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Rech Tondin A, Lanzoni G. Islet Cell Replacement and Regeneration for Type 1 Diabetes: Current Developments and Future Prospects. BioDrugs 2025; 39:261-280. [PMID: 39918671 PMCID: PMC11906537 DOI: 10.1007/s40259-025-00703-7] [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] [Accepted: 01/05/2025] [Indexed: 03/14/2025]
Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disorder characterized by the destruction of insulin-producing beta cells in the pancreas, leading to insulin deficiency and chronic hyperglycemia. The main current therapeutic strategies for clinically overt T1D - primarily exogenous insulin administration combined with blood glucose monitoring - fail to fully mimic physiological insulin regulation, often resulting in suboptimal or insufficient glycemic control. Islet cell transplantation has emerged as a promising avenue for functionally replacing endogenous insulin production and achieving long-term glycemic stability. Here, we provide an overview of current islet replacement strategies, ranging from islet transplantation to stem cell-derived islet cell transplantation, and highlight emerging approaches such as immunoengineering. We examine the advancements in immunosuppressive protocols to enhance graft survival, innovative encapsulation, and immunomodulation techniques to protect transplanted islets, and the ongoing challenges in achieving durable and functional islet integration. Additionally, we discuss the latest clinical outcomes, the potential of gene editing technologies, and the emerging strategies for islet cell regeneration. This review aims to highlight the potential of these approaches to transform the management of T1D and improve the quality of life of individuals affected by this condition.
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Affiliation(s)
- Arthur Rech Tondin
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Giacomo Lanzoni
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA.
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA.
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Campo F, Neroni A, Pignatelli C, Pellegrini S, Marzinotto I, Valla L, Manenti F, Policardi M, Lampasona V, Piemonti L, Citro A. Bioengineering of a human iPSC-derived vascularized endocrine pancreas for type 1 diabetes. Cell Rep Med 2025; 6:101938. [PMID: 39922198 PMCID: PMC11866511 DOI: 10.1016/j.xcrm.2025.101938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 11/18/2024] [Accepted: 01/13/2025] [Indexed: 02/10/2025]
Abstract
Intrahepatic islet transplantation in patients with type 1 diabetes is limited by donor availability and lack of engraftment. Alternative β cell sources and transplantation sites are needed. We demonstrate the feasibility to repurpose a decellularized lung as an endocrine pancreas for β cell replacement. We bioengineer an induced pluripotent stem cell (iPSC)-based version, fabricating a human iPSC-based vascularized endocrine pancreas (iVEP) using iPSC-derived β cells (iPSC-derived islets [SC-islets]) and endothelial cells (iECs). SC-islets and iECs are aggregated into vascularized iβ spheroids (ViβeSs), and over 7 days of culture, spheroids integrate into the bioengineered vasculature, generating a functional, perfusable human endocrine organ. In vitro, the vascularized extracellular matrix (ECM) sustained SC-islet engraftment and survival with a significantly preserved β cell mass and a physiologic insulin release. In vivo, iVEP restores normoglycemia in diabetic NSG mice. We report a human iVEP providing a controlled in vitro insulin-secreting phenotype and in vivo function.
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Affiliation(s)
- 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
| | - Cataldo Pignatelli
- San Raffaele Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Silvia Pellegrini
- San Raffaele Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Ilaria Marzinotto
- San Raffaele Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Libera Valla
- San Raffaele Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy; Chair for Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, 81377 Munich, Germany; Center for Innovative Medical Models (CiMM), LMU Munich, 85764 Oberschleißheim, Germany
| | - Fabio Manenti
- San Raffaele Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Martina Policardi
- San Raffaele Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Vito Lampasona
- San Raffaele Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, 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.
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Mu-u-min RBA, Diane A, Allouch A, Al-Siddiqi HH. Immune Evasion in Stem Cell-Based Diabetes Therapy-Current Strategies and Their Application in Clinical Trials. Biomedicines 2025; 13:383. [PMID: 40002796 PMCID: PMC11853723 DOI: 10.3390/biomedicines13020383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 01/28/2025] [Accepted: 02/03/2025] [Indexed: 02/27/2025] Open
Abstract
Background/Objectives: Human pancreatic islet transplantation shows promise for long-term glycemic control in diabetes patients. A shortage of healthy donors and the need for continuous immunosuppressive therapy complicates this. Enhancing our understanding of the immune tolerance mechanisms related to graft rejection is crucial to generate safer transplantation strategies. This review will examine advancements in immune protection strategies for stem cell-derived islet therapy and discuss key clinical trials involving stem cell-derived β-cells and their protective strategies against the host immune system. Methods: A comprehensive literature search was performed on peer-reviewed publications on Google Scholar, Pubmed, and Scopus up to September 2024 to extract relevant studies on the various strategies of immune evasion of stem cell-derived β-cells in humans. The literature search was extended to assimilate all relevant clinical studies wherein stem cell-derived β-cells are transplanted to treat diabetes. Results: Our analysis highlighted the importance of human pluripotent stem cells (hPSCs) as a potentially unlimited source of insulin-producing β-cells. These cells can be transplanted as an effective source of insulin in diabetes patients if they can be protected against the host immune system. Various strategies of immune protection, such as encapsulation and genetic manipulation, are currently being studied and clinically tested. Conclusions: Investigating immune tolerance in hPSC-derived islets may help achieve a cure for diabetes without relying on exogenous insulin. Although reports of clinical trials show promise in reducing insulin dependency in patients, their safety and efficacy needs to be further studied to promote their use as a long-term solution to cure diabetes.
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Affiliation(s)
- Razik Bin Abdul Mu-u-min
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar; (A.D.); (H.H.A.-S.)
| | - Abdoulaye Diane
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar; (A.D.); (H.H.A.-S.)
| | - Asma Allouch
- College of Health and Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar;
| | - Heba Hussain Al-Siddiqi
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar; (A.D.); (H.H.A.-S.)
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Primavera R, Wang J, Buchwald P, Ganguly A, Patel S, Bettencourt L, Chetty S, Yarani R, Regmi S, Levitte S, Kevadiya B, Guindani M, Decuzzi P, Thakor AS. Controlled Nutrient Delivery to Pancreatic Islets Using Polydopamine-Coated Mesoporous Silica Nanoparticles. NANO LETTERS 2025; 25:939-950. [PMID: 39791700 DOI: 10.1021/acs.nanolett.4c03613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/12/2025]
Abstract
In this study, we designed a nanoscale platform for sustained amino acid delivery to support transplanted pancreatic islets. The platform features mesoporous silica nanoparticles (MSNPs) loaded with glutamine (G), an essential amino acid required for islet survival and function, and coated with polydopamine (PD). We investigated various PD concentrations (0.5-2 mg/mL) and incubation times (0.5-2 h) to optimize G release, identifying that a PD concentration of 0.5 mg/mL incubated for 0.5 h yielded the best results to support islet viability and functionality ex vivo, particularly under inflammatory conditions. In syngeneic islet transplantation in STZ-diabetic mice, G alone provided only temporary benefits; however, PD-G-MSNPs significantly improved islet engraftment and function, with animals maintaining glycemic control for 30 days due to controlled G release. Our findings support the use of this nanoscale platform to provide essential nutrients like G to transplanted islets until they can establish their own blood and nutrient supply.
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Affiliation(s)
- Rosita Primavera
- Department of Radiology, Interventional Radiology Innovation at Stanford (IRIS), Stanford University School of Medicine, Palo Alto, California 94304, United States
| | - Jing Wang
- Department of Radiology, Interventional Radiology Innovation at Stanford (IRIS), Stanford University School of Medicine, Palo Alto, California 94304, United States
| | - Peter Buchwald
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, Florida 33136, United States
| | - Abantika Ganguly
- Department of Radiology, Interventional Radiology Innovation at Stanford (IRIS), Stanford University School of Medicine, Palo Alto, California 94304, United States
| | - Shaini Patel
- Department of Radiology, Interventional Radiology Innovation at Stanford (IRIS), Stanford University School of Medicine, Palo Alto, California 94304, United States
| | - Lili Bettencourt
- Department of Radiology, Interventional Radiology Innovation at Stanford (IRIS), Stanford University School of Medicine, Palo Alto, California 94304, United States
| | - Shashank Chetty
- Department of Radiology, Interventional Radiology Innovation at Stanford (IRIS), Stanford University School of Medicine, Palo Alto, California 94304, United States
| | - Reza Yarani
- Translational Type 1 Diabetes Research, Department of Clinical, Research, Steno Diabetes Center Copenhagen, Herlev 2730, Denmark
| | - Shobha Regmi
- Department of Radiology, Interventional Radiology Innovation at Stanford (IRIS), Stanford University School of Medicine, Palo Alto, California 94304, United States
| | - Steven Levitte
- Department of Radiology, Interventional Radiology Innovation at Stanford (IRIS), Stanford University School of Medicine, Palo Alto, California 94304, United States
| | - Bhavesh Kevadiya
- Department of Radiology, Interventional Radiology Innovation at Stanford (IRIS), Stanford University School of Medicine, Palo Alto, California 94304, United States
| | - Michele Guindani
- Department of Biostatistics, Jonathan and Karin Fielding School of Public Health, University of California Los Angeles, Los Angeles, California 90095, United States
| | - Paolo Decuzzi
- Laboratory of Nanotechnology for Precision Medicine, Fondazione Istituto Italiano di Tecnologia, Via Morego 30, Genoa 16163, Italy
| | - Avnesh S Thakor
- Department of Radiology, Interventional Radiology Innovation at Stanford (IRIS), Stanford University School of Medicine, Palo Alto, California 94304, United States
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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.
