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Gabriel Silvério Scholl V, Todeschini Justus L, Girotto OS, Karine Pasqual K, Garcia MHH, da Silva Petronio FG, de Moraes AF, Maria Barbalho S, Araújo AC, Fornari Laurindo L, Camargo CP, Miglino MA. Assessing Implantation Sites for Pancreatic Islet Cell Transplantation: Implications for Type 1 Diabetes Mellitus Treatment. Bioengineering (Basel) 2025; 12:499. [PMID: 40428118 DOI: 10.3390/bioengineering12050499] [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: 03/28/2025] [Revised: 04/24/2025] [Accepted: 04/28/2025] [Indexed: 05/29/2025] Open
Abstract
Type 1 diabetes mellitus (T1DM) involves the destruction of pancreatic β-cells, requiring ongoing insulin therapy. A promising alternative for management is pancreatic islet transplantation, or the bioartificial pancreas. Here, we examine the primary implantation sites for the bioartificial pancreas, highlighting their anatomical, physical, and immunological characteristics in the context of T1DM treatment. Traditionally used for islet transplantation, the liver promotes metabolic efficiency due to portal drainage; however, it presents issues such as hypoxia and inflammatory responses. The omentum offers excellent vascularization but has limited capacity for subsequent transplants. The renal subcapsular space is advantageous when combined with kidney transplants; however, its use is limited due to low vascularization. The subcutaneous space is notable for its accessibility and lower invasiveness, although its poor vascularization poses significant challenges. These challenges can be mitigated with bioengineering strategies. The gastrointestinal submucosa provides easy access and good vascularization, which makes it a promising option for endoscopic approaches. Additionally, the intrapleural space, which remains underexplored, offers benefits such as increased oxygenation and reduced inflammatory response. Selecting the ideal site for bioartificial pancreas implantation should balance graft support, complication reduction, and surgical accessibility. Bioengineered devices and scaffolds can address the limitations of traditional sites and enhance T1DM management.
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Affiliation(s)
- Vinícius Gabriel Silvério Scholl
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
| | - Leonardo Todeschini Justus
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
| | - Otávio Simões Girotto
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
| | - Kelly Karine Pasqual
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
| | - Matheus Henrique Herminio Garcia
- Postgraduate Program in Animal Health, Production and Environment, School of Veterinary Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
| | | | - Aline Flores de Moraes
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
| | - Sandra Maria Barbalho
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
- Department of Biochemistry and Nutrition, School of Food and Technology of Marília (FATEC), Marília 17500-000, SP, Brazil
| | - Adriano Cressoni Araújo
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
| | - Lucas Fornari Laurindo
- Department of Biochemistry and Pharmacology, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
| | - Cristina Pires Camargo
- Microsurgery and Plastic Surgery Laboratory (LIM-04), Faculdade de Medicina, Universidade de São Paulo, São Paulo 05508-220, SP, Brazil
| | - Maria Angélica Miglino
- Postgraduate Program in Animal Health, Production and Environment, School of Veterinary Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, School of Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
- Department of Animal Anatomy, School of Veterinary Medicine, Universidade de Marília (UNIMAR), Marília 17525-902, SP, Brazil
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Kieffer TJ, Hoesli CA, Shapiro AMJ. Advances in Islet Transplantation and the Future of Stem Cell-Derived Islets to Treat Diabetes. Cold Spring Harb Perspect Med 2025; 15:a041624. [PMID: 39074874 PMCID: PMC12047745 DOI: 10.1101/cshperspect.a041624] [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: 07/31/2024]
Abstract
β-Cell replacement for type 1 diabetes (T1D) can restore normal glucose homeostasis, thereby eliminating the need for exogenous insulin and halting the progression of diabetes complications. Success in achieving insulin independence following transplantation of cadaveric islets fueled academic and industry efforts to develop techniques to mass produce β cells from human pluripotent stem cells, and these have now been clinically validated as an alternative source of regulated insulin production. Various encapsulation strategies are being pursued to contain implanted cells in a retrievable format, and different implant sites are being explored with some strategies reaching clinical studies. Stem cell lines, whether derived from embryonic sources or reprogrammed somatic cells, are being genetically modified for designer features, including immune evasiveness to enable implant without the use of chronic immunosuppression. Although hurdles remain in optimizing large-scale manufacturing, demonstrating efficacy, durability, and safety, products containing stem cell-derived β cells promise to provide a potent treatment for insulin-dependent diabetes.
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Affiliation(s)
- Timothy J Kieffer
- Department of Cellular and Physiological Sciences, Life Sciences Institute, School of Biomedical Engineering
- Department of Surgery, The University of British Columbia, Vancouver V6T1Z3, British Columbia, Canada
| | - Corinne A Hoesli
- Department of Chemical Engineering, Department of Biomedical Engineering, McGill University, Montreal H3A 0C5, Québec, Canada
- Associate Member, Department of Biomedical Engineering, McGill University, Montreal H3A 0C5, Québec, Canada
| | - A M James Shapiro
- Clinical Islet Transplant Program, University of Alberta, Edmonton T6G2E1, Alberta, Canada
- Department of Surgery, University of Alberta, Edmonton T6G2E1, Alberta, Canada
- Alberta Diabetes Institute, University of Alberta, Edmonton T6G2E1, Alberta, Canada
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Fujikura J, Anazawa T, Toyoda T, Ito R, Kimura Y, Yabe D. Toward a cure for diabetes: iPSC and ESC-derived islet cell transplantation trials. J Diabetes Investig 2025; 16:384-388. [PMID: 39575893 PMCID: PMC11871380 DOI: 10.1111/jdi.14366] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 11/08/2024] [Accepted: 11/10/2024] [Indexed: 03/03/2025] Open
Abstract
Advancements in regenerative medicine, particularly through the use of induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs), are garnering substantial attention as potential solutions to the limited availability of donors, leading to prolonged waiting periods for people with type 1 diabetes who require transplantation of pancreatic islets from deceased donors. The promising outcomes from recent clinical trials suggest that transplantation of iPSC- or ESC-derived islet cells could pave the way for more effective and broadly accessible treatment options. This progress holds potential not only for individuals with type 1 diabetes but may also extend to type 2 diabetes treatment in the future.
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Affiliation(s)
- Junji Fujikura
- Department of Diabetes, Endocrinology and NutritionKyoto University Graduate School of MedicineKyotoJapan
| | - Takayuki Anazawa
- Division of Hepato‐Biliary‐Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Taro Toyoda
- Department of Life Science Frontiers, Center for iPS Cell Research and ApplicationKyoto UniversityKyotoJapan
| | - Ryo Ito
- Orizuru Therapeutics, Inc.FujisawaKanagawaJapan
| | - Yasuko Kimura
- Institute for Advancement of Clinical and Translational ScienceKyoto University HospitalKyotoJapan
| | - Daisuke Yabe
- Department of Diabetes, Endocrinology and NutritionKyoto University Graduate School of MedicineKyotoJapan
- Yutaka Seino Distinguished Center for Diabetes ResearchKansai Electric Power Medical Research InstituteKyotoJapan
- Center for One Medicine Innovative Translational ResearchGifu University Institute for Advanced StudiesGifuJapan
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Li S, Zhou Y, Kong D, Miao Y, Guan N, Gao G, Jin J, Ye H. A visually-induced optogenetically-engineered system enables autonomous glucose homeostasis in mice. J Control Release 2025; 378:27-37. [PMID: 39645086 DOI: 10.1016/j.jconrel.2024.12.006] [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: 08/20/2024] [Revised: 12/02/2024] [Accepted: 12/03/2024] [Indexed: 12/09/2024]
Abstract
With the global population increasing and the demographic shifting toward an aging society, the number of patients diagnosed with conditions such as peripheral neuropathies resulting from diabetes is expected to rise significantly. This growing health burden has emphasized the need for innovative solutions, such as brain-computer interfaces. brain-computer interfaces, a multidisciplinary field that integrates neuroscience, engineering, and computer science, enable direct communication between the human brain and external devices. In this study, we developed an autonomous diabetes therapeutic system that employs visually-induced electroencephalography devices to capture and decode event-related potentials using machine learning techniques. We present the visually-induced optogenetically-engineered system for therapeutic expression regulation (VISITER), which generates diverse output commands to control illumination durations. This system regulates insulin expression through optogenetically-engineered cells, achieving blood glucose homeostasis in mice. Our results demonstrate that VISITER effectively and precisely modulates therapeutic protein expression in mammalian cells, facilitating the rapid restoration of blood glucose homeostasis in diabetic mice. These findings underscore the potential for diabetic patients to manage insulin levels autonomously by focusing on target images, paving the way for a more self-directed approach to blood glucose control.
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Affiliation(s)
- Shurui Li
- School of Mathematics, East China University of Science and Technology, Shanghai 200237, China
| | - Yang Zhou
- Synthetic Biology and Biomedical Engineering Laboratory, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China; Wuhu Hospital, Health Science Center, East China Normal University, Anhui 241001, China
| | - Deqiang Kong
- Synthetic Biology and Biomedical Engineering Laboratory, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Yangyang Miao
- School of Electrical Engineering and Automation, Nantong University, Jiangsu 226019, China
| | - Ningzi Guan
- Synthetic Biology and Biomedical Engineering Laboratory, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Ganglong Gao
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
| | - Jing Jin
- School of Mathematics, East China University of Science and Technology, Shanghai 200237, China; Key Laboratory of Smart Manufacturing in Energy Chemical Process, Ministry of Education, East China University of Science and Technology, Shanghai 200237, China.
| | - Haifeng Ye
- Synthetic Biology and Biomedical Engineering Laboratory, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China; Wuhu Hospital, Health Science Center, East China Normal University, Anhui 241001, China.
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Canavesi I, Viswakarma N, Epel B, Kotecha M. In Vivo Mouse Abdominal Oxygen Imaging And Assessment of Subcutaneously Implanted Beta Cell Replacement Devices. Mol Imaging Biol 2025; 27:64-77. [PMID: 39633071 DOI: 10.1007/s11307-024-01963-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 09/19/2024] [Accepted: 11/04/2024] [Indexed: 12/07/2024]
Abstract
PURPOSE Type 1 diabetes (T1D) is an autoimmune disease that leads to the loss of insulin-producing pancreatic beta cells. Beta cell replacement devices or bioartificial pancreas (BAP) have shown promise in curing T1D and providing long-term insulin independence without the need for immunosuppressants. Hypoxia in BAP devices damages cells and imposes limitations on device dimensions. Noninvasive in vivo oxygen imaging assessment of implanted BAP devices will provide the necessary feedback and improve the chances of success. Pulse-mode electron paramagnetic resonance (EPR) oxygen imaging (EPROI) using injectable trityl OX071 as the oxygen-sensitive agent is an excellent technique for obtaining partial oxygen pressure (pO2) maps in vitro and in vivo. In this study, our goal was to optimize in vivo mouse abdominal EPROI and demonstrate proof-of-concept pO2 imaging of subcutaneously implanted BAP devices. METHODS All EPROI experiments were performed using a 25 mT EPROI instrument, JIVA-25®. For in vivo EPROI experiments, trityl OX071, a whole-body mouse resonator (∅32 mm × 35 mm), C57BL6 mice, and the inversion recovery electron spin echo (IRESE) pulse sequence were utilized. We investigated the signal amplitude and pO2 in mouse abdomen region for intravenous (i.v.) and intraperitoneal (i.p.) injection methods with either only a single bolus (B) or bolus plus infusion (BI) for 72.2 mM OX071 and the effect of OX071 concentrations from 18 to 72.2 mM for the i.p.-B injection method. We also investigated the impact of animal respiratory rate on mouse abdominal pO2. Finally, we performed proof-of-concept pO2 imaging of two subcutaneously implanted BAP devices, OxySite and TheraCyte. At the end of the four-week study, the TheraCyte devices were extracted and analyzed for fibrosis, vascular differentiation, and immune cell infiltration. RESULTS We established that mouse abdominal pO2 remains stable irrespective of trityl injection methods, concentrations, imaging time, or animal breathing rate. We demonstrate that the i.p.-B and i.p.-BI methods are suitable for EPROI, and i.p.-B method provides higher signal amplitude compared to i.v.-BI and up to 75 min of imaging. An injection with a reduced trityl concentration and higher volume provides higher signal amplitude for i.p.-B method at the beginning. We also highlight the advantage of milder anesthesia for consistent, reliable mouse pO2 imaging. Finally, we demonstrate that EPROI could provide longitudinal noninvasive oxygen assessment of subcutaneously implanted BAP devices in vivo. CONCLUSIONS In vivo EPROI is a reliable technique for mouse abdominal oxygen imaging and longitudinal assessment of subcutaneously implanted BAP devices noninvasively. This work reports abdominal oxygen imaging in the mouse model and demonstrates its application for the assessment of BAP devices. Even though the application focus of this work was on cell therapy, the techniques developed will have a much broader use in the biomedical field.
