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Wang Y, Chen Y, McGarrigle J, Cook J, Rios PD, La Monica G, Wei W, Oberholzer J. Cell Therapy for T1D Beyond BLA: Gearing Up Toward Clinical Practice. Diabetes Ther 2025; 16:1125-1138. [PMID: 40214896 PMCID: PMC12085407 DOI: 10.1007/s13300-025-01732-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Accepted: 03/18/2025] [Indexed: 05/18/2025] Open
Abstract
Type 1 diabetes (T1D) remains a significant global health challenge and patients with T1D need lifelong insulin therapy. Islet transplantation holds transformative potential by replacing autoimmune-mediated destruction of insulin-producing beta cells. This review examines the trajectory of islet transplantation for T1D, focusing on the process and benefits of obtaining biologics license application (BLA) approval for cell-based therapies. Following US Food and Drug Administration (FDA) approval, the authors identify key steps urgently needed to foster islet transplantation as a viable treatment for a broader population of patients with T1D. Furthermore, the authors highlight recent advances in encapsulation technologies, stem cell-derived islets, xenogeneic islets, and gene editing as strategies to overcome challenges such as immune rejection and limited islet sources. These innovations are pivotal in enhancing the safety and efficacy of islet transplantation. Ultimately, this review emphasizes that while BLA approval represents a critical milestone, realizing the full potential of cell therapy for T1D requires addressing the scientific, clinical, and logistical challenges of its real-world implementation. By fostering innovation, collaboration, and strategic partnerships, the field can transform T1D care, offering patients a durable, life-changing alternative to traditional insulin therapy.
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Affiliation(s)
- Yong Wang
- CellTrans, Inc., 2201 W. Campbell Park Dr, Chicago, IL, 60612, USA.
- University of Zürich Hospital, Ramistrasse 100, 8991, Zürich, Switzerland.
- Visceral and Transplant Department, University of Zürich Hospital, Ramistrasse 100, 8991, Zürich, Switzerland.
| | - YingYing Chen
- University of Zürich Hospital, Ramistrasse 100, 8991, Zürich, Switzerland
| | - James McGarrigle
- CellTrans, Inc., 2201 W. Campbell Park Dr, Chicago, IL, 60612, USA
| | - Jenny Cook
- CellTrans, Inc., 2201 W. Campbell Park Dr, Chicago, IL, 60612, USA
| | - Peter D Rios
- CellTrans, Inc., 2201 W. Campbell Park Dr, Chicago, IL, 60612, USA
| | | | - Wei Wei
- University of Zürich Hospital, Ramistrasse 100, 8991, Zürich, Switzerland
| | - Jose Oberholzer
- CellTrans, Inc., 2201 W. Campbell Park Dr, Chicago, IL, 60612, USA.
- University of Zürich Hospital, Ramistrasse 100, 8991, Zürich, Switzerland.
- Visceral and Transplant Department, University of Zürich Hospital, Ramistrasse 100, 8991, Zürich, Switzerland.
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Wang Y, McGarrigle J, Cook J, Rios P, Monica GL, Chen Y, Wei W, Oberholzer J. The future of islet transplantation beyond the BLA approval: challenges and opportunities. FRONTIERS IN TRANSPLANTATION 2025; 4:1522409. [PMID: 40124184 PMCID: PMC11925927 DOI: 10.3389/frtra.2025.1522409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 02/19/2025] [Indexed: 03/25/2025]
Abstract
This opinion paper explores the path forward for islet transplantation as a cell therapy for type 1 diabetes, following the Biologics License Application (BLA) approval. The authors review key challenges and opportunities that lie ahead. After a brief overview of the history of human islet transplantation, the paper examines the FDA's regulatory stance on isolated islet cells and the requirements for obtaining a BLA. The authors discuss the significance of this approval and the critical steps necessary to broaden patient access, such as scaling up production, clinical integration, reimbursement frameworks, post-marketing surveillance, and patient education initiatives. The paper highlights that the approval of LANTIDRA as an allogeneic cell transplant for uncontrolled type 1 diabetes marks the beginning of new chapters in improving islet transplantation. The authors emphasize essential areas for development, including advancements in islet manufacturing, optimization of transplant sites, islet encapsulation, exploration of unlimited cell sources, and gene editing technologies. In conclusion, the future of islet transplantation beyond the BLA approval presents challenges and opportunities. While significant regulatory milestones have been reached, hurdles remain. Innovations in stem cell-derived islets, cell encapsulation, and gene editing show promise in enhancing graft survival, expanding the availability of transplantable cells, and reducing the reliance on immunosuppressive drugs. These advancements could pave the way for more accessible, durable, and personalized diabetes treatments.