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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
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Opara A, Canning P, Alwan A, Opara EC. Challenges and Perspectives for Future Considerations in the Bioengineering of a Bioartificial Pancreas. Ann Biomed Eng 2024; 52:1795-1803. [PMID: 36913086 DOI: 10.1007/s10439-023-03180-7] [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: 10/21/2022] [Accepted: 02/25/2023] [Indexed: 03/14/2023]
Abstract
There is an unrelenting interest in the development of a reliable bioartificial pancreas construct since the first description of this technology of encapsulated islets by Lim and Sun in 1980 because it promised to be a curative treatment for Type 1 Diabetes Mellitus (T1DM). Despite the promise of the concept of encapsulated islets, there are still some challenges that impede the full realization of the clinical potential of the technology. In this review, we will first present the justification for continued research and development of this technology. Next, we will review key barriers that impede progress in this field and discuss strategies that can be used to design a reliable construct capable of effective long-term performance after transplantation in diabetic patients. Finally, we will share our perspectives on areas of additional work for future research and development of the technology.
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Affiliation(s)
- Amoge Opara
- Diabetes Section, Biologics Delivery Technologies, Reno, NV, 89502, USA
| | - Priyadarshini Canning
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA
| | - Abdelrahman Alwan
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA
| | - Emmanuel C Opara
- Diabetes Section, Biologics Delivery Technologies, Reno, NV, 89502, USA.
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
- Virginia Tech-Wake Forest School of Biomedical Engineering and Sciences (SBES), Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
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7
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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.
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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
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8
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De Toni T, Dal Buono T, Li CM, Gonzalez GC, Chuang ST, Buchwald P, Tomei AA, Velluto D. Drug Integrating Amphiphilic Nano-Assemblies: 2. Spatiotemporal Distribution within Inflammation Sites. Pharmaceutics 2024; 16:652. [PMID: 38794314 PMCID: PMC11124943 DOI: 10.3390/pharmaceutics16050652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Revised: 05/01/2024] [Accepted: 05/09/2024] [Indexed: 05/26/2024] Open
Abstract
The need for chronic systemic immunosuppression, which is associated with unavoidable side-effects, greatly limits the applicability of allogeneic cell transplantation for regenerative medicine applications including pancreatic islet cell transplantation to restore insulin production in type 1 diabetes (T1D). Cell transplantation in confined sites enables the localized delivery of anti-inflammatory and immunomodulatory drugs to prevent graft loss by innate and adaptive immunity, providing an opportunity to achieve local effects while minimizing unwanted systemic side effects. Nanoparticles can provide the means to achieve the needed localized and sustained drug delivery either by graft targeting or co-implantation. Here, we evaluated the potential of our versatile platform of drug-integrating amphiphilic nanomaterial assemblies (DIANAs) for targeted drug delivery to an inflamed site model relevant for islet transplantation. We tested either passive targeting of intravenous administered spherical nanomicelles (nMIC; 20-25 nm diameter) or co-implantation of elongated nanofibrils (nFIB; 5 nm diameter and >1 μm length). To assess the ability of nMIC and nFIB to target an inflamed graft site, we used a lipophilic fluorescent cargo (DiD and DiR) and evaluated the in vivo biodistribution and cellular uptake in the graft site and other organs, including draining and non-draining lymph nodes, after systemic administration (nMIC) and/or graft co-transplantation (nFIB) in mice. Localized inflammation was generated either by using an LPS injection or by using biomaterial-coated islet-like bead implantation in the subcutaneous site. A cell transplant inflammation model was used as well to test nMIC- and nFIB-targeted biodistribution. We found that nMIC can reach the inflamed site after systemic administration, while nFIB remains localized for several days after co-implantation. We confirmed that DIANAs are taken up by different immune cell populations responsible for graft inflammation. Therefore, DIANA is a useful approach for targeted and/or localized delivery of immunomodulatory drugs to decrease innate and adaptive immune responses that cause graft loss after transplantation of therapeutic cells.
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Affiliation(s)
- Teresa De Toni
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (T.D.T.); (T.D.B.); (C.M.L.); (G.C.G.); (S.-T.C.); (P.B.); (A.A.T.)
- Department of Biomedical Engineering, University of Miami, Miami, FL 33146, USA
| | - Teodora Dal Buono
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (T.D.T.); (T.D.B.); (C.M.L.); (G.C.G.); (S.-T.C.); (P.B.); (A.A.T.)
| | - Chris M. Li
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (T.D.T.); (T.D.B.); (C.M.L.); (G.C.G.); (S.-T.C.); (P.B.); (A.A.T.)
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Grisell C. Gonzalez
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (T.D.T.); (T.D.B.); (C.M.L.); (G.C.G.); (S.-T.C.); (P.B.); (A.A.T.)
| | - Sung-Ting Chuang
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (T.D.T.); (T.D.B.); (C.M.L.); (G.C.G.); (S.-T.C.); (P.B.); (A.A.T.)
| | - Peter Buchwald
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (T.D.T.); (T.D.B.); (C.M.L.); (G.C.G.); (S.-T.C.); (P.B.); (A.A.T.)
- Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Alice A. Tomei
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (T.D.T.); (T.D.B.); (C.M.L.); (G.C.G.); (S.-T.C.); (P.B.); (A.A.T.)
- Department of Biomedical Engineering, University of Miami, Miami, FL 33146, USA
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Diana Velluto
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (T.D.T.); (T.D.B.); (C.M.L.); (G.C.G.); (S.-T.C.); (P.B.); (A.A.T.)
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
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9
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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.
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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.
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Hogrebe NJ, Ishahak M, Millman JR. Developments in stem cell-derived islet replacement therapy for treating type 1 diabetes. Cell Stem Cell 2023; 30:530-548. [PMID: 37146579 PMCID: PMC10167558 DOI: 10.1016/j.stem.2023.04.002] [Citation(s) in RCA: 74] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/20/2023] [Accepted: 04/05/2023] [Indexed: 05/07/2023]
Abstract
The generation of islet-like endocrine clusters from human pluripotent stem cells (hPSCs) has the potential to provide an unlimited source of insulin-producing β cells for the treatment of diabetes. In order for this cell therapy to become widely adopted, highly functional and well-characterized stem cell-derived islets (SC-islets) need to be manufactured at scale. Furthermore, successful SC-islet replacement strategies should prevent significant cell loss immediately following transplantation and avoid long-term immune rejection. This review highlights the most recent advances in the generation and characterization of highly functional SC-islets as well as strategies to ensure graft viability and safety after transplantation.
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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.
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11
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Konoe R, Morizane R. Strategies for Improving Vascularization in Kidney Organoids: A Review of Current Trends. BIOLOGY 2023; 12:503. [PMID: 37106704 PMCID: PMC10135596 DOI: 10.3390/biology12040503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 03/23/2023] [Accepted: 03/25/2023] [Indexed: 03/29/2023]
Abstract
Kidney organoids possess the potential to revolutionize the treatment of renal diseases. However, their growth and maturation are impeded by insufficient growth of blood vessels. Through a PubMed search, we have identified 34 studies that attempted to address this challenge. Researchers are exploring various approaches including animal transplantation, organ-on-chips, and extracellular matrices (ECMs). The most prevalent method to promote the maturation and vascularization of organoids involves transplanting them into animals for in vivo culture, creating an optimal environment for organoid growth and the development of a chimeric vessel network between the host and organoids. Organ-on-chip technology permits the in vitro culture of organoids, enabling researchers to manipulate the microenvironment and investigate the key factors that influence organoid development. Lastly, ECMs have been discovered to aid the formation of blood vessels during organoid differentiation. ECMs from animal tissue have been particularly successful, although the underlying mechanisms require further research. Future research building upon these recent studies may enable the generation of functional kidney tissues for replacement therapies.
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Affiliation(s)
| | - Ryuji Morizane
- Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
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12
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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: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [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.
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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.
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13
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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.
