ/kg BW) with different isolation purities (80%, 90%, and 99%). Impure islet preparations containing pancreatic non-islet cells, which are common in the clinical setting, permit examination of the effect of increased overall oxygen demand. Our transplantation outcomes showed that elevating the oxygen demand of the graft with decreasing isolation purity resulted in decreased graft efficacy for control implants, while the integration of OxySite significantly mitigated this impact and resulted in improved graft outcomes. Results highlight the superior clinical translational potential of these off-the-shelf OxySite scaffolds, where islet purity and the overall oxygen demands of implants are increased and highly variable. The oxygen-generating porous scaffold further provides a broad platform for enhancing the survival and efficacy of cellular implants for numerous other applications. STATEMENT OF SIGNIFICANCE: Hypoxia is a serious issue within tissue engineered implants. To address this challenge, we developed a distinct macroporous scaffold platform containing oxygen-generating microbeads. This oxygen-generating scaffold showed the potential to support clinically relevant cell dosages for islet transplantation, leading to improved treatment efficacy. This platform can also be used to mitigate hypoxia for other biomedical applications.
Collapse
Affiliation(s)
- Jia-Pu Liang
- J. Crayton Pruitt Family Department of Biomedical Engineering, Gainesville, FL, USA
| | - Robert P Accolla
- J. Crayton Pruitt Family Department of Biomedical Engineering, Gainesville, FL, USA
| | | | - Amy Emerson
- J. Crayton Pruitt Family Department of Biomedical Engineering, Gainesville, FL, USA
| | - Maria M Coronel
- J. Crayton Pruitt Family Department of Biomedical Engineering, Gainesville, FL, USA
| | - Cherie L Stabler
- J. Crayton Pruitt Family Department of Biomedical Engineering, Gainesville, FL, USA; University of Florida Diabetes Institute, University of Florida, Gainesville, FL, USA.
| |
Collapse
|
|
49
|
Nagaya M, Hasegawa K, Uchikura A, Nakano K, Watanabe M, Umeyama K, Matsunari H, Osafune K, Kobayashi E, Nakauchi H, Nagashima H. Feasibility of large experimental animal models in testing novel therapeutic strategies for diabetes. World J Diabetes 2021; 12:306-330. [PMID: 33889282 PMCID: PMC8040081 DOI: 10.4239/wjd.v12.i4.306] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 01/30/2021] [Accepted: 03/11/2021] [Indexed: 02/06/2023] Open
Abstract
Diabetes is among the top 10 causes of death in adults and caused approximately four million deaths worldwide in 2017. The incidence and prevalence of diabetes is predicted to increase. To alleviate this potentially severe situation, safer and more effective therapeutics are urgently required. Mice have long been the mainstay as preclinical models for basic research on diabetes, although they are not ideally suited for translating basic knowledge into clinical applications. To validate and optimize novel therapeutics for safe application in humans, an appropriate large animal model is needed. Large animals, especially pigs, are well suited for biomedical research and share many similarities with humans, including body size, anatomical features, physiology, and pathophysiology. Moreover, pigs already play an important role in translational studies, including clinical trials for xenotransplantation. Progress in genetic engineering over the past few decades has facilitated the development of transgenic animals, including porcine models of diabetes. This article discusses features that attest to the attractiveness of genetically modified porcine models of diabetes for testing novel treatment strategies using recent technical advances.
Collapse
Affiliation(s)
- Masaki Nagaya
- Meiji University International Institute for Bio-Resource Research, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Department of Immunology, St. Marianna University School of Medicine, Kawasaki 261-8511, Kanagawa, Japan
| | - Koki Hasegawa
- Laboratory of Medical Bioengineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
| | - Ayuko Uchikura
- Laboratory of Medical Bioengineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
| | - Kazuaki Nakano
- Meiji University International Institute for Bio-Resource Research, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Laboratory of Medical Bioengineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Research and Development, PorMedTec Co. Ltd, Kawasaki 214-0034, Kanagawa, Japan
| | - Masahito Watanabe
- Meiji University International Institute for Bio-Resource Research, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Laboratory of Medical Bioengineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Research and Development, PorMedTec Co. Ltd, Kawasaki 214-0034, Kanagawa, Japan
| | - Kazuhiro Umeyama
- Meiji University International Institute for Bio-Resource Research, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Laboratory of Medical Bioengineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Research and Development, PorMedTec Co. Ltd, Kawasaki 214-0034, Kanagawa, Japan
| | - Hitomi Matsunari
- Meiji University International Institute for Bio-Resource Research, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Laboratory of Medical Bioengineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
| | - Kenji Osafune
- Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Kyoto, Japan
| | - Eiji Kobayashi
- Department of Organ Fabrication, Keio University School of Medicine, Shinjuku 160-8582, Tokyo, Japan
| | - Hiromitsu Nakauchi
- Institute for Stem Cell Biology and Regenerative Medicine, Department of Genetics, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, United States
- Division of Stem Cell Therapy, Institute of Medical Science, The University of Tokyo, Minato 108-8639, Tokyo, Japan
| | - Hiroshi Nagashima
- Meiji University International Institute for Bio-Resource Research, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Laboratory of Medical Bioengineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
| |
Collapse
|
|
50
|
Speer AL, Ren X, McNeill EP, Aziz JM, Muir SM, Marino DI, Dadhich P, Sawant K, Ciccocioppo R, Asthana A, Bitar KN, Orlando G. Bioengineering of the digestive tract: approaching the clinic. Cytotherapy 2021; 23:381-389. [PMID: 33840629 DOI: 10.1016/j.jcyt.2021.02.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 01/29/2021] [Accepted: 02/08/2021] [Indexed: 12/18/2022]
Abstract
The field of regenerative medicine is developing technologies that, in the near future, will offer alternative approaches to either cure diseases affecting the gastrointestinal tract or slow their progression by leveraging the intrinsic ability of our tissues and organs to repair after damage. This article will succinctly illustrate the three technologies that are closer to clinical translation-namely, human intestinal organoids, sphincter bioengineering and decellularization, whereby the cellular compartment of a given segment of the digestive tract is removed to obtain a scaffold consisting of the extracellular matrix. The latter will be used as a template for the regeneration of a functional organ, whereby the newly generated cellular compartment will be obtained from the patient's own cells. Although clinical application of this technology is approaching, product development challenges are being tackled to warrant safety and efficacy.
Collapse
Affiliation(s)
- Allison L Speer
- McGovern Medical School, The University of Texas Health Science Center, Houston, Texas, USA
| | - Xi Ren
- Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA
| | - Eoin P McNeill
- McGovern Medical School, The University of Texas Health Science Center, Houston, Texas, USA
| | - Justine M Aziz
- Wake Forest Baptist Medical Center, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Sean M Muir
- Wake Forest Baptist Medical Center, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Domenica I Marino
- College of Arts and Sciences, Ohio State University, Columbus, Ohio, USA
| | | | - Ketki Sawant
- Cellf Bio LLC, Winston-Salem, North Carolina, USA
| | - Rachele Ciccocioppo
- Department of Medicine, Gastroenterology Unit, Giambattista Rossi University Hospital, University Hospital Integrated Trust of Verona, University of Verona, Verona, Italy
| | - Amish Asthana
- Wake Forest Baptist Medical Center, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Khalil N Bitar
- Wake Forest Baptist Medical Center, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA; Cellf Bio LLC, Winston-Salem, North Carolina, USA
| | - Giuseppe Orlando
- Wake Forest Baptist Medical Center, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
| |
Collapse
|