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Affiliation(s)
- Yong Wang
- Clinic of Visceral and Transplant Surgery, University Hospital Zurich, Zurich, Switzerland
- Faculty of Medicine, University of Zurich, Zürich, Switzerland
- CellTrans, Inc., Chicago, IL, United States
| | | | - Jenny Cook
- CellTrans, Inc., Chicago, IL, United States
| | - Peter Rios
- CellTrans, Inc., Chicago, IL, United States
| | | | - Yingying Chen
- Clinic of Visceral and Transplant Surgery, University Hospital Zurich, Zurich, Switzerland
- Faculty of Medicine, University of Zurich, Zürich, Switzerland
| | - Wei Wei
- Clinic of Visceral and Transplant Surgery, University Hospital Zurich, Zurich, Switzerland
- Faculty of Medicine, University of Zurich, Zürich, Switzerland
| | - Jose Oberholzer
- Clinic of Visceral and Transplant Surgery, University Hospital Zurich, Zurich, Switzerland
- Faculty of Medicine, University of Zurich, Zürich, Switzerland
- CellTrans, Inc., Chicago, IL, United States
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Rech Tondin A, Lanzoni G. Islet Cell Replacement and Regeneration for Type 1 Diabetes: Current Developments and Future Prospects. BioDrugs 2025; 39:261-280. [PMID: 39918671 PMCID: PMC11906537 DOI: 10.1007/s40259-025-00703-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/05/2025] [Indexed: 03/14/2025]
Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disorder characterized by the destruction of insulin-producing beta cells in the pancreas, leading to insulin deficiency and chronic hyperglycemia. The main current therapeutic strategies for clinically overt T1D - primarily exogenous insulin administration combined with blood glucose monitoring - fail to fully mimic physiological insulin regulation, often resulting in suboptimal or insufficient glycemic control. Islet cell transplantation has emerged as a promising avenue for functionally replacing endogenous insulin production and achieving long-term glycemic stability. Here, we provide an overview of current islet replacement strategies, ranging from islet transplantation to stem cell-derived islet cell transplantation, and highlight emerging approaches such as immunoengineering. We examine the advancements in immunosuppressive protocols to enhance graft survival, innovative encapsulation, and immunomodulation techniques to protect transplanted islets, and the ongoing challenges in achieving durable and functional islet integration. Additionally, we discuss the latest clinical outcomes, the potential of gene editing technologies, and the emerging strategies for islet cell regeneration. This review aims to highlight the potential of these approaches to transform the management of T1D and improve the quality of life of individuals affected by this condition.
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Affiliation(s)
- Arthur Rech Tondin
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Giacomo Lanzoni
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA.
- Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA.
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Mima A, Kimura A, Ito R, Hatano Y, Tsujimoto H, Mae SI, Yamane J, Fujibuchi W, Uza N, Toyoda T, Seno H, Osafune K. Mechanistic elucidation of human pancreatic acinar development using single-cell transcriptome analysis on a human iPSC differentiation model. Sci Rep 2025; 15:4668. [PMID: 39920294 PMCID: PMC11806057 DOI: 10.1038/s41598-025-88690-1] [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: 05/07/2024] [Accepted: 01/30/2025] [Indexed: 02/09/2025] Open
Abstract
Few effective treatments have been developed for intractable pancreatic exocrine disorders due to the lack of suitable disease models using human cells. Pancreatic acinar cells differentiated from human induced pluripotent stem cells (hiPSCs) have the potential to solve this issue. In this study, we aimed to elucidate the developmental mechanisms of pancreatic exocrine acinar lineages to establish a directed differentiation method for pancreatic acinar cells from hiPSCs. hiPSC-derived pancreatic endoderm cells were spontaneously differentiated into both pancreatic exocrine and endocrine tissues by implantation into the renal subcapsular space of NOD/SCID mice. Single-cell RNA-seq analysis of the retrieved grafts confirmed the differentiation of pancreatic acinar lineage cells and identified REG4 as a candidate marker for pancreatic acinar progenitor cells. Furthermore, differential gene expression analysis revealed upregulated pathways, including cAMP-related signals, involved in the differentiation of hiPSC-derived pancreatic acinar lineage cells in vivo, and we found that a cAMP activator, forskolin, facilitates the differentiation from hiPSC-derived pancreatic endoderm into pancreatic acinar progenitor cells in our in vitro differentiation culture. Therefore, this platform contributes to our understanding of the developmental mechanisms of pancreatic acinar lineage cells and the establishment of differentiation methods for acinar cells from hiPSCs.