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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
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14
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Geng Z, Zhang Q, Li T, Huang T, Wang H, Zhou Q, Deng S, Zhao Y, Li Y, Cheng C, Gonelle-Gispert C, Buhler LH, Wang Y. Advantages of the retroperitoneal retrocolic space as the transplant site for encapsulated xenogeneic islets. Xenotransplantation 2023; 30:e12787. [PMID: 36454040 DOI: 10.1111/xen.12787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 10/14/2022] [Accepted: 10/18/2022] [Indexed: 12/03/2022]
Abstract
OBJECTIVE Islet allotransplantation has demonstrated improved clinical outcomes using the hepatic portal vein as the standard infusion method. However, the current implantation site is not ideal due to the short-term thrombotic and long-term immune destruction. Meanwhile, the shortage of human organ donors further limits its application. To find a new strategy, we tested a new polymer combination for islet encapsulation and transplantation. Meanwhile, we explored a new site for xenogeneic islet transplantation in mice. METHOD We synthesized a hydrogel combining alginate plus poly-ethylene-imine (Alg/PEI) for the encapsulation of rat, neonatal porcine, and human islets. Transplantation was performed into the retroperitoneal retro-colic space of diabetic mice. Control mice received free islets under the kidney capsule or encapsulated islets into the peritoneum. The biochemical indexes were measured, and the transplanted islets were harvested for immunohistochemical staining of insulin and glucagon. RESULTS Mice receiving encapsulated rat, porcine and human islets transplanted into the retroperitoneal space maintained normoglycemia for a median of 275, 145.5, and 146 days, respectively. In contrast, encapsulated xenogeneic islets transplanted into the peritoneum, maintained function for a median of 61, 95.5, and 82 days, respectively. Meanwhile, xenogeneic islets transplanted free into the kidney capsule lost their function within 3 days after transplantation. Immunohistochemical staining of encapsulated rat, porcine and human islets, retrieved from the retroperitoneal space, allowed to distinguish morphological normal insulin expressing β- and glucagon expressing α-cells at 70, 60, and 100 days post-transplant, respectively. CONCLUSION Transplantation of Alg/PEI encapsulated xenogeneic islets into the retroperitoneal space provides a valuable new implantation strategy for the treatment of type 1 diabetes.
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Affiliation(s)
- Zhen Geng
- Health Management Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Qi Zhang
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Ting Li
- Department of Rheumatology, Wenjiang District People's Hospital, Chengdu, China
| | - Ting Huang
- Department of Breast Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Hailian Wang
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Institute of Organ Transplantation, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Qiao Zhou
- Department of Rheumatology and Immunology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Shaoping Deng
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Institute of Organ Transplantation, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Yanshuang Zhao
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yanjiao Li
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Chunming Cheng
- Department of Radiation Oncology, James Comprehensive Cancer Center and College of Medicine, The Ohio State University, Columbus, Ohio, USA
| | | | - Leo H Buhler
- Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Yi Wang
- Department of Critical Care Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, 610072, China
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15
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Abstract
BACKGROUND The lack of a suitable transplantation site has become a bottleneck restricting the development of islet transplantation. METHODS In this study, for the first time, a prevascularized sinus tract (PST) for islet transplantation was constructed in a mouse model by temporarily embedding a 4× silk thread between the liver surface and the attached decellularized human amniotic membrane. After which, the characteristics of the PST and the function of the islet graft within the PST were evaluated. RESULTS The results showed that PST was lined with granulation tissue, the blood vessel density of the local tissue increased, and proangiogenic proteins were upregulated, which mimics the microenvironment of the islets in the pancreas to a certain extent. Transplantation of ~200 syngeneic islets into the PST routinely reversed the hyperglycemia of the recipient mice and maintained euglycemia for >100 d until the islet grafts were retrieved. The islet grafts within the PST achieved better results to those in the nonprevascularized control groups and comparable results to those under the kidney capsule with respect to glycemic control and glucose tolerance. CONCLUSIONS By attaching a decellularized human amniotic membrane to the surface of mouse liver and temporarily embedding a 4× silk thread, the PST formed on the liver surface has a favorable local microenvironment and is a potential clinical islet transplantation site.
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16
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Paez-Mayorga J, Campa-Carranza JN, Capuani S, Hernandez N, Liu HC, Chua CYX, Pons-Faudoa FP, Malgir G, Alvarez B, Niles JA, Argueta LB, Shelton KA, Kezar S, Nehete PN, Berman DM, Willman MA, Li XC, Ricordi C, Nichols JE, Gaber AO, Kenyon NS, Grattoni A. Implantable niche with local immunosuppression for islet allotransplantation achieves type 1 diabetes reversal in rats. Nat Commun 2022; 13:7951. [PMID: 36572684 PMCID: PMC9792517 DOI: 10.1038/s41467-022-35629-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 12/14/2022] [Indexed: 12/27/2022] Open
Abstract
Pancreatic islet transplantation efficacy for type 1 diabetes (T1D) management is limited by hypoxia-related graft attrition and need for systemic immunosuppression. To overcome these challenges, we developed the Neovascularized Implantable Cell Homing and Encapsulation (NICHE) device, which integrates direct vascularization for facile mass transfer and localized immunosuppressant delivery for islet rejection prophylaxis. Here, we investigated NICHE efficacy for allogeneic islet transplantation and long-term diabetes reversal in an immunocompetent, male rat model. We demonstrated that allogeneic islets transplanted within pre-vascularized NICHE were engrafted, revascularized, and functional, reverting diabetes in rats for over 150 days. Notably, we confirmed that localized immunosuppression prevented islet rejection without inducing toxicity or systemic immunosuppression. Moreover, for translatability efforts, we showed NICHE biocompatibility and feasibility of deployment as well as short-term allogeneic islet engraftment in an MHC-mismatched nonhuman primate model. In sum, the NICHE holds promise as a viable approach for safe and effective islet transplantation and long-term T1D management.
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Affiliation(s)
- Jesus Paez-Mayorga
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, USA
- School of Medicine and Health Sciences, Tecnologico de Monterrey, Monterrey, NL, Mexico
| | - Jocelyn Nikita Campa-Carranza
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, USA
- School of Medicine and Health Sciences, Tecnologico de Monterrey, Monterrey, NL, Mexico
| | - Simone Capuani
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, USA
- University of the Chinese Academy of Sciences (UCAS), Shijingshan, Beijing, China
| | - Nathanael Hernandez
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, USA
| | - Hsuan-Chen Liu
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, USA
| | | | | | - Gulsah Malgir
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, USA
| | - Bella Alvarez
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, USA
- School of Medicine and Health Sciences, Tecnologico de Monterrey, Monterrey, NL, Mexico
| | - Jean A Niles
- Center for Tissue Engineering, Houston Methodist Research Institute, Houston, TX, USA
| | - Lissenya B Argueta
- Center for Tissue Engineering, Houston Methodist Research Institute, Houston, TX, USA
| | - Kathryn A Shelton
- Department of Comparative Medicine, Michael E. Keeling Center for Comparative Medicine and Research, MD Anderson Cancer Center, Bastrop, TX, USA
| | - Sarah Kezar
- Department of Comparative Medicine, Michael E. Keeling Center for Comparative Medicine and Research, MD Anderson Cancer Center, Bastrop, TX, USA
| | - Pramod N Nehete
- Department of Comparative Medicine, Michael E. Keeling Center for Comparative Medicine and Research, MD Anderson Cancer Center, Bastrop, TX, USA
- The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA
| | - Dora M Berman
- Diabetes Research Institute, University of Miami, Miami, FL, USA
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
| | | | - Xian C Li
- Department of Surgery, Houston Methodist Hospital, Houston, TX, USA
- Immunobiology and Transplant Science Center, Houston Methodist Hospital, Houston, TX, USA
| | - Camillo Ricordi
- Diabetes Research Institute, University of Miami, Miami, FL, USA
| | - Joan E Nichols
- Center for Tissue Engineering, Houston Methodist Research Institute, Houston, TX, USA
- Department of Surgery, Houston Methodist Hospital, Houston, TX, USA
| | - A Osama Gaber
- Department of Surgery, Houston Methodist Hospital, Houston, TX, USA
| | - Norma S Kenyon
- Diabetes Research Institute, University of Miami, Miami, FL, USA
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, USA
- Department of Biomedical Engineering, University of Miami, Miami, FL, USA
- Department of Biochemistry and Molecular Biology, University of Miami, Miami, FL, USA
| | - Alessandro Grattoni
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, USA.
- Department of Surgery, Houston Methodist Hospital, Houston, TX, USA.
- Department of Biochemistry and Molecular Biology, University of Miami, Miami, FL, USA.
- Department of Radiation Oncology, Houston Methodist Hospital, Houston, TX, USA.
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17
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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.
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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
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18
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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.
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19
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Emerson AE, McCall AB, Brady SR, Slaby EM, Weaver JD. Hydrogel Injection Molding to Generate Complex Cell Encapsulation Geometries. ACS Biomater Sci Eng 2022; 8:4002-4013. [DOI: 10.1021/acsbiomaterials.2c00640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Amy E. Emerson
- School of Biological and Health Systems Engineering, Arizona State University, 550 East Orange Street, Tempe, Arizona 85281, United States
| | - Alec B. McCall
- School of Biological and Health Systems Engineering, Arizona State University, 550 East Orange Street, Tempe, Arizona 85281, United States
| | - Sarah R. Brady
- School of Biological and Health Systems Engineering, Arizona State University, 550 East Orange Street, Tempe, Arizona 85281, United States
| | - Emily M. Slaby
- School of Biological and Health Systems Engineering, Arizona State University, 550 East Orange Street, Tempe, Arizona 85281, United States
| | - Jessica D. Weaver
- School of Biological and Health Systems Engineering, Arizona State University, 550 East Orange Street, Tempe, Arizona 85281, United States
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20
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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.