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Affiliation(s)
- Irene Canavesi
- Oxygen Measurement Core, O2M Technologies, Chicago, IL, 60612, USA
| | - Navin Viswakarma
- Oxygen Measurement Core, O2M Technologies, Chicago, IL, 60612, USA
| | - Boris Epel
- Oxygen Measurement Core, O2M Technologies, Chicago, IL, 60612, USA
- Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL, 60637, USA
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Altshuler PJ, Bodzin AS, Andreoni KA, Singh P, Yadav A, Glorioso JM, Shah AP, Ramirez CGB, Maley WR, Frank AM. Deceased Donor Renal Allograft Utility in Adult Single and Multi-organ Transplantation in the United States. Transplant Direct 2025; 11:e1744. [PMID: 39703726 PMCID: PMC11658743 DOI: 10.1097/txd.0000000000001744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 10/28/2024] [Accepted: 10/29/2024] [Indexed: 12/21/2024] Open
Abstract
Background Deceased donor multiorgan transplants utilizing kidneys (MOTs) can improve outcomes for multiorgan recipients but reduces kidneys for chronic renal failure patients. Methods We reviewed the Organ Procurement and Transplantation Network database from 2015 through 2019, for adult deceased donor kidney transplants. Recipients were classified as kidney transplant alone (KTA) (n = 62,252) or MOTs pancreas-kidney, simultaneous pancreas-kidney (n = 3,976), liver-kidney, simultaneous liver-kidney (n = 3,212), heart-kidney, simultaneous heart-kidney (n = 808), and "other"-kidney, simultaneous "other" kidney (n = 73). Results Liver, heart, and lung-alone transplants were at least 7 times more frequent than their MOT correlate, whereas the inverse was true with pancreas transplantation with SPKs being by far the most common pancreas transplant type. On average, KTA recipients waited between 2.8 and 21.4 times longer than MOTs, with SPKs waiting the longest of the MOT types. Predialysis initiation transplants were less frequent in KTAs compared with MOTs. Use of high-quality grafts according to Kidney Donor Profile Index < 35% was frequent among MOTs, but uncommon in KTAs who had an Estimated Post Transplant Survival score (EPTS) of >20%. For recipients older than 65, SPKs and SOKs were rare, but SLKs and SHKs had a higher fraction of recipients than KTAs and were much more likely to use a Kidney Donor Profile Index <35% kidney. SPKs and KTAs with an EPTS ≤20% had the best kidney graft survival. KTAs with an EPTS ≤80% had better kidney graft survival than SLKs, SHKs, and SOKs. Conclusions This study highlights disparities in access to deceased donor kidneys for kidney-alone candidates versus MOTs and suggests opportunities to improve allocation.
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Affiliation(s)
- Peter J. Altshuler
- Department of Surgery, Division of Transplant Surgery, University of California San Francisco, San Francisco, CA
| | - Adam S. Bodzin
- Department of Surgery, Division of Transplantation, Thomas Jefferson University Hospital, Philadelphia, PA
| | - Kenneth A. Andreoni
- Department of Surgery, Division of Transplantation, Thomas Jefferson University Hospital, Philadelphia, PA
| | - Pooja Singh
- Department of Medicine, Division of Nephrology, Thomas Jefferson University Hospital, Philadelphia, PA
| | - Anju Yadav
- Department of Medicine, Division of Nephrology, Thomas Jefferson University Hospital, Philadelphia, PA
| | - Jaime M. Glorioso
- Department of Surgery, Division of Transplantation, Thomas Jefferson University Hospital, Philadelphia, PA
| | - Ashesh P. Shah
- Department of Surgery, Division of Transplantation, Thomas Jefferson University Hospital, Philadelphia, PA
| | - Carlo Gerado B. Ramirez
- Department of Surgery, Division of Transplantation, Thomas Jefferson University Hospital, Philadelphia, PA
| | - Warren R. Maley
- Department of Surgery, Division of Transplantation, Thomas Jefferson University Hospital, Philadelphia, PA
| | - Adam M. Frank
- Department of Surgery, Division of Transplantation, Thomas Jefferson University Hospital, Philadelphia, PA
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Moeun BN, Lemaire F, Smink AM, Ebrahimi Orimi H, Leask RL, de Vos P, Hoesli CA. Oxygenation and function of endocrine bioartificial pancreatic tissue constructs under flow for preclinical optimization. J Tissue Eng 2025; 16:20417314241284826. [PMID: 39866963 PMCID: PMC11758540 DOI: 10.1177/20417314241284826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Accepted: 09/02/2024] [Indexed: 01/28/2025] Open
Abstract
Islet transplantation and more recently stem cell-derived islets were shown to successfully re-establish glycemic control in people with type 1 diabetes under immunosuppression. These results were achieved through intraportal infusion which leads to early graft losses and limits the capacity to contain and retrieve implanted cells in case of adverse events. Extra-hepatic sites and encapsulation devices have been developed to address these challenges and potentially create an immunoprotective or immune-privileged environment. Many strategies have achieved reversal of hyperglycemia in diabetic rodents. So far, the results have been less promising when transitioning to humans and larger animal models due to challenges in oxygenation and insulin delivery. We propose a versatile in vitro perfusion system to culture and experimentally study the function of centimeter-scale tissues and devices for insulin-secreting cell delivery. The system accommodates various tissue geometries, experimental readouts, and oxygenation tensions reflective of potential transplantation sites. We highlight the system's applications by using case studies to explore three prominent bioartificial endocrine pancreas (BAP) configurations: (I) with internal flow, (II) with internal flow and microvascularized, and (III) without internal flow. Oxygen concentration profiles modeled computationally were analogous to viability gradients observed experimentally through live/dead endpoint measurements and in case I, time-lapse fluorescence imaging was used to monitor the viability of GFP-expressing cells in real time. Intervascular BAPs were cultured under flow for up to 3 days and BAPs without internal flow for up to 7 days, showing glucose-responsive insulin secretion quantified through at-line non-disruptive sampling. This system can complement other preclinical platforms to de-risk and optimize BAPs and other artificial tissue designs prior to clinical studies.
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Affiliation(s)
- Brenden N Moeun
- Department of Chemical Engineering, McGill University, Montreal, QC, Canada
| | - Florent Lemaire
- Department of Chemical Engineering, McGill University, Montreal, QC, Canada
| | - Alexandra M Smink
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | | | - Richard L Leask
- Department of Chemical Engineering, McGill University, Montreal, QC, Canada
- Department of Biological and Biomedical Engineering, McGill University, Montreal, QC, Canada
| | - Paul de Vos
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Corinne A Hoesli
- Department of Chemical Engineering, McGill University, Montreal, QC, Canada
- Department of Biological and Biomedical Engineering, McGill University, Montreal, QC, Canada
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Xu J, Huang Z, Duan H, Li W, Zhuang J, Xiong L, Tang Y, Liu G. In Silico Prediction of ERRα Agonists Based on Combined Features and Stacking Ensemble Method. ChemMedChem 2024; 19:e202400298. [PMID: 38923819 DOI: 10.1002/cmdc.202400298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 06/07/2024] [Accepted: 06/21/2024] [Indexed: 06/28/2024]
Abstract
Estrogen-related receptor α (ERRα) is considered a very promising target for treating metabolic diseases such as type 2 diabetes. Development of a prediction model to quickly identify potential ERRα agonists can significantly reduce the time spent on virtual screening. In this study, 298 ERRα agonists and numerous nonagonists were collected from various sources to build a new dataset of ERRα agonists. Then a total of 90 models were built using a combination of different algorithms, molecular characterization methods, and data sampling techniques. The consensus model with optimal performance was also validated on the test set (AUC=0.876, BA=0.816) and external validation set (AUC=0.867, BA=0.777) based on five selected baseline models. Furthermore, the model's applicability domain and privileged substructures were examined, and the feature importance was analyzed using the SHAP method to help interpret the model. Based on the above, it's hoped that our publicly accessible data, models, codes, and analytical techniques will prove valuable in quick screening and rational designing more novel and potent ERRα agonists.
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Affiliation(s)
- Jiahao Xu
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
| | - Zejun Huang
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
| | - Hao Duan
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
| | - Weihua Li
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
| | - Jingyan Zhuang
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
| | - Le Xiong
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
| | - Yun Tang
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
| | - Guixia Liu
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China
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Zhao J, Liang S, Cen HH, Li Y, Baker RK, Ruprai B, Gao G, Zhang C, Ren H, Tang C, Chen L, Liu Y, Lynn FC, Johnson JD, Kieffer TJ. PDX1+ cell budding morphogenesis in a stem cell-derived islet spheroid system. Nat Commun 2024; 15:5894. [PMID: 39003281 PMCID: PMC11246529 DOI: 10.1038/s41467-024-50109-2] [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: 01/06/2024] [Accepted: 07/01/2024] [Indexed: 07/15/2024] Open
Abstract
Remarkable advances in protocol development have been achieved to manufacture insulin-secreting islets from human pluripotent stem cells (hPSCs). Distinct from current approaches, we devised a tunable strategy to generate islet spheroids enriched for major islet cell types by incorporating PDX1+ cell budding morphogenesis into staged differentiation. In this process that appears to mimic normal islet morphogenesis, the differentiating islet spheroids organize with endocrine cells that are intermingled or arranged in a core-mantle architecture, accompanied with functional heterogeneity. Through in vitro modelling of human pancreas development, we illustrate the importance of PDX1 and the requirement for EphB3/4 signaling in eliciting cell budding morphogenesis. Using this new approach, we model Mitchell-Riley syndrome with RFX6 knockout hPSCs illustrating unexpected morphogenesis defects in the differentiation towards islet cells. The tunable differentiation system and stem cell-derived islet models described in this work may facilitate addressing fundamental questions in islet biology and probing human pancreas diseases.
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Affiliation(s)
- Jia Zhao
- Life Sciences Institute, Departments of Cellular & Physiological Sciences and Surgery, University of British Columbia, Vancouver, BC, Canada.
| | - Shenghui Liang
- Life Sciences Institute, Departments of Cellular & Physiological Sciences and Surgery, University of British Columbia, Vancouver, BC, Canada
| | - Haoning Howard Cen
- Life Sciences Institute, Departments of Cellular & Physiological Sciences and Surgery, University of British Columbia, Vancouver, BC, Canada
| | - Yanjun Li
- Institute of Molecular Medicine, School of Future Technology, National Biomedical Imaging Center, Peking University, Beijing, China
| | - Robert K Baker
- Life Sciences Institute, Departments of Cellular & Physiological Sciences and Surgery, University of British Columbia, Vancouver, BC, Canada
| | - Balwinder Ruprai
- Life Sciences Institute, Departments of Cellular & Physiological Sciences and Surgery, University of British Columbia, Vancouver, BC, Canada
| | - Guang Gao
- Imaging Core Facility, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
| | - Chloe Zhang
- Life Sciences Institute, Departments of Cellular & Physiological Sciences and Surgery, University of British Columbia, Vancouver, BC, Canada
| | - Huixia Ren
- Institute of Molecular Medicine, School of Future Technology, National Biomedical Imaging Center, Peking University, Beijing, China
- Center for Quantitative Biology, Peking University, Beijing, China
| | - Chao Tang
- Center for Quantitative Biology, Peking University, Beijing, China
| | - Liangyi Chen
- Institute of Molecular Medicine, School of Future Technology, National Biomedical Imaging Center, Peking University, Beijing, China
- PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China
| | - Yanmei Liu
- Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, South China Normal University, 510631, Guangzhou, China
- Institute for Brain Research and Rehabilitation, and Guangdong Key Laboratory of Mental Health and Cognitive Science, South China Normal University, 510631, Guangzhou, China
| | - Francis C Lynn
- BC Children's Hospital Research Institute, Department of Surgery, University of British Columbia, Vancouver, BC, Canada
| | - James D Johnson
- Life Sciences Institute, Departments of Cellular & Physiological Sciences and Surgery, University of British Columbia, Vancouver, BC, Canada
| | - Timothy J Kieffer
- Life Sciences Institute, Departments of Cellular & Physiological Sciences and Surgery, University of British Columbia, Vancouver, BC, Canada.
- School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada.
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10
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Quizon MJ, Deppen JN, Barber GF, Kalelkar PP, Coronel MM, Levit RD, García AJ. VEGF-delivering PEG hydrogels promote vascularization in the porcine subcutaneous space. J Biomed Mater Res A 2024; 112:866-880. [PMID: 38189109 PMCID: PMC10984793 DOI: 10.1002/jbm.a.37666] [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: 11/16/2023] [Revised: 12/21/2023] [Accepted: 12/24/2023] [Indexed: 01/09/2024]
Abstract
For cell therapies, the subcutaneous space is an attractive transplant site due to its large surface area and accessibility for implantation, monitoring, biopsy, and retrieval. However, its poor vascularization has catalyzed research to induce blood vessel formation within the site to enhance cell revascularization and survival. Most studies focus on the subcutaneous space of rodents, which does not recapitulate important anatomical features and vascularization responses of humans. Herein, we evaluate biomaterial-driven vascularization in the porcine subcutaneous space. Additionally, we report the first use of cost-effective fluorescent microspheres to quantify perfusion in the porcine subcutaneous space. We investigate the vascularization-inducing efficacy of vascular endothelial growth factor (VEGF)-delivering synthetic hydrogels based on 4-arm poly(ethylene) glycol macromers with terminal maleimides (PEG-4MAL). We compare three groups: a non-degradable hydrogel with a VEGF-releasing PEG-4MAL gel coating (Core+VEGF gel); an uncoated, non-degradable hydrogel (Core-only); and naïve tissue. After 2 weeks, Core+VEGF gel has significantly higher tissue perfusion, blood vessel area, blood vessel density, and number of vessels compared to both Core-only and naïve tissue. Furthermore, healthy vital signs during surgery and post-procedure metrics demonstrate the safety of hydrogel delivery. We demonstrate that VEGF-delivering synthetic hydrogels induce robust vascularization and perfusion in the porcine subcutaneous space.