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Affiliation(s)
- Atsushi Mima
- Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
- Department of Gastroenterology and Hepatology, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Azuma Kimura
- Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
- Rege Nephro Co., Ltd., Med-Pharm Collaboration Building, Kyoto University, 46-29 Yoshidashimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan
| | - Ryo Ito
- Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Yu Hatano
- Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Hiraku Tsujimoto
- Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
- Rege Nephro Co., Ltd., Med-Pharm Collaboration Building, Kyoto University, 46-29 Yoshidashimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan
| | - Shin-Ichi Mae
- Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Junko Yamane
- Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Wataru Fujibuchi
- Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Norimitsu Uza
- Department of Gastroenterology and Hepatology, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Taro Toyoda
- Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
| | - Hiroshi Seno
- Department of Gastroenterology and Hepatology, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
| | - Kenji Osafune
- Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
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Tran HT, Rodprasert W, Padeta I, Oontawee S, Purbantoro SD, Thongsit A, Siriarchavatana P, Srisuwatanasagul S, Egusa H, Osathanon T, Sawangmake C. Establishment of subcutaneous transplantation platform for delivering induced pluripotent stem cell-derived insulin-producing cells. PLoS One 2025; 20:e0318204. [PMID: 39883721 PMCID: PMC11781742 DOI: 10.1371/journal.pone.0318204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Accepted: 01/10/2025] [Indexed: 02/01/2025] Open
Abstract
Potential trend of regenerative treatment for type I diabetes has been introduced for more than a decade. However, the technologies regarding insulin-producing cell (IPC) production and transplantation are still being developed. Here, we propose the potential IPC production protocol employing mouse gingival fibroblast-derived induced pluripotent stem cells (mGF-iPSCs) as a resource and the pre-clinical approved subcutaneous IPC transplantation platform for further clinical confirmation study. With a multi-step induction protocol, the functional and matured IPCs were generated by 13 days with a long-term survival capability. Further double encapsulation of mGF-iPSC-derived IPCs (mGF-iPSC-IPCs) could preserve the insulin secretion capacity and the transplantation potential of the generated IPCs. To address the potential on IPC transplantation, a 2-step subcutaneous transplantation procedure was established, comprising 1) vascularized subcutaneous pocket formation and 2) encapsulated IPC bead transplantation. The in vivo testing confirmed the safety and efficiency of the platform along with less inflammatory response which may help minimize tissue reaction and graft rejection. Further preliminary in vivo testing on subcutaneous IPC-bead transplantation in an induced type I diabetic mouse model showed beneficial trends on blood glucose control and survival rate sustainability of diabetic mice. Taken together, an established mGF-iPSC-IPC generation protocol in this study will be the potential backbone for developing the iPSC-derived IPC production employing human and animal cell resources. As well as the potential further development of IPC transplantation platform for diabetes treatment in human and veterinary practices using an established subcutaneous encapsulated IPC-bead transplantation platform presented in this study.