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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
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21
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A Prevascularized Sinus Tract on the Liver Surface for Islet Transplantation. Transplantation 2022. [DOI: 10.1097/10.1097/tp.0000000000004236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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22
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Stock AA, Gonzalez GC, Pete SI, De Toni T, Berman DM, Rabassa A, Diaz W, Geary JC, Willman M, Jackson JM, DeHaseth NH, Ziebarth NM, Hogan AR, Ricordi C, Kenyon NS, Tomei AA. Performance of islets of Langerhans conformally coated via an emulsion cross-linking method in diabetic rodents and nonhuman primates. SCIENCE ADVANCES 2022; 8:eabm3145. [PMID: 35767620 PMCID: PMC9242596 DOI: 10.1126/sciadv.abm3145] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 05/10/2022] [Indexed: 06/15/2023]
Abstract
Polyethylene glycol (PEG)-based conformal coating (CC) encapsulation of transplanted islets is a promising β cell replacement therapy for the treatment of type 1 diabetes without chronic immunosuppression because it minimizes capsule thickness, graft volume, and insulin secretion delay. However, we show here that our original CC method, the direct method, requiring exposure of islets to low pH levels and inclusion of viscosity enhancers during coating, severely affected the viability, scalability, and biocompatibility of CC islets in nonhuman primate preclinical models of type 1 diabetes. We therefore developed and validated in vitro and in vivo, in several small- and large-animal models of type 1 diabetes, an augmented CC method-emulsion method-that achieves hydrogel CCs around islets at physiological pH for improved cytocompatibility, with PEG hydrogels for increased biocompatibility and with fivefold increase in encapsulation throughput for enhanced scalability.
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Affiliation(s)
- Aaron A. Stock
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA
- Department of Biomedical Engineering, University of Miami, Miami, FL 33146, USA
| | - Grisell C. Gonzalez
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Sophia I. Pete
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA
- Department of Biomedical Engineering, University of Miami, Miami, FL 33146, USA
| | - Teresa De Toni
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA
- Department of Biomedical Engineering, University of Miami, Miami, FL 33146, USA
| | - Dora M. Berman
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Alexander Rabassa
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Waldo Diaz
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - James C. Geary
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Melissa Willman
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Joy M. Jackson
- Department of Biomedical Engineering, University of Miami, Miami, FL 33146, USA
| | - Noa H. DeHaseth
- Department of Biomedical Engineering, University of Miami, Miami, FL 33146, USA
| | - Noel M. Ziebarth
- Department of Biomedical Engineering, University of Miami, Miami, FL 33146, USA
| | - Anthony R. Hogan
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Camillo Ricordi
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA
- Department of Biomedical Engineering, University of Miami, Miami, FL 33146, USA
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Norma S. Kenyon
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA
- Department of Biomedical Engineering, University of Miami, Miami, FL 33146, USA
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Alice A. Tomei
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA
- Department of Biomedical Engineering, University of Miami, Miami, FL 33146, USA
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
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23
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Habeeb MA, Vishwakarma SK, Habeeb S, Khan AA. Current progress and emerging technologies for generating extrapancreatic functional insulin-producing cells. World J Transl Med 2022; 10:1-13. [DOI: 10.5528/wjtm.v10.i1.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 03/05/2022] [Accepted: 06/03/2022] [Indexed: 02/06/2023] Open
Affiliation(s)
- Md Aejaz Habeeb
- Centre for Liver Research and Diagnostics, Deccan College of Medical Sciences, Hyderabad 500058, Telangana, India
| | - Sandeep Kumar Vishwakarma
- Centre for Liver Research and Diagnostics, Deccan College of Medical Sciences, Hyderabad 500058, Telangana, India
| | - Safwaan Habeeb
- Centre for Liver Research and Diagnostics, Deccan College of Medical Sciences, Hyderabad 500058, Telangana, India
| | - Aleem Ahmed Khan
- Centre for Liver Research and Diagnostics, Deccan College of Medical Sciences, Hyderabad 500058, Telangana, India
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24
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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.
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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
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25
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Lei J, Coronel MM, Yolcu ES, Deng H, Grimany-Nuno O, Hunckler MD, Ulker V, Yang Z, Lee KM, Zhang A, Luo H, Peters CW, Zou Z, Chen T, Wang Z, McCoy CS, Rosales IA, Markmann JF, Shirwan H, García AJ. FasL microgels induce immune acceptance of islet allografts in nonhuman primates. SCIENCE ADVANCES 2022; 8:eabm9881. [PMID: 35559682 PMCID: PMC9106299 DOI: 10.1126/sciadv.abm9881] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 03/30/2022] [Indexed: 05/23/2023]
Abstract
Islet transplantation to treat insulin-dependent diabetes is greatly limited by the need for maintenance immunosuppression. We report a strategy through which cotransplantation of allogeneic islets and streptavidin (SA)-FasL-presenting microgels to the omentum under transient rapamycin monotherapy resulted in robust glycemic control, sustained C-peptide levels, and graft survival in diabetic nonhuman primates for >6 months. Surgical extraction of the graft resulted in prompt hyperglycemia. In contrast, animals receiving microgels without SA-FasL under the same rapamycin regimen rejected islet grafts acutely. Graft survival was associated with increased number of FoxP3+ cells in the graft site with no significant changes in T cell systemic frequencies or responses to donor and third-party antigens, indicating localized tolerance. Recipients of SA-FasL microgels exhibited normal liver and kidney metabolic function, demonstrating safety. This localized immunomodulatory strategy succeeded with unmodified islets and does not require long-term immunosuppression, showing translational potential in β cell replacement for treating type 1 diabetes.
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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
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26
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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.
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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
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27
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Kovacevic B, Jones M, Ionescu C, Walker D, Wagle S, Chester J, Foster T, Brown D, Mikov M, Mooranian A, Al-Salami H. The emerging role of bile acids as critical components in nanotechnology and bioengineering: Pharmacology, formulation optimizers and hydrogel-biomaterial applications. Biomaterials 2022; 283:121459. [PMID: 35303546 DOI: 10.1016/j.biomaterials.2022.121459] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 02/27/2022] [Accepted: 03/04/2022] [Indexed: 12/16/2022]
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28
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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]
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29
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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.
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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; ,
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30
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Paget MB, Murray HE, Bailey CJ, Downing R. From insulin injections to islet transplantation: An overview of the journey. Diabetes Obes Metab 2022; 24 Suppl 1:5-16. [PMID: 34431589 DOI: 10.1111/dom.14526] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Revised: 08/10/2021] [Accepted: 08/11/2021] [Indexed: 12/21/2022]
Abstract
When, in 1869, Paul Langerhans detected the "islands of tissue" in the pancreas, he took the first step on a journey towards islet transplantation as a treatment for type 1 diabetes. The route has embraced developments across biosciences, surgery, gene therapy and clinical research. This review highlights major milestones along that journey involving whole pancreas transplantation, islet transplantation, the creation of surrogate insulin-secreting cells and novel islet-like structures using genetic and bio-engineering technologies. To obviate the paucity of human tissue, pluripotent stem cells and non-β-cells within the pancreas have been modified to create physiologically responsive insulin-secreting cells. Before implantation, these can be co-cultured with endothelial cells to promote vascularisation and with immune defence cells such as placental amnion cells to reduce immune rejection. Scaffolds to contain grafts and facilitate surgical placement provide further opportunities to achieve physiological insulin delivery. Alternatively, xenotransplants such as porcine islets might be reconsidered as opportunities exist to circumvent safety concerns and immune rejection. Thus, despite a long and arduous journey, the prospects for increased use of tissue transplantation to provide physiological insulin replacement are drawing ever closer.