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Affiliation(s)
- Michelle J. Quizon
- Woodruff School of Mechanical Engineering and Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Dr. NW, Atlanta, GA 30332, USA
| | - Juline N. Deppen
- Division of Cardiology, Emory University School of Medicine, 1440 Clifton Rd, Atlanta, GA 30322, USA
| | - Graham F. Barber
- Woodruff School of Mechanical Engineering and Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Dr. NW, Atlanta, GA 30332, USA
| | - Pranav P. Kalelkar
- Woodruff School of Mechanical Engineering and Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Dr. NW, Atlanta, GA 30332, USA
| | - María M. Coronel
- Woodruff School of Mechanical Engineering and Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Dr. NW, Atlanta, GA 30332, USA
| | - Rebecca D. Levit
- Division of Cardiology, Emory University School of Medicine, 1440 Clifton Rd, Atlanta, GA 30322, USA
| | - Andrés J. García
- Woodruff School of Mechanical Engineering and Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Dr. NW, Atlanta, GA 30332, USA
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11
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Deng X, Peng D, Yao Y, Huang K, Wang J, Ma Z, Fu J, Xu Y. Optogenetic therapeutic strategies for diabetes mellitus. J Diabetes 2024; 16:e13557. [PMID: 38751366 PMCID: PMC11096815 DOI: 10.1111/1753-0407.13557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 02/28/2024] [Accepted: 03/11/2024] [Indexed: 05/18/2024] Open
Abstract
Diabetes mellitus (DM) is a common chronic disease affecting humans globally. It is characterized by abnormally elevated blood glucose levels due to the failure of insulin production or reduction of insulin sensitivity and functionality. Insulin and glucagon-like peptide (GLP)-1 replenishment or improvement of insulin resistance are the two major strategies to treat diabetes. Recently, optogenetics that uses genetically encoded light-sensitive proteins to precisely control cell functions has been regarded as a novel therapeutic strategy for diabetes. Here, we summarize the latest development of optogenetics and its integration with synthetic biology approaches to produce light-responsive cells for insulin/GLP-1 production, amelioration of insulin resistance and neuromodulation of insulin secretion. In addition, we introduce the development of cell encapsulation and delivery methods and smart bioelectronic devices for the in vivo application of optogenetics-based cell therapy in diabetes. The remaining challenges for optogenetics-based cell therapy in the clinical translational study are also discussed.
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Affiliation(s)
- Xin Deng
- Department of EndocrinologyChildren's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child HealthHangzhouChina
- Department of Biomedical Engineering, MOE Key Laboratory of Biomedical Engineering, Zhejiang Provincial Key Laboratory of Cardio‐Cerebral Vascular Detection Technology and Medicinal Effectiveness Appraisal, Zhejiang Provincial Key Laboratory of Traditional Chinese Medicine for Clinical Evaluation and Translational ResearchZhejiang UniversityHangzhouChina
| | - Dandan Peng
- Department of EndocrinologyChildren's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child HealthHangzhouChina
| | - Yuanfa Yao
- Department of Biomedical Engineering, MOE Key Laboratory of Biomedical Engineering, Zhejiang Provincial Key Laboratory of Cardio‐Cerebral Vascular Detection Technology and Medicinal Effectiveness Appraisal, Zhejiang Provincial Key Laboratory of Traditional Chinese Medicine for Clinical Evaluation and Translational ResearchZhejiang UniversityHangzhouChina
| | - Ke Huang
- Department of EndocrinologyChildren's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child HealthHangzhouChina
| | - Jinling Wang
- Department of EndocrinologyChildren's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child HealthHangzhouChina
| | - Zhihao Ma
- Department of Biomedical Engineering, MOE Key Laboratory of Biomedical Engineering, Zhejiang Provincial Key Laboratory of Cardio‐Cerebral Vascular Detection Technology and Medicinal Effectiveness Appraisal, Zhejiang Provincial Key Laboratory of Traditional Chinese Medicine for Clinical Evaluation and Translational ResearchZhejiang UniversityHangzhouChina
| | - Junfen Fu
- Department of EndocrinologyChildren's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child HealthHangzhouChina
| | - Yingke Xu
- Department of EndocrinologyChildren's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child HealthHangzhouChina
- Department of Biomedical Engineering, MOE Key Laboratory of Biomedical Engineering, Zhejiang Provincial Key Laboratory of Cardio‐Cerebral Vascular Detection Technology and Medicinal Effectiveness Appraisal, Zhejiang Provincial Key Laboratory of Traditional Chinese Medicine for Clinical Evaluation and Translational ResearchZhejiang UniversityHangzhouChina
- Binjiang Institute of Zhejiang UniversityHangzhouChina
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12
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Hiyoshi H, Sakuma K, Asano S, Napier SC, Konagaya S, Mochida T, Ueno H, Watanabe T, Kassai Y, Matsumoto H, Ito R, Toyoda T. Identification and removal of unexpected proliferative off-target cells emerging after iPSC-derived pancreatic islet cell implantation. Proc Natl Acad Sci U S A 2024; 121:e2320883121. [PMID: 38598342 PMCID: PMC11032438 DOI: 10.1073/pnas.2320883121] [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: 12/11/2023] [Accepted: 03/12/2024] [Indexed: 04/12/2024] Open
Abstract
Differentiation of pancreatic endocrine cells from human pluripotent stem cells (PSCs) has been thoroughly investigated for application in cell therapy against diabetes. In the context of induced pancreatic endocrine cell implantation, previous studies have reported graft enlargement resulting from off-target pancreatic lineage cells. However, there is currently no documented evidence of proliferative off-target cells beyond the pancreatic lineage in existing studies. Here, we show that the implantation of seven-stage induced PSC-derived pancreatic islet cells (s7-iPICs) leads to the emergence of unexpected off-target cells with proliferative capacity via in vivo maturation. These cells display characteristics of both mesenchymal stem cells (MSCs) and smooth muscle cells (SMCs), termed proliferative MSC- and SMC-like cells (PMSCs). The frequency of PMSC emergence was found to be high when 108 s7-iPICs were used. Given that clinical applications involve the use of a greater number of induced cells than 108, it is challenging to ensure the safety of clinical applications unless PMSCs are adequately addressed. Accordingly, we developed a detection system and removal methods for PMSCs. To detect PMSCs without implantation, we implemented a 4-wk-extended culture system and demonstrated that putative PMSCs could be reduced by compound treatment, particularly with the taxane docetaxel. When docetaxel-treated s7-iPICs were implanted, the PMSCs were no longer observed. This study provides useful insights into the identification and resolution of safety issues, which are particularly important in the field of cell-based medicine using PSCs.
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Affiliation(s)
- Hideyuki Hiyoshi
- Takeda-CiRA Discovery and Innovation, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa251-8555, Japan
- Takeda-CiRA Joint Program for iPS Cell Applications, Fujisawa, Kanagawa251-8555, Japan
| | - Kensuke Sakuma
- Takeda-CiRA Discovery and Innovation, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa251-8555, Japan
- Takeda-CiRA Joint Program for iPS Cell Applications, Fujisawa, Kanagawa251-8555, Japan
| | - Shinya Asano
- Axcelead Drug Discovery Partners, Inc., Fujisawa, Kanagawa251-8555, Japan
| | - Stephanie C. Napier
- Takeda-CiRA Discovery and Innovation, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa251-8555, Japan
- Takeda-CiRA Joint Program for iPS Cell Applications, Fujisawa, Kanagawa251-8555, Japan
| | - Shuhei Konagaya
- Takeda-CiRA Joint Program for iPS Cell Applications, Fujisawa, Kanagawa251-8555, Japan
- Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto606-8397, Japan
| | - Taisuke Mochida
- Takeda-CiRA Discovery and Innovation, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa251-8555, Japan
- Takeda-CiRA Joint Program for iPS Cell Applications, Fujisawa, Kanagawa251-8555, Japan
| | - Hikaru Ueno
- Takeda-CiRA Discovery and Innovation, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa251-8555, Japan
- Takeda-CiRA Joint Program for iPS Cell Applications, Fujisawa, Kanagawa251-8555, Japan
| | - Takeshi Watanabe
- Drug Safety Research and Evaluation, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa251-8555, Japan
| | - Yoshiaki Kassai
- Takeda-CiRA Discovery and Innovation, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa251-8555, Japan
- Takeda-CiRA Joint Program for iPS Cell Applications, Fujisawa, Kanagawa251-8555, Japan
| | - Hirokazu Matsumoto
- Takeda-CiRA Discovery and Innovation, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa251-8555, Japan
- Takeda-CiRA Joint Program for iPS Cell Applications, Fujisawa, Kanagawa251-8555, Japan
| | - Ryo Ito
- Takeda-CiRA Discovery and Innovation, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa251-8555, Japan
- Takeda-CiRA Joint Program for iPS Cell Applications, Fujisawa, Kanagawa251-8555, Japan
| | - Taro Toyoda
- Takeda-CiRA Joint Program for iPS Cell Applications, Fujisawa, Kanagawa251-8555, Japan
- Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto606-8397, Japan
- Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto606-8397, Japan
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13
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Wang Y, Ding H, Guo C, Bao Q, Li D, Xiong Y. LncRNA Malat1 regulates iPSC-derived β-cell differentiation by targeting the miR-15b-5p/Ihh axis. Cell Signal 2024; 113:110975. [PMID: 37972802 DOI: 10.1016/j.cellsig.2023.110975] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 10/18/2023] [Accepted: 11/13/2023] [Indexed: 11/19/2023]
Abstract
BACKGROUND Differentiation of induced pluripotent stem cells (iPSCs)-derived β-like cells is a novel strategy for treatment of type 1 diabetes. Elucidation of the regulatory mechanisms of long noncoding RNAs (lncRNAs) in β-like cells derived from iPSCs is important for understanding the development of the pancreas and pancreatic β-cells and may improve the quality of β-like cells for stem cell therapy. METHODS β-like cells were derived from iPSCs in a three-step protocol. RNA sequencing and bioinformatics analysis were carried out to screen the differentially expressed lncRNAs and identify the putative target genes separately. LncRNA Malat1 was chosen for further research. Series of loss and gain of functions experiments were performed to study the biological function of LncRNA Malat1. Quantitative real-time PCR (qRT-PCR), Western blot (WB) analysis and immunofluorescence (IF) staining were carried out to separately detect the functions of pancreatic β-cells at the mRNA and protein levels. Cytoplasmic and nuclear RNA fractionation and fluorescence in situ hybridization (FISH) were used to determine the subcellar location of lncRNA Malat1 in β-like cells. Enzyme-linked immunosorbent assays (ELISAs) were performed to examine the differentiation and insulin secretion of β-like cells after stimulation with different glucose concentrations. Structural interactions between lncRNA Malat1 and miR-15b-5p and between miR-15b-5p/Ihh were detected by dual luciferase reporter assays (LRAs). RESULTS We found that the expression of lncRNA Malat1 declined during differentiation, and overexpression (OE) of lncRNA Malat1 notably impaired the differentiation and maturation of β-like cells derived from iPSCs in vitro and in vivo. Most importantly, lncRNA Malat1 could function as a competing endogenous RNA (ceRNA) of miR-15b-5p to regulate the expression of Ihh according to bioinformatics prediction, mechanistic analysis and downstream experiments. CONCLUSION This study established an unreported regulatory network of lncRNA Malat1 and the miR-15b-5p/Ihh axis during the differentiation of iPSCs into β-like cells. In addition to acting as an oncogene promoting tumorigenesis, lncRNA Malat1 may be an effective and novel target for treatment of diabetes in the future.
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Affiliation(s)
- Yao Wang
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University, Nantong 226001, China; Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, China
| | - Haoxiang Ding
- Nantong University Medical School, Nantong 226001, China
| | - Chengfeng Guo
- Nantong University Medical School, Nantong 226001, China
| | - Qian Bao
- Nantong University Medical School, Nantong 226001, China
| | - Dongqian Li
- Nantong University Medical School, Nantong 226001, China
| | - Yicheng Xiong
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University, Nantong 226001, China.
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14
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Askari MR, Ahmadasas M, Shahidehpour A, Rashid M, Quinn L, Park M, Cinar A. Multivariable Automated Insulin Delivery System for Handling Planned and Spontaneous Physical Activities. J Diabetes Sci Technol 2023; 17:1456-1469. [PMID: 37908123 PMCID: PMC10658686 DOI: 10.1177/19322968231204884] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/02/2023]
Abstract
BACKGROUND Hybrid closed-loop control of glucose levels in people with type 1 diabetes mellitus (T1D) is limited by the requirements on users to manually announce physical activity (PA) and meals to the artificial pancreas system. Multivariable automated insulin delivery (mvAID) systems that can handle unannounced PAs and meals without any manual announcements by the user can improve glycemic control by modulating insulin dosing in response to the occurrence and intensity of spontaneous physical activities. METHODS An mvAID system is developed to supplement the glucose measurements with additional physiological signals from a wristband device, with the signals analyzed using artificial intelligence algorithms to automatically detect the occurrence of PA and estimate its intensity. This additional information gained from the physiological signals enables more proactive insulin dosing adjustments in response to both planned exercise and spontaneous unanticipated physical activities. RESULTS In silico studies of the mvAID illustrate the safety and efficacy of the system. The mvAID is translated to pilot clinical studies to assess its performance, and the clinical experiments demonstrate an increased time in range and reduced risk of hypoglycemia following unannounced PA and meals. CONCLUSIONS The mvAID systems can increase the safety and efficacy of insulin delivery in the presence of unannounced physical activities and meals, leading to improved lives and less burden on people with T1D.
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Affiliation(s)
- Mohammad Reza Askari
- Department of Chemical and Biological
Engineering, Illinois Institute of Technology, Chicago, IL, USA
| | - Mohammad Ahmadasas
- Department of Chemical and Biological
Engineering, Illinois Institute of Technology, Chicago, IL, USA
| | - Andrew Shahidehpour
- Department of Chemical and Biological
Engineering, Illinois Institute of Technology, Chicago, IL, USA
| | - Mudassir Rashid
- Department of Chemical and Biological
Engineering, Illinois Institute of Technology, Chicago, IL, USA
| | - Laurie Quinn
- College of Nursing, University of
Illinois Chicago, Chicago, IL, USA
| | - Minsun Park
- College of Nursing, University of
Illinois Chicago, Chicago, IL, USA
| | - Ali Cinar
- Department of Chemical and Biological
Engineering, Illinois Institute of Technology, Chicago, IL, USA
- Department of Biomedical Engineering,
Illinois Institute of Technology, Chicago, IL, USA
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15
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Zhou X, Xu Z, You Y, Yang W, Feng B, Yang Y, Li F, Chen J, Gao H. Subcutaneous device-free islet transplantation. Front Immunol 2023; 14:1287182. [PMID: 37965322 PMCID: PMC10642112 DOI: 10.3389/fimmu.2023.1287182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 10/04/2023] [Indexed: 11/16/2023] Open
Abstract
Diabetes mellitus is a chronic metabolic disease, characterized by high blood sugar levels; it affects more than 500 million individuals worldwide. Type 1 diabetes mellitus (T1DM) is results from insufficient insulin secretion by islets; its treatment requires lifelong use of insulin injections, which leads to a large economic burden on patients. Islet transplantation may be a promising effective treatment for T1DM. Clinically, this process currently involves directly infusing islet cells into the hepatic portal vein; however, transplantation at this site often elicits immediate blood-mediated inflammatory and acute immune responses. Subcutaneous islet transplantation is an attractive alternative to islet transplantation because it is simpler, demonstrates lower surgical complication risks, and enables graft monitoring and removal. In this article, we review the current methods of subcutaneous device-free islet transplantation. Recent subcutaneous islet transplantation techniques with high success rate have involved the use of bioengineering technology and biomaterial cotransplantation-including cell and cell growth factor co-transplantation and hydrogel- or simulated extracellular matrix-wrapped subcutaneous co-transplantation. In general, current subcutaneous device-free islet transplantation modalities can simplify the surgical process and improve the posttransplantation graft survival rate, thus aiding effective T1DM management.