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Affiliation(s)
- Hong Thuan Tran
- Second Century Fund (C2F) Chulalongkorn University for Doctoral Scholarship, Chulalongkorn University, Bangkok, Thailand
- Faculty of Veterinary Science, The International Graduate Program of Veterinary Science and Technology (VST), Chulalongkorn University, Bangkok, Thailand
- Faculty of Veterinary Science, Veterinary Clinical Stem Cell and Bioengineering Research Unit, Chulalongkorn University, Bangkok, Thailand
- Faculty of Veterinary Science, Veterinary Stem Cell and Bioengineering Innovation Center (VSCBIC), Chulalongkorn University, Bangkok, Thailand
| | - Watchareewan Rodprasert
- Faculty of Veterinary Science, Veterinary Clinical Stem Cell and Bioengineering Research Unit, Chulalongkorn University, Bangkok, Thailand
- Faculty of Veterinary Science, Veterinary Stem Cell and Bioengineering Innovation Center (VSCBIC), Chulalongkorn University, Bangkok, Thailand
| | - Irma Padeta
- Second Century Fund (C2F) Chulalongkorn University for Doctoral Scholarship, Chulalongkorn University, Bangkok, Thailand
- Faculty of Veterinary Science, The International Graduate Program of Veterinary Science and Technology (VST), Chulalongkorn University, Bangkok, Thailand
- Faculty of Veterinary Science, Veterinary Clinical Stem Cell and Bioengineering Research Unit, Chulalongkorn University, Bangkok, Thailand
- Faculty of Veterinary Science, Veterinary Stem Cell and Bioengineering Innovation Center (VSCBIC), Chulalongkorn University, Bangkok, Thailand
| | - Saranyou Oontawee
- Faculty of Veterinary Science, Veterinary Clinical Stem Cell and Bioengineering Research Unit, Chulalongkorn University, Bangkok, Thailand
- Faculty of Veterinary Science, Veterinary Stem Cell and Bioengineering Innovation Center (VSCBIC), Chulalongkorn University, Bangkok, Thailand
| | - Steven dwi Purbantoro
- Second Century Fund (C2F) Chulalongkorn University for Doctoral Scholarship, Chulalongkorn University, Bangkok, Thailand
- Faculty of Veterinary Science, The International Graduate Program of Veterinary Science and Technology (VST), Chulalongkorn University, Bangkok, Thailand
- Faculty of Veterinary Science, Veterinary Clinical Stem Cell and Bioengineering Research Unit, Chulalongkorn University, Bangkok, Thailand
- Faculty of Veterinary Science, Veterinary Stem Cell and Bioengineering Innovation Center (VSCBIC), Chulalongkorn University, Bangkok, Thailand
| | - Anatcha Thongsit
- Faculty of Veterinary Science, Veterinary Clinical Stem Cell and Bioengineering Research Unit, Chulalongkorn University, Bangkok, Thailand
- Faculty of Veterinary Science, Veterinary Stem Cell and Bioengineering Innovation Center (VSCBIC), Chulalongkorn University, Bangkok, Thailand
| | - Parkpoom Siriarchavatana
- Faculty of Veterinary Science, Veterinary Clinical Stem Cell and Bioengineering Research Unit, Chulalongkorn University, Bangkok, Thailand
- Faculty of Veterinary Science, Veterinary Stem Cell and Bioengineering Innovation Center (VSCBIC), Chulalongkorn University, Bangkok, Thailand
- Faculty of Veterinary Medicine, Western University, Kanchanaburi, Thailand
| | - Sayamon Srisuwatanasagul
- Faculty of Veterinary Science, Department of Anatomy, Chulalongkorn University, Bangkok, Thailand
| | - Hiroshi Egusa
- Division of Molecular and Regenerative Prosthodontics, Center for Advanced Stem Cell and Regenerative Research, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Thanaphum Osathanon
- Faculty of Dentistry, Dental Stem Cell Biology Research Unit and Department of Anatomy, Chulalongkorn University, Bangkok, Thailand
- Faculty of Dentistry, Center of Excellence in Regenerative Dentistry, Chulalongkorn University, Bangkok, Thailand
| | - Chenphop Sawangmake
- Faculty of Veterinary Science, Veterinary Clinical Stem Cell and Bioengineering Research Unit, Chulalongkorn University, Bangkok, Thailand
- Faculty of Veterinary Science, Veterinary Stem Cell and Bioengineering Innovation Center (VSCBIC), Chulalongkorn University, Bangkok, Thailand
- Faculty of Veterinary Science, Department of Pharmacology, Chulalongkorn University, Bangkok, Thailand
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Madkor HR, Abd El-Aziz MK, Abd El-Maksoud MS, Ibrahim IM, Ali FEM. Stem Cells Reprogramming in Diabetes Mellitus and Diabetic Complications: Recent Advances. Curr Diabetes Rev 2025; 21:21-37. [PMID: 38173073 DOI: 10.2174/0115733998275428231210055650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 11/09/2023] [Accepted: 11/21/2023] [Indexed: 01/05/2024]
Abstract
BACKGROUND The incidence of diabetes mellitus (DM) is dramatically increasing worldwide, and it is expected to affect 700 million cases by 2045. Diabetes influences health care economics, human quality of life, morbidity, and mortality, which were primarily seen extensively in developing countries. Uncontrolled DM, which results in consistent hyperglycemia, may lead to severe life-threatening complications such as nephropathy, retinopathy, neuropathy, and cardiovascular complications. METHODOLOGY In addition to traditional therapies with insulin and oral anti-diabetics, researchers have developed new approaches for treatment, including stem cell (SC) therapy, which exhibits promising outcomes. Besides its significant role in treating type one DM (T1DM) and type two DM (T2DM), it can also attenuate diabetic complications. Furthermore, the development of insulin- producing cells can be achieved by using the different types of SCs, such as embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and multiple types of adult stem cells, such as pancreatic, hepatic, and mesenchymal stem cells (MSC). All these types have been extensively studied and proved their ability to develop insulin-producing cells, but every type has limitations. CONCLUSION This review aims to enlighten researchers about recent advances in stem cell research and their potential benefits in DM and diabetic complications.