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Affiliation(s)
- Michelle B Paget
- Islet Research Laboratory, Worcestershire Clinical Research Unit, Worcestershire Acute Hospitals NHS Trust, Worcester, UK
| | - Hilary E Murray
- Islet Research Laboratory, Worcestershire Clinical Research Unit, Worcestershire Acute Hospitals NHS Trust, Worcester, UK
| | | | - Richard Downing
- Islet Research Laboratory, Worcestershire Clinical Research Unit, Worcestershire Acute Hospitals NHS Trust, Worcester, UK
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31
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Razavi M, Wang J, Thakor AS. Localized drug delivery graphene bioscaffolds for cotransplantation of islets and mesenchymal stem cells. SCIENCE ADVANCES 2021; 7:eabf9221. [PMID: 34788097 PMCID: PMC8597999 DOI: 10.1126/sciadv.abf9221] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Accepted: 09/28/2021] [Indexed: 06/01/2023]
Abstract
In the present work, we developed, characterized, and tested an implantable graphene bioscaffold which elutes dexamethasone (Dex) that can accommodate islets and adipose tissue–derived mesenchymal stem cells (AD-MSCs). In vitro studies demonstrated that islets in graphene–0.5 w/v% Dex bioscaffolds had a substantial higher viability and function compared to islets in graphene-alone bioscaffolds or islets cultured alone (P < 0.05). In vivo studies, in which bioscaffolds were transplanted into the epididymal fat pad of diabetic mice, demonstrated that, when islet:AD-MSC units were seeded into graphene–0.5 w/v% Dex bioscaffolds, this resulted in complete restoration of glycemic control immediately after transplantation with these islets also showing a faster response to glucose challenges (P < 0.05). Hence, this combination approach of using a graphene bioscaffold that can be functionalized for local delivery of Dex into the surrounding microenvironment, together with AD-MSC therapy, can significantly improve the survival and function of transplanted islets.
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Affiliation(s)
- Mehdi Razavi
- Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University School of Medicine, Palo Alto, CA 94304, USA
- Biionix™ (Bionic Materials, Implants & Interfaces) Cluster, Department of Internal Medicine, College of Medicine, University of Central Florida, Orlando, FL 32827, USA
- Department of Materials Science and Engineering, University of Central Florida, Orlando, FL 32816, USA
| | - Jing Wang
- Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University School of Medicine, Palo Alto, CA 94304, USA
| | - Avnesh S. Thakor
- Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University School of Medicine, Palo Alto, CA 94304, USA
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32
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Mishra V, Nayak P, Sharma M, Albutti A, Alwashmi ASS, Aljasir MA, Alsowayeh N, Tambuwala MM. Emerging Treatment Strategies for Diabetes Mellitus and Associated Complications: An Update. Pharmaceutics 2021; 13:1568. [PMID: 34683861 PMCID: PMC8538773 DOI: 10.3390/pharmaceutics13101568] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 09/10/2021] [Accepted: 09/13/2021] [Indexed: 12/13/2022] Open
Abstract
The occurrence of diabetes mellitus (DM) is increasing rapidly at an accelerating rate worldwide. The status of diabetes has changed over the last three generations; whereas before it was deemed a minor disease of older people but currently it is now one of the leading causes of morbidity and mortality among middle-aged and young people. High blood glucose-mediated functional loss, insulin sensitivity, and insulin deficiency lead to chronic disorders such as Type 1 and Type 2 DM. Traditional treatments of DM, such as insulin sensitization and insulin secretion cause undesirable side effects, leading to patient incompliance and lack of treatment. Nanotechnology in diabetes studies has encouraged the development of new modalities for measuring glucose and supplying insulin that hold the potential to improve the quality of life of diabetics. Other therapies, such as β-cells regeneration and gene therapy, in addition to insulin and oral hypoglycemic drugs, are currently used to control diabetes. The present review highlights the nanocarrier-based drug delivery systems and emerging treatment strategies of DM.
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Affiliation(s)
- Vijay Mishra
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara 144411, Punjab, India;
| | - Pallavi Nayak
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara 144411, Punjab, India;
- Faculty of Pharmaceutical Sciences, PCTE Group of Institutes, Ludhiana 142021, Punjab, India
| | - Mayank Sharma
- SVKM’s NMIMS School of Pharmacy & Technology Management, Shirpur 425405, Maharashtra, India;
| | - Aqel Albutti
- Department of Medical Biotechnology, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia
| | - Ameen S. S. Alwashmi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia; (A.S.S.A.); (M.A.A.)
| | - Mohammad Abdullah Aljasir
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia; (A.S.S.A.); (M.A.A.)
| | - Noorah Alsowayeh
- Biology Department, College of Education, Majmaah University, Majmaah 11932, Saudi Arabia;
| | - Murtaza M. Tambuwala
- School of Pharmacy and Pharmaceutical Sciences, Ulster University, Coleraine BT52 1SA, UK;
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Ogasawara H, Inagaki A, Fathi I, Imura T, Yamana H, Saitoh Y, Matsumura M, Fukuoka K, Miyagi S, Nakamura Y, Ohashi K, Unno M, Kamei T, Goto M. Preferable Transplant Site for Hepatocyte Transplantation in a Rat Model. Cell Transplant 2021; 30:9636897211040012. [PMID: 34525872 PMCID: PMC8450989 DOI: 10.1177/09636897211040012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Intraportal injection is regarded as the current standard procedure of hepatocyte transplantation (HTx). In islet transplantation, which shares many aspects with HTx, recent studies have clarified that instant blood-mediated inflammatory reaction (IBMIR), characterized by strong innate immune responses, can cause poor engraftment, so other transplant sites to avoid such a reaction have been established. Although IBMIR was reported to occur in HTx, few reports have evaluated alternative transplant sites for HTx. In this study, we sought to determine the optimum transplant site for HTx. Rat hepatocytes (1.0 × 107) were transplanted at the 9 transplant sites (intraportal (IPO), intrasplenic (IS), liver parenchyma, subcutaneous, intraperitoneal, renal subcapsular, muscle, inguinal subcutaneous white adipose tissue, and omentum) of analbuminemic rats. The serum albumin levels, immunohistochemical staining (albumin, TUNEL, and BrdU), and in vivo imaging of the grafts were evaluated. The serum albumin levels of the IPO group were significantly higher than those of the other groups (p < .0001). The BrdU-positive hepatocyte ratio of liver in the IS group (0.9% ± 0.2%) was comparable to that of the IPO group (0.9% ± 0.3%) and tended to be higher than that of the spleen in the IS group (0.5% ± 0.1%, p = .16). Considering the in vivo imaging evaluation and the influence of splenectomy, the graft function in the IS group may be almost entirely achieved by hepatocytes that have migrated to the liver. The present study clearly showed that the intraportal injection procedure is more efficient than other procedures for performing HTx
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Affiliation(s)
- Hiroyuki Ogasawara
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Akiko Inagaki
- Division of Transplantation and Regenerative Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Ibrahim Fathi
- Division of Transplantation and Regenerative Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takehiro Imura
- Division of Transplantation and Regenerative Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hiroki Yamana
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yoshikatsu Saitoh
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Muneyuki Matsumura
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kengo Fukuoka
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Shigehito Miyagi
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yasuhiro Nakamura
- Division of Pathology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Kazuo Ohashi
- Laboratory of Drug Development and Science, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
| | - Michiaki Unno
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takashi Kamei
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Masafumi Goto
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan.,Division of Transplantation and Regenerative Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
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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: 13] [Impact Index Per Article: 3.3] [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.
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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
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35
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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.
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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.
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36
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Strategies for Vascularizing Pancreatic Islets and Stem Cell–Derived Islet Organoids. CURRENT TRANSPLANTATION REPORTS 2021. [DOI: 10.1007/s40472-021-00334-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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37
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Kharbikar BN, Chendke GS, Desai TA. Modulating the foreign body response of implants for diabetes treatment. Adv Drug Deliv Rev 2021; 174:87-113. [PMID: 33484736 PMCID: PMC8217111 DOI: 10.1016/j.addr.2021.01.011] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 12/30/2020] [Accepted: 01/10/2021] [Indexed: 02/06/2023]
Abstract
Diabetes Mellitus is a group of diseases characterized by high blood glucose levels due to patients' inability to produce sufficient insulin. Current interventions often require implants that can detect and correct high blood glucose levels with minimal patient intervention. However, these implantable technologies have not reached their full potential in vivo due to the foreign body response and subsequent development of fibrosis. Therefore, for long-term function of implants, modulating the initial immune response is crucial in preventing the activation and progression of the immune cascade. This review discusses the different molecular mechanisms and cellular interactions involved in the activation and progression of foreign body response (FBR) and fibrosis, specifically for implants used in diabetes. We also highlight the various strategies and techniques that have been used for immunomodulation and prevention of fibrosis. We investigate how these general strategies have been applied to implants used for the treatment of diabetes, offering insights on how these devices can be further modified to circumvent FBR and fibrosis.
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Affiliation(s)
- Bhushan N Kharbikar
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Gauree S Chendke
- University of California Berkeley - University of California San Francisco Graduate Program in Bioengineering, San Francisco, CA 94143, USA
| | - Tejal A Desai
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA; University of California Berkeley - University of California San Francisco Graduate Program in Bioengineering, San Francisco, CA 94143, USA; Department of Bioengineering, University of California, Berkeley, CA 94720, USA.
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38
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Tissue Engineering Strategies for Improving Beta Cell Transplantation Outcome. CURRENT TRANSPLANTATION REPORTS 2021. [DOI: 10.1007/s40472-021-00333-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Abstract
Purpose of Review
Beta cell replacement therapy as a form of islet transplantation is a promising alternative therapy with the possibility to make selected patients with type 1 diabetes (T1D) insulin independent. However, this technique faces challenges such as extensive activation of the host immune system post-transplantation, lifelong need for immunosuppression, and the scarcity of islet donor pancreas. Advancement in tissue engineering strategies can improve these challenges and allow for a more widespread application of this therapy. This review will discuss the recent development and clinical translation of tissue engineering strategies in beta cell replacement therapy.