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Affiliation(s)
| | - Zhiran Xu
- Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - Yanqiu You
- Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - Wangrong Yang
- Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - BingZheng Feng
- Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - Yuwei Yang
- Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - Fujun Li
- Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - Jibing Chen
- Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - Hongjun Gao
- Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, China
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16
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Vanderlaan EL, Sexton J, Evans-Molina C, Buganza Tepole A, Voytik-Harbin SL. Islet-on-chip: promotion of islet health and function via encapsulation within a polymerizable fibrillar collagen scaffold. LAB ON A CHIP 2023; 23:4466-4482. [PMID: 37740372 DOI: 10.1039/d3lc00371j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/24/2023]
Abstract
The protection and interrogation of pancreatic β-cell health and function ex vivo is a fundamental aspect of diabetes research, including mechanistic studies, evaluation of β-cell health modulators, and development and quality control of replacement β-cell populations. However, present-day islet culture formats, including traditional suspension culture as well as many recently developed microfluidic devices, suspend islets in a liquid microenvironment, disrupting mechanochemical signaling normally found in vivo and limiting β-cell viability and function in vitro. Herein, we present a novel three-dimensional (3D) microphysiological system (MPS) to extend islet health and function ex vivo by incorporating a polymerizable collagen scaffold to restore biophysical support and islet-collagen mechanobiological cues. Informed by computational models of gas and molecular transport relevant to β-cell physiology, a MPS configuration was down-selected based on simulated oxygen and nutrient delivery to collagen-encapsulated islets, and 3D-printing was applied as a readily accessible, low-cost rapid prototyping method. Recreating critical aspects of the in vivo microenvironment within the MPS via perfusion and islet-collagen interactions mitigated post-isolation ischemia and apoptosis in mouse islets over a 5-day period. In contrast, islets maintained in traditional suspension formats exhibited progressive hypoxic and apoptotic cores. Finally, dynamic glucose-stimulated insulin secretion measurements were performed on collagen-encapsulated mouse islets in the absence and presence of well-known chemical stressor thapsigargin using the MPS platform and compared to conventional protocols involving commercial perifusion machines. Overall, the MPS described here provides a user-friendly islet culture platform that not only supports long-term β-cell health and function but also enables multiparametric evaluations.
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Affiliation(s)
- Emma L Vanderlaan
- Weldon School of Biomedical Engineering, College of Engineering, Purdue University, West Lafayette, IN 47907, USA.
- Medical Scientist/Engineer Training Program, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Joshua Sexton
- Weldon School of Biomedical Engineering, College of Engineering, Purdue University, West Lafayette, IN 47907, USA.
| | - Carmella Evans-Molina
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Roudebush VA Medical Center, Indianapolis, IN 46202, USA
| | - Adrian Buganza Tepole
- Weldon School of Biomedical Engineering, College of Engineering, Purdue University, West Lafayette, IN 47907, USA.
- School of Mechanical Engineering, College of Engineering, Purdue University, West Lafayette, IN 47907, USA
| | - Sherry L Voytik-Harbin
- Weldon School of Biomedical Engineering, College of Engineering, Purdue University, West Lafayette, IN 47907, USA.
- Department of Basic Medical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47906, USA
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17
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Kotecha M, Wang L, Hameed S, Viswakarma N, Ma M, Stabler C, Hoesli CA, Epel B. In vitro oxygen imaging of acellular and cell-loaded beta cell replacement devices. Sci Rep 2023; 13:15641. [PMID: 37730815 PMCID: PMC10511476 DOI: 10.1038/s41598-023-42099-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 09/05/2023] [Indexed: 09/22/2023] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disease that leads to the loss of insulin-producing beta cells. Bioartificial pancreas (BAP) or beta cell replacement strategies have shown promise in curing T1D and providing long-term insulin independence. Hypoxia (low oxygen concentration) that may occur in the BAP devices due to cell oxygen consumption at the early stages after implantation damages the cells, in addition to imposing limitations to device dimensions when translating promising results from rodents to humans. Finding ways to provide cells with sufficient oxygenation remains the major challenge in realizing BAP devices' full potential. Therefore, in vitro oxygen imaging assessment of BAP devices is crucial for predicting the devices' in vivo efficiency. Electron paramagnetic resonance oxygen imaging (EPROI, also known as electron MRI or eMRI) is a unique imaging technique that delivers absolute partial pressure of oxygen (pO2) maps and has been used for cancer hypoxia research for decades. However, its applicability for assessing BAP devices has not been explored. EPROI utilizes low magnetic fields in the mT range, static gradients, and the linear relationship between the spin-lattice relaxation rate (R1) of oxygen-sensitive spin probes such as trityl OX071 and pO2 to generate oxygen maps in tissues. With the support of the Juvenile Diabetes Research Foundation (JDRF), an academic-industry partnership consortium, the "Oxygen Measurement Core" was established at O2M to perform oxygen imaging assessment of BAP devices originated from core members' laboratories. This article aims to establish the protocols and demonstrate a few examples of in vitro oxygen imaging of BAP devices using EPROI. All pO2 measurements were performed using a recently introduced 720 MHz/25 mT preclinical oxygen imager instrument, JIVA-25™. We began by performing pO2 calibration of the biomaterials used in BAPs at 25 mT magnetic field since no such data exist. We compared the EPROI pO2 measurement with a single-point probe for a few selected materials. We also performed trityl OX071 toxicity studies with fibroblasts, as well as insulin-producing cells (beta TC6, MIN6, and human islet cells). Finally, we performed proof-of-concept in vitro pO2 imaging of five BAP devices that varied in size, shape, and biomaterials. We demonstrated that EPROI is compatible with commonly used biomaterials and that trityl OX071 is nontoxic to cells. A comparison of the EPROI with a fluorescent-based point oxygen probe in selected biomaterials showed higher accuracy of EPROI. The imaging of typically heterogenous BAP devices demonstrated the utility of obtaining oxygen maps over single-point measurements. In summary, we present EPROI as a quality control tool for developing efficient cell transplantation devices and artificial tissue grafts. Although the focus of this work is encapsulation systems for diabetes, the techniques developed in this project are easily transferable to other biomaterials, tissue grafts, and cell therapy devices used in the field of tissue engineering and regenerative medicine (TERM). In summary, EPROI is a unique noninvasive tool to experimentally study oxygen distribution in cell transplantation devices and artificial tissues, which can revolutionize the treatment of degenerative diseases like T1D.
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Affiliation(s)
- Mrignayani Kotecha
- Oxygen Measurement Core, O2M Technologies, LLC, Chicago, IL, 60612, USA.
| | - Longhai Wang
- Department of Biological and Environmental Engineering, Cornell University, NY, 14853, USA
| | - Safa Hameed
- Oxygen Measurement Core, O2M Technologies, LLC, Chicago, IL, 60612, USA
| | - Navin Viswakarma
- Oxygen Measurement Core, O2M Technologies, LLC, Chicago, IL, 60612, USA
| | - Minglin Ma
- Department of Biological and Environmental Engineering, Cornell University, NY, 14853, USA
| | - Cherie Stabler
- Department of Biomedical Engineering, University of Florida, Gainesville, FL, 32611, USA
| | - Corinne A Hoesli
- Department of Chemical Engineering, McGill University, Montreal, QC, H3C 0C5, Canada
| | - Boris Epel
- Oxygen Measurement Core, O2M Technologies, LLC, Chicago, IL, 60612, USA
- Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL, 60637, USA
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18
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Yabe SG, Fukuda S, Nishida J, Takeda F, Okochi H. The functional maturity of grafted human pluripotent stem cell derived-islets (hSC-Islets) evaluated by the glycemic set point during blood glucose normalizing process in diabetic mice. Heliyon 2023; 9:e19972. [PMID: 37809993 PMCID: PMC10559575 DOI: 10.1016/j.heliyon.2023.e19972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Revised: 09/05/2023] [Accepted: 09/07/2023] [Indexed: 10/10/2023] Open
Abstract
Human pluripotent stem cell (hPSCs) derived-pancreatic islets (hSC-islets) are good candidates for cell replacement therapy for patients with diabetes as substitutes for deceased donor-derived islets, because they are pluripotent and have infinite proliferation potential. Grafted hSC-islets ameliorate hyperglycemia in diabetic mice; however, several weeks are needed to normalize the hyperglycemia. These data suggest hSC-islets require maturation, but their maturation process in vivo is not yet fully understood. In this study, we utilized two kinds of streptozotocin (STZ)-induced diabetes model mice by changing the administration timing in order to examine the time course of maturation of hSC-islets and the effects of hyperglycemia on their maturation. We found no hyperglycemia in immune-compromised mice when hSC-islets had been transplanted under their kidney capsules in advance, and STZ was administered 4 weeks after transplantation. Of note, the blood glucose levels of those mice were stably maintained under 100 mg/dl 10 weeks after transplantation; this is lower than the mouse glycemic set point (120-150 mg/dl), suggesting that hSC-islets control blood glucose levels to the human glycemic set point. We confirmed that gene expression of maturation markers of pancreatic beta cells tended to upregulate during 4 weeks after transplantation. Periodical histological analysis revealed that revascularization was observed as early as 1 week after transplantation, but reinnervation in the grafted hSC-islets was not detected at all, even 15 weeks after transplantation. In conclusion, our hSC-islets need at least 4 weeks to mature, and the human glycemic set point is a good index for evaluating ultimate maturity for hSC-islets in vivo.
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Affiliation(s)
- 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
| | - Satsuki Fukuda
- Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama Shinjuku-ku, Tokyo, 162-8655, Japan
| | - Junko Nishida
- Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama Shinjuku-ku, Tokyo, 162-8655, Japan
| | - Fujie Takeda
- 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
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19
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Liang S, Zhao J, Baker RK, Tran E, Zhan L, Kieffer TJ. Differentiation of stem cell-derived pancreatic progenitors into insulin-secreting islet clusters in a multiwell-based static 3D culture system. CELL REPORTS METHODS 2023; 3:100466. [PMID: 37323565 PMCID: PMC10261893 DOI: 10.1016/j.crmeth.2023.100466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 11/08/2022] [Accepted: 04/12/2023] [Indexed: 06/17/2023]
Abstract
Orbital shaker-based suspension culture systems have been in widespread use for differentiating human pluripotent stem cell (hPSC)-derived pancreatic progenitors toward islet-like clusters during endocrine induction stages. However, reproducibility between experiments is hampered by variable degrees of cell loss in shaking cultures, which contributes to variable differentiation efficiencies. Here, we describe a 96-well-based static suspension culture method for differentiation of pancreatic progenitors into hPSC-islets. Compared with shaking culture, this static 3D culture system induces similar islet gene expression profiles during differentiation processes but significantly reduces cell loss and improves cell viability of endocrine clusters. This static culture method results in more reproducible and efficient generation of glucose-responsive, insulin-secreting hPSC-islets. The successful differentiation and well-to-well consistency in 96-well plates also provides a proof of principle that the static 3D culture system can serve as a platform for small-scale compound screening experiments as well as facilitating further protocol development.
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Affiliation(s)
- Shenghui Liang
- Department of Cellular & Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Jia Zhao
- Department of Cellular & Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Robert K. Baker
- Department of Cellular & Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Elisa Tran
- Department of Cellular & Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Lisa Zhan
- Department of Cellular & Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Timothy J. Kieffer
- Department of Cellular & Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
- Department of Surgery, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
- School of Biomedical Engineering, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
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20
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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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21
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Lindheimer F, Lindner MJ, Oos R, Honarpisheh M, Zhang Y, Lei Y, Wolf-van Buerck L, Gildehaus FJ, Lindner S, Bartenstein P, Kemter E, Wolf E, Seissler J, Ziegler S. Non-invasive in vivo imaging of porcine islet xenografts in a preclinical model with [ 68Ga]Ga-exendin-4. FRONTIERS IN NUCLEAR MEDICINE (LAUSANNE, SWITZERLAND) 2023; 3:1157480. [PMID: 39355020 PMCID: PMC11440980 DOI: 10.3389/fnume.2023.1157480] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 04/07/2023] [Indexed: 10/03/2024]
Abstract
Introduction Islet xenotransplantation may be a therapeutic option in type 1 diabetes. Recent advances in generating genetically modified source pigs offer advantages as immune suppressants can potentially be eliminated after the transplantation. Therapy monitoring would greatly benefit from noninvasive methods for assessing the viability of transplanted islets. Peptide-based positron emission tomography (PET) targeting the glucagon-like peptide-1 receptor (GLP1R) expression on beta cells may offer a procedure that can directly be translated from an experimental setting to the clinic. The aim of this study was to establish the labeling of the GLP1R ligand [68Ga]Ga-exendin-4, to demonstrate the feasibility of imaging porcine islet xenografts in vivo and to compare signal quality for three different transplantation sites in a mouse model. Materials and methods Mice with engrafted neonatal porcine islet cell clusters (NPICCs) under the kidney capsule, into the inguinal fold, or the lower hindlimb muscle were studied. After reaching normoglycemia, the mice were injected with [68Ga]Ga-exendin-4 for PET data acquisition. Subsequent autoradiography (AR) was used for comparing ex vivo data with in vivo uptake. Results NPICCs in the lower right hindlimb muscle could be detected in vivo and in AR. Due to the high background in the kidney and urinary bladder, islets could not be detected in the PET data at transplantation sites close to these organs, while AR showed a clear signal for the islets in the inguinal fold. Discussion PET with [68Ga]Ga-exendin-4 detects islets transplanted in the hindlimb muscle tissue of mice, offering the potential of longitudinal monitoring of viable porcine islets. Other sites are not suitable for in vivo imaging owing to high activity accumulation of Exendin-4 in kidney and bladder.