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Affiliation(s)
- Hafez R Madkor
- Department of Biochemistry, Faculty of Pharmacy, Al-Azhar University, Assiut, 71524, Egypt
| | | | | | - Islam M Ibrahim
- Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, 71524, Egypt
| | - Fares E M Ali
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, 71524, Egypt
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Ghassemifard L, Hasanlu M, Parsamanesh N, Atkin SL, Almahmeed W, Sahebkar A. Cell Therapies and Gene Therapy for Diabetes: Current Progress. Curr Diabetes Rev 2025; 21:e130524229899. [PMID: 38747221 DOI: 10.2174/0115733998292392240425122326] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Revised: 03/07/2024] [Accepted: 03/21/2024] [Indexed: 04/23/2025]
Abstract
The epidemic of diabetes continues to be an increasing problem, and there is a need for new therapeutic strategies. There are several promising drugs and molecules in synthetic medicinal chemistry that are developing for diabetes. In addition to this approach, extensive studies with gene and cell therapies are being conducted. Gene therapy is an existing approach in treating several diseases, such as cancer, autoimmune diseases, heart disease and diabetes. Several reports have also suggested that stem cells have the differentiation capability to functional pancreatic beta cell development in vitro and in vivo, with the utility to treat diabetes and prevent the progression of diabetes-related complications. In this current review, we have focused on the different types of cell therapies and vector-based gene therapy in treating or preventing diabetes.
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Affiliation(s)
- Leila Ghassemifard
- Department of Physiology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
- Department of Persian Medicine, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Masumeh Hasanlu
- Department of Internal Medicine, Vali-e-Asr Hospital, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Negin Parsamanesh
- Metabolic Diseases Research Center, Zanjan University of Medical Sciences, Zanjan, Iran
- Department of Genetics and Molecular Medicine, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Stephen L Atkin
- Research Department, Royal College of Surgeons in Ireland Bahrain, Adliya, Bahrain
| | - Wael Almahmeed
- Heart and Vascular Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Amirhossein Sahebkar
- Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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Maestas MM, Bui MH, Millman JR. Recent progress in modeling and treating diabetes using stem cell-derived islets. Stem Cells Transl Med 2024; 13:949-958. [PMID: 39159002 PMCID: PMC11465181 DOI: 10.1093/stcltm/szae059] [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: 05/02/2024] [Accepted: 07/12/2024] [Indexed: 08/21/2024] Open
Abstract
Stem cell-derived islets (SC-islets) offer the potential to be an unlimited source of cells for disease modeling and the treatment of diabetes. SC-islets can be genetically modified, treated with chemical compounds, or differentiated from patient derived stem cells to model diabetes. These models provide insights into disease pathogenesis and vulnerabilities that may be targeted to provide treatment. SC-islets themselves are also being investigated as a cell therapy for diabetes. However, the transplantation process is imperfect; side effects from immunosuppressant use have reduced SC-islet therapeutic potential. Alternative methods to this include encapsulation, use of immunomodulating molecules, and genetic modification of SC-islets. This review covers recent advances using SC-islets to understand different diabetes pathologies and as a cell therapy.