Recent Findings
Tissue engineering offers innovative solutions for producing unlimited glucose responsive cells and fabrication of appropriate devices/scaffolds for transplantation applications. Generation of pancreatic organoids with supporting cells in biocompatible biomaterials is a powerful technique to improve the function of insulin-producing cell clusters. Fabrication of physical barriers such as encapsulation strategies can protect the cells from the host immune system and allow for graft retrieval, although this strategy still faces major challenges to fully restore physiological glucose regulation.
Summary
The three main components of tissue engineering strategies including the generation of stem cell-derived insulin-producing cells and organoids and the possibilities for therapeutic delivery of cell-seeded devices to extra-hepatic sites need to come together in order to provide safe and functional insulin-producing devices for clinical beta cell replacement therapy.
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39
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Encapsulation Strategies for Pancreatic Islet Transplantation without Immune Suppression. CURRENT STEM CELL REPORTS 2021. [DOI: 10.1007/s40778-021-00190-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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40
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Migliorini A, Nostro MC, Sneddon JB. Human pluripotent stem cell-derived insulin-producing cells: A regenerative medicine perspective. Cell Metab 2021; 33:721-731. [PMID: 33826915 PMCID: PMC8117263 DOI: 10.1016/j.cmet.2021.03.021] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Tremendous progress has been made over the last two decades in the field of pancreatic beta cell replacement therapy as a curative measure for diabetes. Transplantation studies have demonstrated therapeutic efficacy, and cGMP-grade cell products are currently being deployed for the first time in human clinical trials. In this perspective, we discuss current challenges surrounding the generation, delivery, and engraftment of stem cell-derived islet-like cells, along with strategies to induce durable tolerance to grafted cells, with an eye toward a functional cellular-based therapy enabling insulin independence for patients with diabetes.
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Affiliation(s)
- Adriana Migliorini
- McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada
| | - Maria Cristina Nostro
- McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Toronto General Hospital, Ajmera Transplant Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
| | - Julie B Sneddon
- Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA; Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.
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41
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Ozawa F, Nagata S, Oda H, Yabe SG, Okochi H, Takeuchi S. Lotus-root-shaped cell-encapsulated construct as a retrieval graft for long-term transplantation of human iPSC-derived β-cells. iScience 2021; 24:102309. [PMID: 33997668 PMCID: PMC8101052 DOI: 10.1016/j.isci.2021.102309] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 11/16/2020] [Accepted: 03/11/2021] [Indexed: 11/18/2022] Open
Abstract
Cell therapy using human-stem-cell-derived pancreatic beta cells (hSC-βs) is a potential treatment method for type 1 diabetes mellitus (T1D). For therapeutic safety, hSC-βs need encapsulation in grafts that are scalable and retrievable. In this study, we developed a lotus-root-shaped cell-encapsulated construct (LENCON) as a graft that can be retrieved after long-term hSC-β transplantation. This graft had six multicores encapsulating hSC-βs located within 1 mm from the edge. It controlled the recipient blood glucose levels for a long-term, following transplantation in immunodeficient diabetic mice. LENCON xenotransplanted into immunocompetent mice exhibited retrievability and maintained the functionality of hSC-βs for over 1 year after transplantation. We believe that LENCON can contribute to the treatment of T1D through long-term transplantation of hSC-βs and in many other forms of cell therapy.
A lotus-root-shaped cell-encapsulated construct as a retrieval graft Advantages in terms of FBR mitigation and mechanical strength as a graft Control the recipient blood glucose levels of NOD-Scid mice for up to half a year Retrieval without adhesion over 1 year after transplantation
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Affiliation(s)
- Fumisato Ozawa
- Institute of Industrial Science, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8505, Japan
| | - Shogo Nagata
- Institute of Industrial Science, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8505, Japan
| | - Haruka Oda
- Graduate School of Information Science and Technology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan
| | - Shigeharu G. Yabe
- Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan
| | - Hitoshi Okochi
- Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan
| | - Shoji Takeuchi
- Institute of Industrial Science, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8505, Japan
- Graduate School of Information Science and Technology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan
- Corresponding author
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42
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Huang L, Xiang J, Cheng Y, Xiao L, Wang Q, Zhang Y, Xu T, Chen Q, Xin H, Wang X. Regulation of Blood Glucose Using Islets Encapsulated in a Melanin-Modified Immune-Shielding Hydrogel. ACS APPLIED MATERIALS & INTERFACES 2021; 13:12877-12887. [PMID: 33689267 DOI: 10.1021/acsami.0c23010] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Islet transplantation is currently a promising treatment for type 1 diabetes mellitus. However, the foreign body reaction and retrieval difficulty often lead to transplantation failure and hinder the clinical application. To address these two challenges, we propose a balanced charged sodium alginate-polyethyleneimine-melanin (SA-PEI-Melanin) threadlike hydrogel with immune shielding and retrievable properties. The attractiveness of this study lies in that the introduction of melanin can stimulate insulin secretion, especially under near-infrared (NIR) irradiation. After demonstrating a good immune-shielding effect, we performed an in vivo transplantation experiment. The results showed that the blood glucose level in the SA-PEI-Melanin group was stably controlled below the diabetic blood glucose criterion, and this blood glucose level could be further adjusted after NIR irradiation. In addition, the evaluation after retrieving the SA-PEI-Melanin hydrogel indicated that the islets still maintained a normal physiological function, further proving its excellent immunological protection. This study provides a new approach for the accurate regulation of blood glucose in patients with type 1 diabetes mellitus and contributes to developing a promising transplant system to reconcile real-time and precise light-defined insulin secretion regulation.
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Affiliation(s)
- Ling Huang
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi 330088, P. R. China
| | - Jiajia Xiang
- College of Pharmacy, Nanchang University, Nanchang, Jiangxi 330006, P. R. China
| | - Yukai Cheng
- College of Pharmacy, Nanchang University, Nanchang, Jiangxi 330006, P. R. China
| | - Ling Xiao
- College of Pharmacy, Nanchang University, Nanchang, Jiangxi 330006, P. R. China
| | - Qingqing Wang
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi 330088, P. R. China
| | - Yini Zhang
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi 330088, P. R. China
| | - Tieling Xu
- College of Pharmacy, Nanchang University, Nanchang, Jiangxi 330006, P. R. China
| | - Qianrui Chen
- College of Pharmacy, Nanchang University, Nanchang, Jiangxi 330006, P. R. China
| | - Hongbo Xin
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi 330088, P. R. China
| | - Xiaolei Wang
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi 330088, P. R. China
- College of Chemistry, Nanchang University, Nanchang, Jiangxi 330088, P. R. China
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Hladíková Z, Voglová B, Pátíková A, Berková Z, Kříž J, Vojtíšková A, Leontovyč I, Jirák D, Saudek F. Bioluminescence Imaging In Vivo Confirms the Viability of Pancreatic Islets Transplanted into the Greater Omentum. Mol Imaging Biol 2021; 23:639-649. [PMID: 33599904 DOI: 10.1007/s11307-021-01588-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Revised: 02/01/2021] [Accepted: 02/02/2021] [Indexed: 01/28/2023]
Abstract
PURPOSE The liver is the most widely used site for pancreatic islet transplantation. However, several site-specific limitations impair functional success, with instant blood-mediated inflammatory reaction being the most important. The aim of this study was to develop a preclinical model for placement of the islet graft into a highly vascularized omental flap using a fibrin gel. For this purpose, we tested islet viability by bioluminescence imaging (BLI). PROCEDURES Pancreatic islets were isolated from luciferase-positive and luciferase-negative rats, mixed at a 1:1 ratio, placed into a plasma-thrombin bioscaffold, and transplanted in standard (10 pancreatic islets/g wt; n = 10) and marginal (4 pancreatic islets/g wt; n = 7) numbers into the omentums of syngeneic diabetic animals. For the control, 4 pancreatic islets/g were transplanted into the liver using the standard procedure (n = 7). Graft viability was tested by bioluminescence at days 14, 30, 60, and 90 post transplant. Glucose levels, intravenous glucose tolerance, and serum C-peptide were assessed regularly. RESULTS Nonfasting glucose levels < 10 mmol/l were restored in all animals. While islet viability in the omentum was clearly detected by stable luminescence signals throughout the whole study period, no signals were detected from islets transplanted into the liver. The bioluminescence signals were highly correlated with stimulated C-peptide levels detected at 80 days post transplant. Glucose tolerance did not differ among the 3 groups. CONCLUSIONS We successfully tested a preclinical model of islet transplantation into the greater omentum using a biocompatible scaffold made from autologous plasma and human thrombin. Both standard and marginal pancreatic islet numbers in a gel-form bioscaffold placed in the omentum restored glucose homeostasis in recipients with diabetes. Bioluminescence was shown promising as a direct proof of islet viability.