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Affiliation(s)
- Felix Lindheimer
- Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany
| | | | - Rosel Oos
- Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany
| | - Mohsen Honarpisheh
- Medizinische Klinik und Poliklinik IV, Diabetes Center, University Hospital of Munich, LMU Munich, Munich, Germany
| | - Yichen Zhang
- Medizinische Klinik und Poliklinik IV, Diabetes Center, University Hospital of Munich, LMU Munich, Munich, Germany
| | - Yutian Lei
- Medizinische Klinik und Poliklinik IV, Diabetes Center, University Hospital of Munich, LMU Munich, Munich, Germany
| | - Lelia Wolf-van Buerck
- Medizinische Klinik und Poliklinik IV, Diabetes Center, University Hospital of Munich, LMU Munich, Munich, Germany
| | - Franz Josef Gildehaus
- Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany
| | - Simon Lindner
- Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany
| | - Peter Bartenstein
- Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany
| | - Elisabeth Kemter
- Chair for Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, Munich, Germany
- Center for Innovative Medical Models (CiMM), LMU Munich, Oberschleissheim, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Eckhard Wolf
- Chair for Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, Munich, Germany
- Center for Innovative Medical Models (CiMM), LMU Munich, Oberschleissheim, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Jochen Seissler
- Medizinische Klinik und Poliklinik IV, Diabetes Center, University Hospital of Munich, LMU Munich, Munich, Germany
| | - Sibylle Ziegler
- Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany
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22
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Jiang H, Jiang FX. Human pluripotent stem cell-derived β cells: Truly immature islet β cells for type 1 diabetes therapy? World J Stem Cells 2023; 15:182-195. [PMID: 37180999 PMCID: PMC10173812 DOI: 10.4252/wjsc.v15.i4.182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 01/30/2023] [Accepted: 03/20/2023] [Indexed: 04/26/2023] Open
Abstract
A century has passed since the Nobel Prize winning discovery of insulin, which still remains the mainstay treatment for type 1 diabetes mellitus (T1DM) to this day. True to the words of its discoverer Sir Frederick Banting, “insulin is not a cure for diabetes, it is a treatment”, millions of people with T1DM are dependent on daily insulin medications for life. Clinical donor islet transplantation has proven that T1DM is curable, however due to profound shortages of donor islets, it is not a mainstream treatment option for T1DM. Human pluripotent stem cell derived insulin-secreting cells, pervasively known as stem cell-derived β cells (SC-β cells), are a promising alternative source and have the potential to become a T1DM treatment through cell replacement therapy. Here we briefly review how islet β cells develop and mature in vivo and several types of reported SC-β cells produced using different ex vivo protocols in the last decade. Although some markers of maturation were expressed and glucose stimulated insulin secretion was shown, the SC-β cells have not been directly compared to their in vivo counterparts, generally have limited glucose response, and are not yet fully matured. Due to the presence of extra-pancreatic insulin-expressing cells, and ethical and technological issues, further clarification of the true nature of these SC-β cells is required.
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Affiliation(s)
- Helen Jiang
- Sir Charles Gairdner Hospital, University of Western Australia, Perth 6009, Australia
| | - Fang-Xu Jiang
- School of Biomedical Sciences, University of Western Australia, Perth 6009, Australia
- School of Health and Medical Sciences, Edith Cowan University, Perth 6027, Australia
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23
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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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24
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Sackett SD, Kaplan SJ, Mitchell SA, Brown ME, Burrack AL, Grey S, Huangfu D, Odorico J. Genetic Engineering of Immune Evasive Stem Cell-Derived Islets. Transpl Int 2022; 35:10817. [PMID: 36545154 PMCID: PMC9762357 DOI: 10.3389/ti.2022.10817] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 11/14/2022] [Indexed: 12/12/2022]
Abstract
Genome editing has the potential to revolutionize many investigative and therapeutic strategies in biology and medicine. In the field of regenerative medicine, one of the leading applications of genome engineering technology is the generation of immune evasive pluripotent stem cell-derived somatic cells for transplantation. In particular, as more functional and therapeutically relevant human pluripotent stem cell-derived islets (SCDI) are produced in many labs and studied in clinical trials, there is keen interest in studying the immunogenicity of these cells and modulating allogeneic and autoimmune immune responses for therapeutic benefit. Significant experimental work has already suggested that elimination of Human Leukocytes Antigen (HLA) expression and overexpression of immunomodulatory genes can impact survival of a variety of pluripotent stem cell-derived somatic cell types. Limited work published to date focuses on stem cell-derived islets and work in a number of labs is ongoing. Rapid progress is occurring in the genome editing of human pluripotent stem cells and their progeny focused on evading destruction by the immune system in transplantation models, and while much research is still needed, there is no doubt the combined technologies of genome editing and stem cell therapy will profoundly impact transplantation medicine in the future.
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Affiliation(s)
- Sara D. Sackett
- Division of Transplantation, Department of Surgery, UW Transplant Center, School of Medicine and Public Health, University of Wisconsin, Madison, WI, United States,*Correspondence: Sara D. Sackett,
| | - Samuel J. Kaplan
- Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, United States,Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, United States
| | - Samantha A. Mitchell
- Division of Transplantation, Department of Surgery, UW Transplant Center, School of Medicine and Public Health, University of Wisconsin, Madison, WI, United States
| | - Matthew E. Brown
- Division of Transplantation, Department of Surgery, UW Transplant Center, School of Medicine and Public Health, University of Wisconsin, Madison, WI, United States
| | - Adam L. Burrack
- Department of Microbiology and Immunology, Medical School, University of Minnesota, Minneapolis, MN,Center for Immunology, Medical School, University of Minnesota, Minneapolis, MN, United States
| | - Shane Grey
- Immunology Division, Garvan Institute of Medical Research, St Vincent’s Hospital, Sydney, NSW, Australia
| | - Danwei Huangfu
- Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Jon Odorico
- Division of Transplantation, Department of Surgery, UW Transplant Center, School of Medicine and Public Health, University of Wisconsin, Madison, WI, United States
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25
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Verhoeff K, Cuesta-Gomez N, Jasra I, Marfil-Garza B, Dadheech N, Shapiro AMJ. Optimizing Generation of Stem Cell-Derived Islet Cells. Stem Cell Rev Rep 2022; 18:2683-2698. [PMID: 35639237 DOI: 10.1007/s12015-022-10391-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/13/2022] [Indexed: 02/06/2023]
Abstract
Islet transplantation is a highly effective treatment for select patients with type 1 diabetes. Unfortunately, current use is limited to those with brittle disease due to donor limitations and immunosuppression requirements. Discovery of factors for induction of pluripotent stem cells from adult somatic cells into a malleable state has reinvigorated the possibility of autologous-based regenerative cell therapies. Similarly, recent progress in allogeneic human embryonic stem cell islet products is showing early success in clinical trials. Describing safe and standardized differentiation protocols with clear pathways to optimize yield and minimize off-target growth is needed to efficiently move the field forward. This review discusses current islet differentiation protocols with a detailed break-down of differentiation stages to guide step-wise controlled generation of functional islet products.
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Affiliation(s)
- Kevin Verhoeff
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
- Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Nerea Cuesta-Gomez
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
- Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Ila Jasra
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
- Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Braulio Marfil-Garza
- National Institute of Medical Sciences and Nutrition Salvador Zubiran, Mexico City, and CHRISTUS-LatAm Hub - Excellence and Innovation Center, Monterrey, Mexico
| | - Nidheesh Dadheech
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
- Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
| | - A M James Shapiro
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
- Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
- 1-002 Li Ka Shing Centre for Health Research Innovation, 112 St. NW & 87 Ave NW, Edmonton, Alberta, T6G 2E1, Canada.
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26
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Chmielowiec J, Szlachcic WJ, Yang D, Scavuzzo MA, Wamble K, Sarrion-Perdigones A, Sabek OM, Venken KJT, Borowiak M. Human pancreatic microenvironment promotes β-cell differentiation via non-canonical WNT5A/JNK and BMP signaling. Nat Commun 2022; 13:1952. [PMID: 35414140 PMCID: PMC9005503 DOI: 10.1038/s41467-022-29646-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 03/21/2022] [Indexed: 12/24/2022] Open
Abstract
In vitro derivation of pancreatic β-cells from human pluripotent stem cells holds promise as diabetes treatment. Despite recent progress, efforts to generate physiologically competent β-cells are still hindered by incomplete understanding of the microenvironment's role in β-cell development and maturation. Here, we analyze the human mesenchymal and endothelial primary cells from weeks 9-20 fetal pancreas and identify a time point-specific microenvironment that permits β-cell differentiation. Further, we uncover unique factors that guide in vitro development of endocrine progenitors, with WNT5A markedly improving human β-cell differentiation. WNT5A initially acts through the non-canonical (JNK/c-JUN) WNT signaling and cooperates with Gremlin1 to inhibit the BMP pathway during β-cell maturation. Interestingly, we also identify the endothelial-derived Endocan as a SST+ cell promoting factor. Overall, our study shows that the pancreatic microenvironment-derived factors can mimic in vivo conditions in an in vitro system to generate bona fide β-cells for translational applications.
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Affiliation(s)
- Jolanta Chmielowiec
- Molecular and Cellular Biology Department, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Wojciech J Szlachcic
- Institute of Molecular Biology and Biotechnology, Adam Mickiewicz University, ul. Uniwersytetu Poznanskiego 6, 61-614, Poznan, Poland
| | - Diane Yang
- Molecular and Cellular Biology Department, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Marissa A Scavuzzo
- Program in Developmental Biology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Katrina Wamble
- Stem Cell and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Alejandro Sarrion-Perdigones
- Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Omaima M Sabek
- Department of Surgery, The Methodist Hospital, Houston, TX, USA.,Weill Cornell Medical College, New York, NY, USA
| | - Koen J T Venken
- Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.,McNair Medical Institute, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Malgorzata Borowiak
- Molecular and Cellular Biology Department, Baylor College of Medicine, Houston, TX, 77030, USA. .,Institute of Molecular Biology and Biotechnology, Adam Mickiewicz University, ul. Uniwersytetu Poznanskiego 6, 61-614, Poznan, Poland. .,Program in Developmental Biology, Baylor College of Medicine, Houston, TX, 77030, USA. .,Stem Cell and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, 77030, USA. .,McNair Medical Institute, Baylor College of Medicine, Houston, TX, 77030, USA.
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27
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Hiyoshi H, Sakuma K, Tsubooka-Yamazoe N, Asano S, Mochida T, Yamaura J, Konagaya S, Fujii R, Matsumoto H, Ito R, Toyoda T. Characterization and reduction of non-endocrine cells accompanying islet-like endocrine cells differentiated from human iPSC. Sci Rep 2022; 12:4740. [PMID: 35304548 PMCID: PMC8933508 DOI: 10.1038/s41598-022-08753-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 03/11/2022] [Indexed: 11/09/2022] Open
Abstract
The differentiation of pancreatic endocrine cells from human pluripotent stem cells has been thoroughly investigated for their application in cell therapy against diabetes. Although non-endocrine cells are inevitable contaminating by-products of the differentiation process, a comprehensive profile of such cells is lacking. Therefore, we characterized non-endocrine cells in iPSC-derived pancreatic islet cells (iPIC) using single-cell transcriptomic analysis. We found that non-endocrine cells consist of (1) heterogeneous proliferating cells, and (2) cells with not only pancreatic traits but also liver or intestinal traits marked by FGB or AGR2. Non-endocrine cells specifically expressed FGFR2, PLK1, and LDHB. We demonstrated that inhibition of pathways involving these genes selectively reduced the number of non-endocrine cells in the differentiation process. These findings provide useful insights into cell purification approaches and contribute to the improvement of the mass production of endocrine cells for stem cell-derived cell therapy for diabetes.
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Affiliation(s)
- Hideyuki Hiyoshi
- T-CiRA Discovery, Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, 251-8555, Japan. .,Takeda-CiRA Joint Program for iPS Cell Applications (T-CiRA), Fujisawa, Kanagawa, Japan.
| | - Kensuke Sakuma
- T-CiRA Discovery, Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, 251-8555, Japan.,Takeda-CiRA Joint Program for iPS Cell Applications (T-CiRA), Fujisawa, Kanagawa, Japan.,Orizuru Therapeutics, Inc, Fujisawa, Kanagawa, Japan
| | - Noriko Tsubooka-Yamazoe
- T-CiRA Discovery, Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, 251-8555, Japan.,Takeda-CiRA Joint Program for iPS Cell Applications (T-CiRA), Fujisawa, Kanagawa, Japan.,Orizuru Therapeutics, Inc, Fujisawa, Kanagawa, Japan
| | - Shinya Asano
- Axcelead Drug Discovery Partners, Inc, Fujisawa, Kanagawa, Japan
| | - Taisuke Mochida
- T-CiRA Discovery, Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, 251-8555, Japan.,Takeda-CiRA Joint Program for iPS Cell Applications (T-CiRA), Fujisawa, Kanagawa, Japan
| | - Junji Yamaura
- Takeda-CiRA Joint Program for iPS Cell Applications (T-CiRA), Fujisawa, Kanagawa, Japan.,Pharmaceutical Science, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan
| | - Shuhei Konagaya
- Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.,Takeda-CiRA Joint Program for iPS Cell Applications (T-CiRA), Fujisawa, Kanagawa, Japan.,Orizuru Therapeutics, Inc, Fujisawa, Kanagawa, Japan
| | - Ryo Fujii
- Axcelead Drug Discovery Partners, Inc, Fujisawa, Kanagawa, Japan
| | - Hirokazu Matsumoto
- T-CiRA Discovery, Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, 251-8555, Japan.,Takeda-CiRA Joint Program for iPS Cell Applications (T-CiRA), Fujisawa, Kanagawa, Japan
| | - Ryo Ito
- T-CiRA Discovery, Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, 251-8555, Japan.,Takeda-CiRA Joint Program for iPS Cell Applications (T-CiRA), Fujisawa, Kanagawa, Japan.,Orizuru Therapeutics, Inc, Fujisawa, Kanagawa, Japan
| | - Taro Toyoda
- Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan. .,Takeda-CiRA Joint Program for iPS Cell Applications (T-CiRA), Fujisawa, Kanagawa, Japan.