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Affiliation(s)
- Marlie M Maestas
- Roy and Diana Vagelos Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO 63110, United States
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, United States
| | - Maggie H Bui
- Roy and Diana Vagelos Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO 63110, United States
| | - Jeffrey R Millman
- Roy and Diana Vagelos Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO 63110, United States
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, United States
- Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63110, United States
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9
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Wheeler EE, Leach JK. Tissue-Engineered Three-Dimensional Platforms for Disease Modeling and Therapeutic Development. TISSUE ENGINEERING. PART B, REVIEWS 2024. [PMID: 39345164 DOI: 10.1089/ten.teb.2024.0212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/01/2024]
Abstract
Three-dimensional (3D) tissue-engineered models are under investigation to recapitulate tissue architecture and functionality, thereby overcoming limitations of traditional two-dimensional cultures and preclinical animal models. This review highlights recent developments in 3D platforms designed to model diseases in vitro that affect numerous tissues and organs, including cardiovascular, gastrointestinal, bone marrow, neural, reproductive, and pulmonary systems. We discuss current technologies for engineered tissue models, highlighting the advantages, limitations, and important considerations for modeling tissues and diseases. Lastly, we discuss future advancements necessary to enhance the reliability of 3D models of tissue development and disease.
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Affiliation(s)
- Erika E Wheeler
- Department of Orthopaedic Surgery, UC Davis Health, Sacramento, California, USA
- Department of Biomedical Engineering, University of California, Davis, California, USA
| | - J Kent Leach
- Department of Orthopaedic Surgery, UC Davis Health, Sacramento, California, USA
- Department of Biomedical Engineering, University of California, Davis, California, USA
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10
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Arroyave F, Uscátegui Y, Lizcano F. From iPSCs to Pancreatic β Cells: Unveiling Molecular Pathways and Enhancements with Vitamin C and Retinoic Acid in Diabetes Research. Int J Mol Sci 2024; 25:9654. [PMID: 39273600 PMCID: PMC11395045 DOI: 10.3390/ijms25179654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 08/30/2024] [Accepted: 09/03/2024] [Indexed: 09/15/2024] Open
Abstract
Diabetes mellitus, a chronic and non-transmissible disease, triggers a wide range of micro- and macrovascular complications. The differentiation of pancreatic β-like cells (PβLCs) from induced pluripotent stem cells (iPSCs) offers a promising avenue for regenerative medicine aimed at treating diabetes. Current differentiation protocols strive to emulate pancreatic embryonic development by utilizing cytokines and small molecules at specific doses to activate and inhibit distinct molecular signaling pathways, directing the differentiation of iPSCs into pancreatic β cells. Despite significant progress and improved protocols, the full spectrum of molecular signaling pathways governing pancreatic development and the physiological characteristics of the differentiated cells are not yet fully understood. Here, we report a specific combination of cofactors and small molecules that successfully differentiate iPSCs into PβLCs. Our protocol has shown to be effective, with the resulting cells exhibiting key functional properties of pancreatic β cells, including the expression of crucial molecular markers (pdx1, nkx6.1, ngn3) and the capability to secrete insulin in response to glucose. Furthermore, the addition of vitamin C and retinoic acid in the final stages of differentiation led to the overexpression of specific β cell genes.
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Affiliation(s)
- Felipe Arroyave
- Center of Biomedical Investigation (CIBUS), Universidad de La Sabana, Chia 250008, Colombia
- Doctoral Program in Biociencias, Universidad de La Sabana, Chia 250008, Colombia
| | - Yomaira Uscátegui
- Center of Biomedical Investigation (CIBUS), Universidad de La Sabana, Chia 250008, Colombia
| | - Fernando Lizcano
- Center of Biomedical Investigation (CIBUS), Universidad de La Sabana, Chia 250008, Colombia
- Doctoral Program in Biociencias, Universidad de La Sabana, Chia 250008, Colombia
- School of Medicine, Universidad de La Sabana, Chia 250008, Colombia
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11
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Ren R, Jiang J, Li X, Zhang G. Research progress of autoimmune diseases based on induced pluripotent stem cells. Front Immunol 2024; 15:1349138. [PMID: 38720903 PMCID: PMC11076788 DOI: 10.3389/fimmu.2024.1349138] [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: 12/04/2023] [Accepted: 04/12/2024] [Indexed: 05/12/2024] Open
Abstract
Autoimmune diseases can damage specific or multiple organs and tissues, influence the quality of life, and even cause disability and death. A 'disease in a dish' can be developed based on patients-derived induced pluripotent stem cells (iPSCs) and iPSCs-derived disease-relevant cell types to provide a platform for pathogenesis research, phenotypical assays, cell therapy, and drug discovery. With rapid progress in molecular biology research methods including genome-sequencing technology, epigenetic analysis, '-omics' analysis and organoid technology, large amount of data represents an opportunity to help in gaining an in-depth understanding of pathological mechanisms and developing novel therapeutic strategies for these diseases. This paper aimed to review the iPSCs-based research on phenotype confirmation, mechanism exploration, drug discovery, and cell therapy for autoimmune diseases, especially multiple sclerosis, inflammatory bowel disease, and type 1 diabetes using iPSCs and iPSCs-derived cells.