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Affiliation(s)
- Zuzana Hladíková
- Diabetes Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.,First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Barbora Voglová
- Diabetes Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.,First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Alžběta Pátíková
- First Faculty of Medicine, Charles University, Prague, Czech Republic.,Laboratory of Pancreatic Islets, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Zuzana Berková
- Laboratory of Pancreatic Islets, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Jan Kříž
- Diabetes Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.,First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Alžběta Vojtíšková
- First Faculty of Medicine, Charles University, Prague, Czech Republic.,Laboratory of Pancreatic Islets, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Ivan Leontovyč
- Laboratory of Pancreatic Islets, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Daniel Jirák
- MR Unit, Department of Radiodiagnostic and Interventional Radiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - František Saudek
- Diabetes Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic. .,First Faculty of Medicine, Charles University, Prague, Czech Republic.
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Primavera R, Razavi M, Kevadiya BD, Wang J, Vykunta A, Di Mascolo D, Decuzzi P, Thakor AS. Enhancing islet transplantation using a biocompatible collagen-PDMS bioscaffold enriched with dexamethasone-microplates. Biofabrication 2021; 13. [PMID: 33455953 DOI: 10.1088/1758-5090/abdcac] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 01/15/2021] [Indexed: 01/01/2023]
Abstract
Islet transplantation is a promising approach to enable type 1 diabetic patients to attain glycemic control independent of insulin injections. However, up to 60% of islets are lost immediately following transplantation. To improve this outcome, islets can be transplanted within bioscaffolds, however, synthetic bioscaffolds induce an intense inflammatory reaction which can have detrimental effects on islet function and survival. In the present study, we first improved the biocompatibility of polydimethylsiloxane (PDMS) bioscaffolds by coating them with collagen. To reduce the inflammatory response to PDMS bioscaffolds, we then enriched the bioscaffolds with dexamethasone-loaded microplates (DEX-µScaffolds). These DEX-microplates have the ability to release DEX in a sustained manner over 7 weeks within a therapeutic range that does not affect the glucose responsiveness of the islets but which minimizes inflammation in the surrounding microenvironment. The bioscaffold showed excellent mechanical properties that enabled it to resist pore collapse thereby helping to facilitate islet seeding and its handling for implantation, and subsequent engraftment, within the epididymal fat pad (EFP). Following the transplantation of islets into the EFP of diabetic mice using DEX-µScaffolds there was a return in basal blood glucose to normal values by day 4, with normoglycemia maintained for 30 days. Furthermore, these animals demonstrated a normal dynamic response to glucose challenges with histological evidence showing reduced pro-inflammatory cytokines and fibrotic tissue surrounding DEX-µScaffolds at the transplantation site. In contrast, diabetic animals transplanted with either islets alone or islets in bioscaffolds without DEX microplates were not able to regain glycemic control during basal conditions with overall poor islet function. Taken together, our data show that coating PDMS bioscaffolds with collagen, and enriching them with DEX-microplates, significantly prolongs and enhances islet function and survival.
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Affiliation(s)
- Rosita Primavera
- Radiology, Stanford University School of Medicine, 3155 Porter Drive, Stanford, California, 94305-5119, UNITED STATES
| | - Mehdi Razavi
- University of Central Florida, 6900 Lake Nona Blvd, Orlando, Florida, 32827, UNITED STATES
| | - Bhavesh D Kevadiya
- PEN, University of Nebraska Medical Center, Lab-3064,DRC-1,department of pharmacology and experimental neuroscience, Omaha, Nebraska, 68198, UNITED STATES
| | - Jing Wang
- Radiology, Stanford University School of Medicine, 3155 Porter Drive, Stanford, California, 94304, UNITED STATES
| | - Akshara Vykunta
- Radiology, Stanford University School of Medicine, 3155 Porter Drive, Stanford, California, 94304, UNITED STATES
| | - Daniele Di Mascolo
- Central Research Labs Genova, Istituto Italiano di Tecnologia, Via Morego, 30, Genova, Liguria, 16163, ITALY
| | - Paolo Decuzzi
- Istituto Italiano di Tecnologia, Via Morego, 30, Genova, Liguria, 16163, ITALY
| | - Avnesh S Thakor
- Radiology, Stanford University School of Medicine, 3155 Porter Drive, Stanford, California, 94304, UNITED STATES
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45
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Rao P, Deo D, Marchioni M. Differentiation of Human Deceased Donor, Adipose-Derived, Mesenchymal Stem Cells into Functional Beta Cells. J Stem Cells Regen Med 2021; 16:63-72. [PMID: 33414582 DOI: 10.46582/jsrm.1602010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Accepted: 10/14/2020] [Indexed: 12/25/2022]
Abstract
There is an emerging need for the rapid generation of functional beta cells that can be used in cell replacement therapy for the treatment of type 1 diabetes (T1D). Differentiation of stem cells into insulin-producing cells provides a promising strategy to restore pancreatic endocrine function. Stem cells can be isolated from various human tissues including adipose tissue (AT). Our study outlines a novel, non-enzymatic process to harvest mesenchymal stem cells (MSC) from research-consented, deceased donor AT. Following their expansion, MSC were characterised morphologically and phenotypically by flow cytometry to establish their use for downstream differentiation studies. MSC were induced to differentiate into insulin-producing beta cells using a step-wise differentiation medium. The differentiation was evaluated by analysing the morphology, dithizone staining, immunocytochemistry, and expression of pancreatic beta cell marker genes. We stimulated the beta cells with different concentrations of glucose and observed a dose-dependent increase in gene expression. In addition, an increase in insulin and c-Peptide secretion as a function of glucose challenge confirmed the functionality of the differentiated beta cells. The differentiation of adipose-derived MSC into beta cells has been well established. However, our data demonstrates, for the first time, that the ready availability and properties of MSC isolated from deceased donor adipose tissue render them well-suited as a source for increased production of functional beta cells. Consequently, these cells can be a promising therapeutic approach for cell replacement therapy to treat patients with T1D.
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Affiliation(s)
- Prakash Rao
- Personalized Transplant Medicine Institute at NJ Sharing Network, New Providence, NJ, USA
| | - Dayanand Deo
- Personalized Transplant Medicine Institute at NJ Sharing Network, New Providence, NJ, USA
| | - Misty Marchioni
- Personalized Transplant Medicine Institute at NJ Sharing Network, New Providence, NJ, USA
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46
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Cayabyab F, Nih LR, Yoshihara E. Advances in Pancreatic Islet Transplantation Sites for the Treatment of Diabetes. Front Endocrinol (Lausanne) 2021; 12:732431. [PMID: 34589059 PMCID: PMC8473744 DOI: 10.3389/fendo.2021.732431] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 08/13/2021] [Indexed: 01/08/2023] Open
Abstract
Diabetes is a complex disease that affects over 400 million people worldwide. The life-long insulin injections and continuous blood glucose monitoring required in type 1 diabetes (T1D) represent a tremendous clinical and economic burdens that urges the need for a medical solution. Pancreatic islet transplantation holds great promise in the treatment of T1D; however, the difficulty in regulating post-transplantation immune reactions to avoid both allogenic and autoimmune graft rejection represent a bottleneck in the field of islet transplantation. Cell replacement strategies have been performed in hepatic, intramuscular, omentum, and subcutaneous sites, and have been performed in both animal models and human patients. However more optimal transplantation sites and methods of improving islet graft survival are needed to successfully translate these studies to a clinical relevant therapy. In this review, we summarize the current progress in the field as well as methods and sites of islet transplantation, including stem cell-derived functional human islets. We also discuss the contribution of immune cells, vessel formation, extracellular matrix, and nutritional supply on islet graft survival. Developing new transplantation sites with emerging technologies to improve islet graft survival and simplify immune regulation will greatly benefit the future success of islet cell therapy in the treatment of diabetes.