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Pancreatic islet cryopreservation by vitrification achieves high viability, function, recovery and clinical scalability for transplantation. Nat Med 2022; 28:798-808. [PMID: 35288694 PMCID: PMC9018423 DOI: 10.1038/s41591-022-01718-1] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 01/26/2022] [Indexed: 12/15/2022]
Abstract
Pancreatic islet transplantation can cure diabetes but requires accessible, high-quality islets in sufficient quantities. Cryopreservation could solve islet supply chain challenges by enabling quality-controlled banking and pooling of donor islets. Unfortunately, cryopreservation has not succeeded in this objective, as it must simultaneously provide high recovery, viability, function and scalability. Here, we achieve this goal in mouse, porcine, human and human stem cell (SC)-derived beta cell (SC-beta) islets by comprehensive optimization of cryoprotectant agent (CPA) composition, CPA loading and unloading conditions and methods for vitrification and rewarming (VR). Post-VR islet viability, relative to control, was 90.5% for mouse, 92.1% for SC-beta, 87.2% for porcine and 87.4% for human islets, and it remained unchanged for at least 9 months of cryogenic storage. VR islets had normal macroscopic, microscopic, and ultrastructural morphology. Mitochondrial membrane potential and adenosine triphosphate (ATP) levels were slightly reduced, but all other measures of cellular respiration, including oxygen consumption rate (OCR) to produce ATP, were unchanged. VR islets had normal glucose-stimulated insulin secretion (GSIS) function in vitro and in vivo. Porcine and SC-beta islets made insulin in xenotransplant models, and mouse islets tested in a marginal mass syngeneic transplant model cured diabetes in 92% of recipients within 24–48 h after transplant. Excellent glycemic control was seen for 150 days. Finally, our approach processed 2,500 islets with >95% islets recovery at >89% post-thaw viability and can readily be scaled up for higher throughput. These results suggest that cryopreservation can now be used to supply needed islets for improved transplantation outcomes that cure diabetes. Optimization of vitrification approaches substantially improves pancreatic islet cryopreservation for banking and boosts transplantation outcomes in diabetes.
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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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Yu G, Zhang M, Gao L, Zhou Y, Qiao L, Yin J, Wang Y, Zhou J, Ye H. Far-red light-activated human islet-like designer cells enable sustained fine-tuned secretion of insulin for glucose control. Mol Ther 2022; 30:341-354. [PMID: 34530162 PMCID: PMC8753431 DOI: 10.1016/j.ymthe.2021.09.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 08/02/2021] [Accepted: 09/07/2021] [Indexed: 01/07/2023] Open
Abstract
Diabetes affects almost half a billion people, and all individuals with type 1 diabetes (T1D) and a large portion of individuals with type 2 diabetes rely on self-administration of the peptide hormone insulin to achieve glucose control. However, this treatment modality has cumbersome storage and equipment requirements and is susceptible to fatal user error. Here, reasoning that a cell-based therapy could be coupled to an external induction circuit for blood glucose control, as a proof of concept we developed far-red light (FRL)-activated human islet-like designer (FAID) cells and demonstrated how FAID cell implants achieved safe and sustained glucose control in diabetic model mice. Specifically, by introducing a FRL-triggered optogenetic device into human mesenchymal stem cells (hMSCs), which we encapsulated in poly-(l-lysine)-alginate and implanted subcutaneously under the dorsum of T1D model mice, we achieved FRL illumination-inducible secretion of insulin that yielded improvements in glucose tolerance and sustained blood glucose control over traditional insulin glargine treatment. Moreover, the FAID cell implants attenuated both oxidative stress and development of multiple diabetes-related complications in kidneys. This optogenetics-controlled "living cell factory" platform could be harnessed to develop multiple synthetic designer therapeutic cells to achieve long-term yet precisely controllable drug delivery.
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Affiliation(s)
- Guiling Yu
- Synthetic Biology and Biomedical Engineering Laboratory, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai 200241, China
| | - Mingliang Zhang
- Department of Endocrinology and Metabolism, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Ling Gao
- Department of Endocrinology, Renmin Hospital of Wuhan University, Wuhan 430061, China
| | - Yang Zhou
- Synthetic Biology and Biomedical Engineering Laboratory, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai 200241, China
| | - Longliang Qiao
- Synthetic Biology and Biomedical Engineering Laboratory, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai 200241, China
| | - Jianli Yin
- Synthetic Biology and Biomedical Engineering Laboratory, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai 200241, China
| | - Yiwen Wang
- Electron Microscopy Center, School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai 200241, China
| | - Jian Zhou
- Department of Endocrinology and Metabolism, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
| | - Haifeng Ye
- Synthetic Biology and Biomedical Engineering Laboratory, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai 200241, China.
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31
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Memon B, Abdelalim EM. Highly Efficient Differentiation of Human Pluripotent Stem Cells into Pancreatic Progenitors Co-expressing PDX1 and NKX6.1. Methods Mol Biol 2022; 2454:351-363. [PMID: 33190184 DOI: 10.1007/7651_2020_323] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Diabetes is a complex metabolic disorder, with no available treatment. Islet transplantation is currently practiced beta cell replacement therapy option, however, with major limitations. Human pluripotent stem cells (hPSCs) can be used as a scalable source for generation of insulin-secreting cells as hPSCs have high proliferative capacity and can differentiate into any tissue type. In vitro stepwise protocols have been designed for differentiating hPSCs into pancreatic lineages that finally give rise to beta cells; however, these hPSC-derived beta cells are dissimilar to adult human beta cells in key aspects of gene expression and functionality. Alternatively, pancreatic progenitors, when transplanted in the body, have been shown to mature into functional insulin-secreting beta cells, capable of reversing hyperglycemia. These pancreatic progenitors require the co-expression of PDX1, a transcription factor (TF) regulating pancreatic development, and NKX6.1, another TF key for beta cell maturation and function, to produce glucose-responsive beta cells. Given the crucial role played by NKX6.1, we optimized an in vitro differentiation protocol to enhance the generation of pancreatic progenitors co-expressing PDX1 and NKX6.1 by modulating cell density, matrix availability, and cellular dissociation.
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Affiliation(s)
- Bushra Memon
- College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
| | - Essam M Abdelalim
- College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar.
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar.
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Cefalu WT, Andersen DK, Arreaza-Rubín G, Pin CL, Sato S, Verchere CB, Woo M, Rosenblum ND. Heterogeneity of Diabetes: β-Cells, Phenotypes, and Precision Medicine: Proceedings of an International Symposium of the Canadian Institutes of Health Research's Institute of Nutrition, Metabolism and Diabetes and the U.S. National Institutes of Health's National Institute of Diabetes and Digestive and Kidney Diseases. Diabetes Care 2022; 45:3-22. [PMID: 34782355 PMCID: PMC8753760 DOI: 10.2337/dci21-0051] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 09/23/2021] [Indexed: 02/03/2023]
Abstract
One hundred years have passed since the discovery of insulin-an achievement that transformed diabetes from a fatal illness into a manageable chronic condition. The decades since that momentous achievement have brought ever more rapid innovation and advancement in diabetes research and clinical care. To celebrate the important work of the past century and help to chart a course for its continuation into the next, the Canadian Institutes of Health Research's Institute of Nutrition, Metabolism and Diabetes and the U.S. National Institutes of Health's National Institute of Diabetes and Digestive and Kidney Diseases recently held a joint international symposium, bringing together a cohort of researchers with diverse interests and backgrounds from both countries and beyond to discuss their collective quest to better understand the heterogeneity of diabetes and thus gain insights to inform new directions in diabetes treatment and prevention. This article summarizes the proceedings of that symposium, which spanned cutting-edge research into various aspects of islet biology, the heterogeneity of diabetic phenotypes, and the current state of and future prospects for precision medicine in diabetes.
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Affiliation(s)
- William T. Cefalu
- Division of Diabetes, Endocrinology and Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - Dana K. Andersen
- Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - Guillermo Arreaza-Rubín
- Division of Diabetes, Endocrinology and Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - Christopher L. Pin
- Departments of Physiology and Pharmacology, Paediatrics, and Oncology, University of Western Ontario, and Genetics and Development Division, Children’s Health Research Institute, Lawson Health Research Institute, London, Ontario, Canada
| | - Sheryl Sato
- Division of Diabetes, Endocrinology and Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - C. Bruce Verchere
- Departments of Surgery and Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
- BC Children’s Hospital, Vancouver, British Columbia, Canada
- UBC Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada
| | - Minna Woo
- Departments of Medicine and Immunology, University of Toronto, Toronto, Ontario, Canada
- Division of Endocrinology and Metabolism, University Health Network and Sinai Health System, Toronto, Ontario, Canada
- Toronto General Hospital Research Institute, Toronto, Ontario, Canada
| | - Norman D. Rosenblum
- Canadian Institutes of Health Research Institute of Nutrition, Metabolism and Diabetes, Toronto, Ontario, Canada
- Division of Nephrology, Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada
- Program in Stem Cell and Developmental Biology, Research Institute, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada
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33
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Current Status, Barriers, and Future Directions for Humanized Mouse Models to Evaluate Stem Cell–Based Islet Cell Transplant. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1387:89-106. [DOI: 10.1007/5584_2022_711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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34
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Cefalu WT, Andersen DK, Arreaza-Rubín G, Pin CL, Sato S, Verchere CB, Woo M, Rosenblum ND. Heterogeneity of Diabetes: β-Cells, Phenotypes, and Precision Medicine: Proceedings of an International Symposium of the Canadian Institutes of Health Research's Institute of Nutrition, Metabolism and Diabetes and the U.S. National Institutes of Health's National Institute of Diabetes and Digestive and Kidney Diseases. Can J Diabetes 2021; 45:697-713. [PMID: 34794897 DOI: 10.1016/j.jcjd.2021.09.126] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 09/23/2021] [Indexed: 10/19/2022]
Abstract
One hundred years have passed since the discovery of insulin-an achievement that transformed diabetes from a fatal illness into a manageable chronic condition. The decades since that momentous achievement have brought ever more rapid innovation and advancement in diabetes research and clinical care. To celebrate the important work of the past century and help to chart a course for its continuation into the next, the Canadian Institutes of Health Research's Institute of Nutrition, Metabolism and Diabetes and the U.S. National Institutes of Health's National Institute of Diabetes and Digestive and Kidney Diseases recently held a joint international symposium, bringing together a cohort of researchers with diverse interests and backgrounds from both countries and beyond to discuss their collective quest to better understand the heterogeneity of diabetes and thus gain insights to inform new directions in diabetes treatment and prevention. This article summarizes the proceedings of that symposium, which spanned cutting-edge research into various aspects of islet biology, the heterogeneity of diabetic phenotypes, and the current state of and future prospects for precision medicine in diabetes.
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Affiliation(s)
- William T Cefalu
- Division of Diabetes, Endocrinology and Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States.
| | - Dana K Andersen
- Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States
| | - Guillermo Arreaza-Rubín
- Division of Diabetes, Endocrinology and Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States
| | - Christopher L Pin
- Departments of Physiology and Pharmacology, Paediatrics, and Oncology, University of Western Ontario, and Genetics and Development Division, Children's Health Research Institute, Lawson Health Research Institute, London, Ontario, Canada
| | - Sheryl Sato
- Division of Diabetes, Endocrinology and Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States
| | - C Bruce Verchere
- Departments of Surgery and Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada; BC Children's Hospital, Vancouver, British Columbia, Canada; UBC Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada
| | - Minna Woo
- Departments of Medicine and Immunology, University of Toronto, Toronto, Ontario, Canada; Division of Endocrinology and Metabolism, University Health Network and Sinai Health System, Toronto, Ontario, Canada; Toronto General Hospital Research Institute, Toronto, Ontario, Canada
| | - Norman D Rosenblum
- Canadian Institutes of Health Research's Institute of Nutrition, Metabolism and Diabetes, Toronto, Ontario, Canada; Division of Nephrology, Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada; Program in Stem Cell and Developmental Biology, Research Institute, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada
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35
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Kim M, Jang J. Construction of 3D hierarchical tissue platforms for modeling diabetes. APL Bioeng 2021; 5:041506. [PMID: 34703970 PMCID: PMC8530538 DOI: 10.1063/5.0055128] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 09/27/2021] [Indexed: 12/14/2022] Open
Abstract
Diabetes mellitus (DM) is one of the most serious systemic diseases worldwide, and the majority of DM patients face severe complications. However, many of underlying disease mechanisms related to these complications are difficult to understand with the use of currently available animal models. With the urgent need to fundamentally understand DM pathology, a variety of 3D biomimetic platforms have been generated by the convergence of biofabrication and tissue engineering strategies for the potent drug screening platform of pre-clinical research. Here, we suggest key requirements for the fabrication of physiomimetic tissue models in terms of recapitulating the cellular organization, creating native 3D microenvironmental niches for targeted tissue using biomaterials, and applying biofabrication technologies to implement tissue-specific geometries. We also provide an overview of various in vitro DM models, from a cellular level to complex living systems, which have been developed using various bioengineering approaches. Moreover, we aim to discuss the roadblocks facing in vitro tissue models and end with an outlook for future DM research.
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Affiliation(s)
- Myungji Kim
- School of Interdisciplinary Bioscience and Bioengineering, POSTECH, 77 Cheongam-ro, Namgu, Pohang, Kyungbuk, 37673, Republic of Korea
| | - Jinah Jang
- Author to whom correspondence should be addressed:
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Abstract
In Cell Stem Cell, Aghazadeh et al.1 show that human embryonic stem cell-derived pancreatic progenitors can reverse hyperglycemia for several weeks in streptozotocin-induced diabetic mice when co-transplanted with microvessel fragments into the subcutaneous space.
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Affiliation(s)
- Corinne A Hoesli
- Department of Chemical Engineering, McGill University, Montreal, QC, Canada.,Department of Biomedical Engineering, McGill University, Montreal, QC, Canada
| | - Timothy J Kieffer
- Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.,Department of Surgery, University of British Columbia, Vancouver, BC, Canada.,School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada
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37
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Cefalu WT, Andersen DK, Arreaza-Rubín G, Pin CL, Sato S, Verchere CB, Woo M, Rosenblum ND. Heterogeneity of Diabetes: β-Cells, Phenotypes, and Precision Medicine: Proceedings of an International Symposium of the Canadian Institutes of Health Research's Institute of Nutrition, Metabolism and Diabetes and the U.S. National Institutes of Health's National Institute of Diabetes and Digestive and Kidney Diseases. Diabetes 2021; 71:db210777. [PMID: 34782351 PMCID: PMC8763877 DOI: 10.2337/db21-0777] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 09/23/2021] [Indexed: 11/13/2022]
Abstract
One hundred years have passed since the discovery of insulin-an achievement that transformed diabetes from a fatal illness into a manageable chronic condition. The decades since that momentous achievement have brought ever more rapid innovation and advancement in diabetes research and clinical care. To celebrate the important work of the past century and help to chart a course for its continuation into the next, the Canadian Institutes of Health Research's Institute of Nutrition, Metabolism and Diabetes and the U.S. National Institutes of Health's National Institute of Diabetes and Digestive and Kidney Diseases recently held a joint international symposium, bringing together a cohort of researchers with diverse interests and backgrounds from both countries and beyond to discuss their collective quest to better understand the heterogeneity of diabetes and thus gain insights to inform new directions in diabetes treatment and prevention. This article summarizes the proceedings of that symposium, which spanned cutting-edge research into various aspects of islet biology, the heterogeneity of diabetic phenotypes, and the current state of and future prospects for precision medicine in diabetes.
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Affiliation(s)
- William T Cefalu
- Division of Diabetes, Endocrinology and Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - Dana K Andersen
- Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - Guillermo Arreaza-Rubín
- Division of Diabetes, Endocrinology and Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - Christopher L Pin
- Departments of Physiology and Pharmacology, Paediatrics, and Oncology, University of Western Ontario, and Genetics and Development Division, Children's Health Research Institute, Lawson Health Research Institute, London, Ontario, Canada
| | - Sheryl Sato
- Division of Diabetes, Endocrinology and Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - C Bruce Verchere
- Departments of Surgery and Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
- BC Children's Hospital, Vancouver, British Columbia, Canada
- UBC Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada
| | - Minna Woo
- Departments of Medicine and Immunology, University of Toronto, Toronto, Ontario, Canada
- Division of Endocrinology and Metabolism, University Health Network and Sinai Health System, Toronto, Ontario, Canada
- Toronto General Hospital Research Institute, Toronto, Ontario, Canada
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38
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Aghazadeh Y, Poon F, Sarangi F, Wong FTM, Khan ST, Sun X, Hatkar R, Cox BJ, Nunes SS, Nostro MC. Microvessels support engraftment and functionality of human islets and hESC-derived pancreatic progenitors in diabetes models. Cell Stem Cell 2021; 28:1936-1949.e8. [PMID: 34480863 DOI: 10.1016/j.stem.2021.08.001] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 04/27/2021] [Accepted: 08/04/2021] [Indexed: 12/19/2022]
Abstract
Islet transplantation is a promising treatment for type 1 diabetes (T1D), yet the low donor pool, poor islet engraftment, and life-long immunosuppression prevent it from becoming the standard of care. Human embryonic stem cell (hESC)-derived pancreatic cells could eliminate donor shortages, but interventions to improve graft survival are needed. Here, we enhanced subcutaneous engraftment by employing a unique vascularization strategy based on ready-made microvessels (MVs) isolated from the adipose tissue. This resulted in improved cell survival and effective glucose response of both human islets and hESC-derived pancreatic cells, which ameliorated preexisting diabetes in three mouse models of T1D.
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Affiliation(s)
- Yasaman Aghazadeh
- McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada
| | - Frankie Poon
- McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Deparment of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Farida Sarangi
- McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada
| | - Frances T M Wong
- Deparment of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Safwat T Khan
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada
| | - Xuetao Sun
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada
| | - Rupal Hatkar
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada
| | - Brian J Cox
- Deparment of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Obstetrics and Gynecology, University of Toronto, Toronto, ON M5G 1E2, Canada
| | - Sara S Nunes
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada; Laboratory of Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Heart & Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, ON M5S 3H2, Canada.
| | - M Cristina Nostro
- McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Deparment of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
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Wang X, Brown NK, Wang B, Shariati K, Wang K, Fuchs S, Melero‐Martin JM, Ma M. Local Immunomodulatory Strategies to Prevent Allo-Rejection in Transplantation of Insulin-Producing Cells. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:e2003708. [PMID: 34258870 PMCID: PMC8425879 DOI: 10.1002/advs.202003708] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 05/12/2021] [Indexed: 05/02/2023]
Abstract
Islet transplantation has shown promise as a curative therapy for type 1 diabetes (T1D). However, the side effects of systemic immunosuppression and limited long-term viability of engrafted islets, together with the scarcity of donor organs, highlight an urgent need for the development of new, improved, and safer cell-replacement strategies. Induction of local immunotolerance to prevent allo-rejection against islets and stem cell derived β cells has the potential to improve graft function and broaden the applicability of cellular therapy while minimizing adverse effects of systemic immunosuppression. In this mini review, recent developments in non-encapsulation, local immunomodulatory approaches for T1D cell replacement therapies, including islet/β cell modification, immunomodulatory biomaterial platforms, and co-transplantation of immunomodulatory cells are discussed. Key advantages and remaining challenges in translating such technologies to clinical settings are identified. Although many of the studies discussed are preliminary, the growing interest in the field has led to the exploration of new combinatorial strategies involving cellular engineering, immunotherapy, and novel biomaterials. Such interdisciplinary research will undoubtedly accelerate the development of therapies that can benefit the whole T1D population.
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Affiliation(s)
- Xi Wang
- Department of Biological and Environmental EngineeringCornell UniversityIthacaNY14853USA
| | - Natalie K. Brown
- Department of Biological and Environmental EngineeringCornell UniversityIthacaNY14853USA
| | - Bo Wang
- Department of Biological and Environmental EngineeringCornell UniversityIthacaNY14853USA
| | - Kaavian Shariati
- Department of Biological and Environmental EngineeringCornell UniversityIthacaNY14853USA
| | - Kai Wang
- Department of Cardiac SurgeryBoston Children's HospitalBostonMA02115USA
- Department of SurgeryHarvard Medical SchoolBostonMA02115USA
| | - Stephanie Fuchs
- Department of Biological and Environmental EngineeringCornell UniversityIthacaNY14853USA
| | - Juan M. Melero‐Martin
- Department of Cardiac SurgeryBoston Children's HospitalBostonMA02115USA
- Department of SurgeryHarvard Medical SchoolBostonMA02115USA
- Harvard Stem Cell InstituteCambridgeMA02138USA
| | - Minglin Ma
- Department of Biological and Environmental EngineeringCornell UniversityIthacaNY14853USA
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40
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Siehler J, Blöchinger AK, Meier M, Lickert H. Engineering islets from stem cells for advanced therapies of diabetes. Nat Rev Drug Discov 2021; 20:920-940. [PMID: 34376833 DOI: 10.1038/s41573-021-00262-w] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/22/2021] [Indexed: 12/20/2022]
Abstract
Diabetes mellitus is a metabolic disorder that affects more than 460 million people worldwide. Type 1 diabetes (T1D) is caused by autoimmune destruction of β-cells, whereas type 2 diabetes (T2D) is caused by a hostile metabolic environment that leads to β-cell exhaustion and dysfunction. Currently, first-line medications treat the symptomatic insulin resistance and hyperglycaemia, but do not prevent the progressive decline of β-cell mass and function. Thus, advanced therapies need to be developed that either protect or regenerate endogenous β-cell mass early in disease progression or replace lost β-cells with stem cell-derived β-like cells or engineered islet-like clusters. In this Review, we discuss the state of the art of stem cell differentiation and islet engineering, reflect on current and future challenges in the area and highlight the potential for cell replacement therapies, disease modelling and drug development using these cells. These efforts in stem cell and regenerative medicine will lay the foundations for future biomedical breakthroughs and potentially curative treatments for diabetes.
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Affiliation(s)
- Johanna Siehler
- Institute of Stem Cell Research, Helmholtz Zentrum München, Neuherberg, Germany.,Technical University of Munich, Medical Faculty, Munich, Germany.,German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Anna Karolina Blöchinger
- Technical University of Munich, Medical Faculty, Munich, Germany.,German Center for Diabetes Research (DZD), Neuherberg, Germany.,Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Neuherberg, Germany
| | - Matthias Meier
- Technical University of Munich, Medical Faculty, Munich, Germany.,Helmholtz Pioneer Campus, Helmholtz Zentrum München, Neuherberg, Germany
| | - Heiko Lickert
- Institute of Stem Cell Research, Helmholtz Zentrum München, Neuherberg, Germany. .,Technical University of Munich, Medical Faculty, Munich, Germany. .,German Center for Diabetes Research (DZD), Neuherberg, Germany. .,Institute of Diabetes and Regeneration Research, Helmholtz Zentrum München, Neuherberg, Germany.
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41
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Hogrebe NJ, Maxwell KG, Augsornworawat P, Millman JR. Generation of insulin-producing pancreatic β cells from multiple human stem cell lines. Nat Protoc 2021; 16:4109-4143. [PMID: 34349281 DOI: 10.1038/s41596-021-00560-y] [Citation(s) in RCA: 113] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 04/19/2021] [Indexed: 12/13/2022]
Abstract
We detail a six-stage planar differentiation methodology for generating human pluripotent stem cell-derived pancreatic β cells (SC-β cells) that secrete high amounts of insulin in response to glucose stimulation. This protocol first induces definitive endoderm by treatment with Activin A and CHIR99021, then generates PDX1+/NKX6-1+ pancreatic progenitors through the timed application of keratinocyte growth factor, SANT1, TPPB, LDN193189 and retinoic acid. Endocrine induction and subsequent SC-β-cell specification is achieved with a cocktail consisting of the cytoskeletal depolymerizing compound latrunculin A combined with XXI, T3, ALK5 inhibitor II, SANT1 and retinoic acid. The resulting SC-β cells and other endocrine cell types can then be aggregated into islet-like clusters for analysis and transplantation. This differentiation methodology takes ~34 d to generate functional SC-β cells, plus an additional 1-2 weeks for initial stem cell expansion and final cell assessment. This protocol builds upon a large body of previous work for generating β-like cells. In this iteration, we have eliminated the need for 3D culture during endocrine induction, allowing for the generation of highly functional SC-β cells to be done entirely on tissue culture polystyrene. This change simplifies the differentiation methodology, requiring only basic stem cell culture experience as well as familiarity with assessment techniques common in biology laboratories. In addition to expanding protocol accessibility and simplifying SC-β-cell generation, we demonstrate that this planar methodology is amenable for differentiating SC-β cells from a wide variety of cell lines from various sources, broadening its applicability.
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Affiliation(s)
- Nathaniel J Hogrebe
- Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, MO, USA
| | - Kristina G Maxwell
- Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, MO, USA.,Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, USA
| | - Punn Augsornworawat
- Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, MO, USA.,Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, USA
| | - Jeffrey R Millman
- Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, MO, USA. .,Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, USA.
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42
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Soetedjo AAP, Lee JM, Lau HH, Goh GL, An J, Koh Y, Yeong WY, Teo AKK. Tissue engineering and 3D printing of bioartificial pancreas for regenerative medicine in diabetes. Trends Endocrinol Metab 2021; 32:609-622. [PMID: 34154916 DOI: 10.1016/j.tem.2021.05.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 05/17/2021] [Accepted: 05/24/2021] [Indexed: 02/08/2023]
Abstract
Diabetes is a severe chronic disease worldwide. In various types of diabetes, the pancreatic beta cells fail to secrete sufficient insulin, at some point, to regulate blood glucose levels. Therefore, the replacement of dysfunctional pancreas, islets of Langerhans, or even the insulin-secreting beta cells facilitates physiological regulation of blood glucose levels. However, the current lack of sufficient donor human islets for cell replacement therapy precludes a routine and absolute cure for most of the existing diabetes cases globally. It is envisioned that tissue engineering of a bioartificial pancreas will revolutionize regenerative medicine and the treatment of diabetes. In this review, we discuss the anatomy and physiology of the pancreas, and identify the clinical considerations for engineering a bioartificial pancreas. Subsequently, we dissect the bioengineering problem based on the design of the device, the biomaterial used, and the cells involved. Last but not least, we highlight current tissue engineering challenges and explore potential directions for future work.