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Affiliation(s)
- Fritz Cayabyab
- Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, United States
| | - Lina R. Nih
- Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, United States
- David Geffen School of Medicine at University of California, Los Angeles, CA, United States
| | - Eiji Yoshihara
- Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, United States
- David Geffen School of Medicine at University of California, Los Angeles, CA, United States
- *Correspondence: Eiji Yoshihara,
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47
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Han EX, Wang J, Kural M, Jiang B, Leiby KL, Chowdhury N, Tellides G, Kibbey RG, Lawson JH, Niklason LE. Development of a Bioartificial Vascular Pancreas. J Tissue Eng 2021; 12:20417314211027714. [PMID: 34262686 PMCID: PMC8243137 DOI: 10.1177/20417314211027714] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Accepted: 06/08/2021] [Indexed: 12/16/2022] Open
Abstract
Transplantation of pancreatic islets has been shown to be effective, in some patients, for the long-term treatment of type 1 diabetes. However, transplantation of islets into either the portal vein or the subcutaneous space can be limited by insufficient oxygen transfer, leading to islet loss. Furthermore, oxygen diffusion limitations can be magnified when islet numbers are increased dramatically, as in translating from rodent studies to human-scale treatments. To address these limitations, an islet transplantation approach using an acellular vascular graft as a vascular scaffold has been developed, termed the BioVascular Pancreas (BVP). To create the BVP, islets are seeded as an outer coating on the surface of an acellular vascular graft, using fibrin as a hydrogel carrier. The BVP can then be anastomosed as an arterial (or arteriovenous) graft, which allows fully oxygenated arterial blood with a pO2 of roughly 100 mmHg to flow through the graft lumen and thereby supply oxygen to the islets. In silico simulations and in vitro bioreactor experiments show that the BVP design provides adequate survivability for islets and helps avoid islet hypoxia. When implanted as end-to-end abdominal aorta grafts in nude rats, BVPs were able to restore near-normoglycemia durably for 90 days and developed robust microvascular infiltration from the host. Furthermore, pilot implantations in pigs were performed, which demonstrated the scalability of the technology. Given the potential benefits provided by the BVP, this tissue design may eventually serve as a solution for transplantation of pancreatic islets to treat or cure type 1 diabetes.
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Affiliation(s)
- Edward X Han
- Department of Biomedical Engineering,
Yale School of Engineering and Applied Science, New Haven, CT, USA
| | - Juan Wang
- Vascular Biology and Therapeutics
Program, Yale School of Medicine, New Haven, CT, USA
- Department of Anesthesiology, Yale
School of Medicine, New Haven, CT, USA
| | - Mehmet Kural
- Vascular Biology and Therapeutics
Program, Yale School of Medicine, New Haven, CT, USA
- Department of Anesthesiology, Yale
School of Medicine, New Haven, CT, USA
| | - Bo Jiang
- Department of Surgery, Yale School of
Medicine, New Haven, CT, USA
- Department of Vascular Surgery, The
First Hospital of China Medical University, Shenyang, China
| | - Katherine L Leiby
- Department of Biomedical Engineering,
Yale School of Engineering and Applied Science, New Haven, CT, USA
| | - Nazar Chowdhury
- Molecular, Cellular, and Developmental
Biology, Yale University, New Haven, CT, USA
| | - George Tellides
- Vascular Biology and Therapeutics
Program, Yale School of Medicine, New Haven, CT, USA
- Department of Surgery, Yale School of
Medicine, New Haven, CT, USA
- Veterans Affairs Connecticut Healthcare
System, West Haven, CT, USA
| | - Richard G Kibbey
- Department of Internal Medicine
(Endocrinology), Yale University, New Haven, CT, USA
- Department of Cellular & Molecular
Physiology, Yale School of Medicine, New Haven, CT, USA
| | - Jeffrey H Lawson
- Department of Surgery, Duke
University, Durham, NC, USA
- Humacyte Inc., Durham, NC, USA
| | - Laura E Niklason
- Department of Biomedical Engineering,
Yale School of Engineering and Applied Science, New Haven, CT, USA
- Vascular Biology and Therapeutics
Program, Yale School of Medicine, New Haven, CT, USA
- Department of Anesthesiology, Yale
School of Medicine, New Haven, CT, USA
- Humacyte Inc., Durham, NC, USA
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48
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Fuchs S, Ernst AU, Wang LH, Shariati K, Wang X, Liu Q, Ma M. Hydrogels in Emerging Technologies for Type 1 Diabetes. Chem Rev 2020; 121:11458-11526. [DOI: 10.1021/acs.chemrev.0c01062] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Stephanie Fuchs
- Biological and Environmental Engineering, Cornell University, Ithaca, New York 14853, United States
| | - Alexander U. Ernst
- Biological and Environmental Engineering, Cornell University, Ithaca, New York 14853, United States
| | - Long-Hai Wang
- Biological and Environmental Engineering, Cornell University, Ithaca, New York 14853, United States
| | - Kaavian Shariati
- Biological and Environmental Engineering, Cornell University, Ithaca, New York 14853, United States
| | - Xi Wang
- Biological and Environmental Engineering, Cornell University, Ithaca, New York 14853, United States
| | - Qingsheng Liu
- Biological and Environmental Engineering, Cornell University, Ithaca, New York 14853, United States
| | - Minglin Ma
- Biological and Environmental Engineering, Cornell University, Ithaca, New York 14853, United States
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Ghoneim MA, Refaie AF, Elbassiouny BL, Gabr MM, Zakaria MM. From Mesenchymal Stromal/Stem Cells to Insulin-Producing Cells: Progress and Challenges. Stem Cell Rev Rep 2020; 16:1156-1172. [PMID: 32880857 PMCID: PMC7667138 DOI: 10.1007/s12015-020-10036-3] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Mesenchymal stromal cells (MSCs) are an attractive option for cell therapy for type 1 diabetes mellitus (DM). These cells can be obtained from many sources, but bone marrow and adipose tissue are the most studied. MSCs have distinct advantages since they are nonteratogenic, nonimmunogenic and have immunomodulatory functions. Insulin-producing cells (IPCs) can be generated from MSCs by gene transfection, gene editing or directed differentiation. For directed differentiation, MSCs are usually cultured in a glucose-rich medium with various growth and activation factors. The resulting IPCs can control chemically-induced diabetes in immune-deficient mice. These findings are comparable to those obtained from pluripotent cells. PD-L1 and PD-L2 expression by MSCs is upregulated under inflammatory conditions. Immunomodulation occurs due to the interaction between these ligands and PD-1 receptors on T lymphocytes. If this function is maintained after differentiation, life-long immunosuppression or encapsulation could be avoided. In the clinical setting, two sites can be used for transplantation of IPCs: the subcutaneous tissue and the omentum. A 2-stage procedure is required for the former and a laparoscopic procedure for the latter. For either site, cells should be transplanted within a scaffold, preferably one from fibrin. Several questions remain unanswered. Will the transplanted cells be affected by the antibodies involved in the pathogenesis of type 1 DM? What is the functional longevity of these cells following their transplantation? These issues have to be addressed before clinical translation is attempted. Graphical Abstract Bone marrow MSCs are isolated from the long bone of SD rats. Then they are expanded and through directed differentiation insulin-producing cells are formed. The differentiated cells are loaded onto a collagen scaffold. If one-stage transplantation is planned, a drug delivery system must be incorporated to ensure immediate oxygenation, promote vascularization and provide some growth factors. Some mechanisms involved in the immunomodulatory function of MSCs. These are implemented either by cell to cell contact or by the release of soluble factors. Collectively, these pathways results in an increase in T-regulatory cells.
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50
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Lopez-Mendez TB, Santos-Vizcaino E, Pedraz JL, Hernandez RM, Orive G. Cell microencapsulation technologies for sustained drug delivery: Clinical trials and companies. Drug Discov Today 2020; 26:852-861. [PMID: 33242694 DOI: 10.1016/j.drudis.2020.11.019] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 11/03/2020] [Accepted: 11/16/2020] [Indexed: 12/11/2022]
Abstract
In recent years, cell microencapsulation technology has advanced, mainly driven by recent developments in the use of stem cells or the optimization of biomaterials. Old challenges have been addressed from new perspectives, and systems developed and improved for decades are now being transferred to the market by novel start-ups and consolidated companies. These products are mainly intended for the treatment of diabetes mellitus (DM), but also cancer, central nervous system (CNS) disorders or lysosomal diseases, among others. In this review, we analyze the results obtained in clinical trials to date and define the global key players that will lead the cell microencapsulation market to bring this technology to the clinic in the future.
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Affiliation(s)
- Tania B Lopez-Mendez
- NanoBioCel Research Group, School of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz, Spain; Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III, Madrid, Spain
| | - Edorta Santos-Vizcaino
- NanoBioCel Research Group, School of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz, Spain; Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III, Madrid, Spain; Bioaraba, NanoBioCel Research Group, Vitoria-Gasteiz, Spain
| | - Jose Luis Pedraz
- NanoBioCel Research Group, School of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz, Spain; Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III, Madrid, Spain; Bioaraba, NanoBioCel Research Group, Vitoria-Gasteiz, Spain
| | - Rosa Maria Hernandez
- NanoBioCel Research Group, School of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz, Spain; Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III, Madrid, Spain; Bioaraba, NanoBioCel Research Group, Vitoria-Gasteiz, Spain.
| | - Gorka Orive
- NanoBioCel Research Group, School of Pharmacy, University of the Basque Country (UPV/EHU), Vitoria-Gasteiz, Spain; Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III, Madrid, Spain; Bioaraba, NanoBioCel Research Group, Vitoria-Gasteiz, Spain; University Institute for Regenerative Medicine and Oral Implantology - UIRMI (UPV/EHU-Fundación Eduardo Anitua); BTI Biotechnology Institute, Vitoria-Gasteiz, Spain; Singapore Eye Research Institute, The Academia, 20 College Road, Discovery Tower, Singapore.
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