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Affiliation(s)
- Andreas Alvin Purnomo Soetedjo
- Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology (IMCB), A*STAR, Singapore; Integrative Sciences and Engineering Programme, NUS Graduate School, National University of Singapore, Singapore
| | - Jia Min Lee
- School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore
| | - Hwee Hui Lau
- Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology (IMCB), A*STAR, Singapore; School of Biological Sciences, Nanyang Technological University, Singapore
| | - Guo Liang Goh
- Singapore Centre for 3D Printing (SC3DP), School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore
| | - Jia An
- Singapore Centre for 3D Printing (SC3DP), School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore
| | - Yexin Koh
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore
| | - Wai Yee Yeong
- Singapore Centre for 3D Printing (SC3DP), School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore
| | - Adrian Kee Keong Teo
- Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology (IMCB), A*STAR, Singapore; Department of Biochemistry and Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
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43
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Wang X, Maxwell KG, Wang K, Bowers DT, Flanders JA, Liu W, Wang LH, Liu Q, Liu C, Naji A, Wang Y, Wang B, Chen J, Ernst AU, Melero-Martin JM, Millman JR, Ma M. A nanofibrous encapsulation device for safe delivery of insulin-producing cells to treat type 1 diabetes. Sci Transl Med 2021; 13:eabb4601. [PMID: 34078744 PMCID: PMC8563008 DOI: 10.1126/scitranslmed.abb4601] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 02/09/2021] [Accepted: 04/28/2021] [Indexed: 12/12/2022]
Abstract
Transplantation of stem cell-derived β (SC-β) cells represents a promising therapy for type 1 diabetes (T1D). However, the delivery, maintenance, and retrieval of these cells remain a challenge. Here, we report the design of a safe and functional device composed of a highly porous, durable nanofibrous skin and an immunoprotective hydrogel core. The device consists of electrospun medical-grade thermoplastic silicone-polycarbonate-urethane and is soft but tough (~15 megapascal at a rupture strain of >2). Tuning the nanofiber size to less than ~500 nanometers prevented cell penetration while maintaining maximum mass transfer and decreased cellular overgrowth on blank (cell-free) devices to as low as a single-cell layer (~3 micrometers thick) when implanted in the peritoneal cavity of mice. We confirmed device safety, indicated as continuous containment of proliferative cells within the device for 5 months. Encapsulating syngeneic, allogeneic, or xenogeneic rodent islets within the device corrected chemically induced diabetes in mice and cells remained functional for up to 200 days. The function of human SC-β cells was supported by the device, and it reversed diabetes within 1 week of implantation in immunodeficient and immunocompetent mice, for up to 120 and 60 days, respectively. We demonstrated the scalability and retrievability of the device in dogs and observed viable human SC-β cells despite xenogeneic immune responses. The nanofibrous device design may therefore provide a translatable solution to the balance between safety and functionality in developing stem cell-based therapies for T1D.
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Affiliation(s)
- Xi Wang
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Kristina G Maxwell
- Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA
- Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, USA
| | - Kai Wang
- Department of Cardiac Surgery, Boston Children's Hospital, Boston, MA 02115, USA
- Department of Surgery, Harvard Medical School, Boston, MA 02115, USA
| | - Daniel T Bowers
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA
| | - James A Flanders
- Department of Clinical Sciences, Cornell University, Ithaca, NY 14853, USA
| | - Wanjun Liu
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Long-Hai Wang
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Qingsheng Liu
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Chengyang Liu
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Ali Naji
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Yong Wang
- Division of Transplant Surgery, University of Virginia, Charlottesville, VA 22904, USA
| | - Bo Wang
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Jing Chen
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Alexander U Ernst
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Juan M Melero-Martin
- Department of Cardiac Surgery, Boston Children's Hospital, Boston, MA 02115, USA
- Department of Surgery, Harvard Medical School, Boston, MA 02115, USA
- Harvard Stem Cell Institute, Cambridge, MA 02138, USA
| | - Jeffrey R Millman
- Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA.
- Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, USA
| | - Minglin Ma
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA.
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Abstract
As part of the centennial celebration of insulin's discovery, this review summarizes the current understanding of the genetics, pathogenesis, treatment, and outcomes in type 1 diabetes (T1D). T1D results from an autoimmune response that leads to destruction of the β cells in the pancreatic islet and requires lifelong insulin therapy. While much has been learned about T1D, it is now clear that there is considerable heterogeneity in T1D with regard to genetics, pathology, response to immune-based therapies, clinical course, and susceptibility to diabetes-related complications. This Review highlights knowledge gaps and opportunities to improve the understanding of T1D pathogenesis and outlines emerging therapies to treat or prevent T1D and reduce the burden of T1D.
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45
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Li H, Zhu H, Ge T, Wang Z, Zhang C. Mesenchymal Stem Cell-Based Therapy for Diabetes Mellitus: Enhancement Strategies and Future Perspectives. Stem Cell Rev Rep 2021; 17:1552-1569. [PMID: 33675006 DOI: 10.1007/s12015-021-10139-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/14/2021] [Indexed: 12/11/2022]
Abstract
Diabetes mellitus (DM), a chronic disorder of carbohydrate metabolism, is characterized by the unbridled hyperglycemia resulted from the impaired ability of the body to either produce or respond to insulin. As a cell-based regenerative therapy, mesenchymal stem cells (MSCs) hold immense potency for curing DM duo to their easy isolation, multi-differentiation potential, and immunomodulatory property. However, despite the promising efficacy in pre-clinical animal models, naive MSC administration fails to exhibit clinically satisfactory therapeutic outcomes, which varies greatly among individuals with DM. Recently, numbers of innovative strategies have been applied to improve MSC-based therapy. Preconditioning, genetic modification, combination therapy and exosome application are representative strategies to maximize the therapeutic benefits of MSCs. Therefore, in this review, we summarize recent advancements in mechanistic studies of MSCs-based treatment for DM, and mainly focus on the novel approaches aiming to improve the anti-diabetic potentials of naive MSCs. Additionally, the potential directions of MSCs-based therapy for DM are also proposed at a glance.
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Affiliation(s)
- Haisen Li
- Department of Plastic and Reconstructive Surgery, Shanghai Institute of Precision Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China.,Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.,Sinoneural Cell Engineering Group Holdings Co., Ltd., Shanghai 201100, China
| | - Hao Zhu
- Sinoneural Cell Engineering Group Holdings Co., Ltd., Shanghai 201100, China
| | - Ting Ge
- Xinxiang First People's Hospital, Xinxiang 453000, China
| | - Zhifeng Wang
- Department of Plastic and Reconstructive Surgery, Shanghai Institute of Precision Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China. .,Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China. .,Sinoneural Cell Engineering Group Holdings Co., Ltd., Shanghai 201100, China.
| | - Chao Zhang
- Department of Plastic and Reconstructive Surgery, Shanghai Institute of Precision Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China. .,Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
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46
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Pancreas transplant versus islet transplant versus insulin pump therapy: in which patients and when? Curr Opin Organ Transplant 2021; 26:176-183. [PMID: 33650999 DOI: 10.1097/mot.0000000000000857] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
PURPOSE OF REVIEW The aim of the present review is to gather recent reports on the use of pancreas and islet transplantation and conventional insulin therapy for treating patients experiencing diabetes and its related complications. The present review directs attention to the current status, challenges and perspectives of these therapies and sheds light on potential future cellular therapies. RECENT FINDINGS The risks and benefits of diabetes treatment modalities continue to evolve, altering the risk versus benefit calculation for patients. As continuous subcutaneous insulin infusion and monitoring technologies demonstrate increasing effectiveness in achieving better diabetes control and reducing hypoglycemia frequency, so are pancreas and islet transplantation improving and becoming more effective and safer. Both beta-cell replacement therapies, however, are limited by a dependence on immunosuppression and a shortage of cadaver donors, restricting more widespread and safer deployment. Based on the effectiveness of clinical beta-cell replacement for lengthening lifespan and improving quality of life, scientists are aggressively investigating alternative cell sources, transplant platforms, and means of preventing immunological damage of transplanted cells to overcome these principle limitations. SUMMARY Essential goals of diabetes therapy are euglycemia, avoidance of hypoglycemia, and prevention or stabilization of end-organ damage. With these goals in mind, all therapeutic options should be considered.
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Choe HJ, Cho YM. Invincible β-cells in type 1 diabetes. J Diabetes Investig 2021; 12:137-139. [PMID: 32686209 PMCID: PMC7858098 DOI: 10.1111/jdi.13362] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 07/09/2020] [Accepted: 07/13/2020] [Indexed: 12/16/2022] Open
Affiliation(s)
- Hun Jee Choe
- Department of Internal MedicineSeoul National University College of MedicineSeoulKorea
| | - Young Min Cho
- Department of Internal MedicineSeoul National University College of MedicineSeoulKorea
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Verhoeff K, Henschke SJ, Marfil-Garza BA, Dadheech N, Shapiro AMJ. Inducible Pluripotent Stem Cells as a Potential Cure for Diabetes. Cells 2021; 10:cells10020278. [PMID: 33573247 PMCID: PMC7911560 DOI: 10.3390/cells10020278] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2021] [Revised: 01/22/2021] [Accepted: 01/24/2021] [Indexed: 02/07/2023] Open
Abstract
Over the last century, diabetes has been treated with subcutaneous insulin, a discovery that enabled patients to forego death from hyperglycemia. Despite novel insulin formulations, patients with diabetes continue to suffer morbidity and mortality with unsustainable costs to the health care system. Continuous glucose monitoring, wearable insulin pumps, and closed-loop artificial pancreas systems represent an advance, but still fail to recreate physiologic euglycemia and are not universally available. Islet cell transplantation has evolved into a successful modality for treating a subset of patients with ‘brittle’ diabetes but is limited by organ donor supply and immunosuppression requirements. A novel approach involves generating autologous or immune-protected islet cells for transplant from inducible pluripotent stem cells to eliminate detrimental immune responses and organ supply limitations. In this review, we briefly discuss novel mechanisms for subcutaneous insulin delivery and define their shortfalls. We describe embryological development and physiology of islets to better understand their role in glycemic control and, finally, discuss cell-based therapies for diabetes and barriers to widespread use. In response to these barriers, we present the promise of stem cell therapy, and review the current gaps requiring solutions to enable widespread use of stem cells as a potential cure for diabetes.
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Affiliation(s)
- Kevin Verhoeff
- Department of Surgery, University of Alberta, Edmonton, AB T6G 2B7, Canada;
- Correspondence: ; Tel.: +1-780-984-1836
| | - Sarah J. Henschke
- Department of Emergency Medicine, University of Saskatchewan, Saskatoon, SK S7N 0W8, Canada;
| | | | - Nidheesh Dadheech
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB T6G 2B7, Canada;
| | - Andrew Mark James Shapiro
- FRCS (Eng) FRCSC MSM FCAHS, Clinical Islet Transplant Program, Alberta Diabetes Institute, Department of Surgery, Canadian National Transplant Research Program, Edmonton, AB T6G 2B7, Canada;
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49
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Helman A, Melton DA. A Stem Cell Approach to Cure Type 1 Diabetes. Cold Spring Harb Perspect Biol 2021; 13:cshperspect.a035741. [PMID: 32122884 PMCID: PMC7778150 DOI: 10.1101/cshperspect.a035741] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Treatment of type 1 diabetes with insulin injection is expensive, complicated, and insufficient. While cadaveric islet transplantations coupled with immunosuppressants can cure diabetes, the scarcity of acceptable islets is problematic. Developmental research on pancreas formation has informed in vitro differentiation of human pluripotent stem cells into functional islets. Although generating β cells from stem cells offers a potential cure for type 1 diabetes, several challenges remain, including protecting the cells from the immune system.
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50
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Yang H, Qin D, Xu S, He C, Sun J, Hua J, Peng S. Folic acid promotes proliferation and differentiation of porcine pancreatic stem cells into insulin-secreting cells through canonical Wnt and ERK signaling pathway. J Steroid Biochem Mol Biol 2021; 205:105772. [PMID: 33091596 DOI: 10.1016/j.jsbmb.2020.105772] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Revised: 09/29/2020] [Accepted: 10/04/2020] [Indexed: 11/16/2022]
Abstract
Porcine pancreatic stem cells (pPSCs) can be induced to differentiate into insulin-producing cells in vitro and thus serve as a major cells source for β-cell regeneration. However, this application is limited by the weak cell proliferation ability and low insulin induction efficiency. In this study, we explored the role of folic acid in the proliferation of pPSCs and the formation of insulin-secreting cells. We found that FA-treated pPSCs cells had a high EDU positive rate, and the proliferation marker molecules PCNA, CyclinD1 and c-Myc were up-regulated, while the expression of folate receptor α (FOLRα) was up-regulated. In further research, interference FOLRα or adding canonical Wnt signaling pathway or ERK signaling pathway inhibitors could significantly inhibit the effect of FA on pPSCs proliferation. Meanwhile, during the differentiation of pPSCs into insulin-secreting cells, we found that the maturation marker genes Insulin, NKX6.1, MafA, and NeuroD1 was upregulated in insulin-secreting cell masses differentiationed from pPSCs after FA treatment, and the functional molecules Insulin and C-peptide were increased, the ability to secrete insulin in response to high glucose was also increased. With the addition of Wnt and ERK signaling pathway inhibitors, the pro-differentiation effect of FA was weakened. In conclusion, FA promotes the proliferation of pPSCs by binding to folate receptor α (FOLRα) and increase the efficiency of directed differentiation of pPSCs into insulin-producing cells by regulating canonical Wnt and ERK signaling pathway. This study lays theoretical foundation for solving the bottleneck in the treatment of diabetes with stem cell transplantation in future.
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Affiliation(s)
- Hong Yang
- College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering & Technology, Northwest A&F University, Yangling, Shaanxi, 712100, PR China
| | - Dezhe Qin
- College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering & Technology, Northwest A&F University, Yangling, Shaanxi, 712100, PR China
| | - Shuanshuan Xu
- College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering & Technology, Northwest A&F University, Yangling, Shaanxi, 712100, PR China
| | - Chen He
- College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering & Technology, Northwest A&F University, Yangling, Shaanxi, 712100, PR China
| | - Jing Sun
- College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering & Technology, Northwest A&F University, Yangling, Shaanxi, 712100, PR China
| | - Jinlian Hua
- College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering & Technology, Northwest A&F University, Yangling, Shaanxi, 712100, PR China
| | - Sha Peng
- College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering & Technology, Northwest A&F University, Yangling, Shaanxi, 712100, PR China.
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