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Affiliation(s)
| | | | | | - Guirong Zhang
- Shandong Yinfeng Academy of Life Science, Jinan, Shandong, China
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12
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Goyal P, Malviya R. Stem Cell Therapy for the Management of Type 1 Diabetes: Advances and Perspectives. Endocr Metab Immune Disord Drug Targets 2024; 24:549-561. [PMID: 37861029 DOI: 10.2174/0118715303256582230919093535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 07/20/2023] [Accepted: 08/25/2023] [Indexed: 10/21/2023]
Abstract
Due to insulin resistance and excessive blood sugar levels, type 1 diabetes mellitus (T1DM) is characterized by pancreatic cell loss. This condition affects young people at a higher rate than any other chronic autoimmune disease. Regardless of the method, exogenous insulin cannot substitute for insulin produced by a healthy pancreas. An emerging area of medicine is pancreatic and islet transplantation for type 1 diabetics to restore normal blood sugar regulation. However, there are still obstacles standing in the way of the widespread use of these therapies, including very low availability of pancreatic and islets supplied from human organ donors, challenging transplantation conditions, high expenses, and a lack of easily accessible methods. Efforts to improve Type 1 Diabetes treatment have been conducted in response to the disease's increasing prevalence. Type 1 diabetes may one day be treated with stem cell treatment. Stem cell therapy has proven to be an effective treatment for type 1 diabetes. Recent progress in stem cell-based diabetes treatment is summarised, and the authors show how to isolate insulin-producing cells (IPCs) from a variety of progenitor cells.
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Affiliation(s)
- Priyanshi Goyal
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
| | - Rishabha Malviya
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
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13
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Yi X, Xie Y, Gerber DA. Pancreas patch grafting to treat type 1 diabetes. Biochem Biophys Res Commun 2023; 686:149200. [PMID: 37926045 DOI: 10.1016/j.bbrc.2023.149200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Accepted: 10/31/2023] [Indexed: 11/07/2023]
Abstract
Stem/progenitor cell therapy is a promising treatment option for patients with type 1 diabetes (T1D) a disease characterized by autoimmune destruction of pancreatic β cells. Actively injecting cells into an organ is one option for cell delivery, but in the pancreas, this contributes to acute inflammation and pancreatitis. We employed a patch grafting approach to transplant biliary tree stem cells/progenitor cells (BTSC) onto the surface of the pancreas in diabetic mice. The cells engraft and differentiate into β-like cells reversing hyperglycemia during a four-month period of observation. In addition, C-peptide and insulin gradually increase in blood circulation without detectable adverse effects during this period. Moreover, the patch graft transplant promoted the proliferation and differentiation of pancreatic β-like cells with co-expression of the β cell biomarker. CONCLUSION: BTSC transplantation can effectively attenuate T1D over a four-month period that is vital important for clinical applications.
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Affiliation(s)
- Xianwen Yi
- Department of Surgery, University of North Carolina, Chapel Hill, NC, 27599, USA.
| | - Youmei Xie
- Department of Surgery, University of North Carolina, Chapel Hill, NC, 27599, USA.
| | - David A Gerber
- Department of Surgery, University of North Carolina, Chapel Hill, NC, 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, 27599, USA.
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14
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Fujisaka Y, Nakagawa T, Tomoda K, Watanabe M, Matsunaga N, Tamura Y, Ikeda S, Imagawa A, Asahi M. The cytotoxicity of gefitinib on patient‑derived induced pluripotent stem cells reflects gefitinib‑induced liver injury in the clinical setting. Oncol Lett 2023; 26:520. [PMID: 37927418 PMCID: PMC10623090 DOI: 10.3892/ol.2023.14108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 09/22/2023] [Indexed: 11/07/2023] Open
Abstract
Gefitinib is a key drug used in the treatment of non-small cell lung cancer (NSCLC) with EGFR mutations. Gefitinib therapy is superior to conventional chemotherapy for the progression-free survival rate of patients with EGFR mutations. However, 10-26% of patients develop grade 3 or higher hepatotoxicity during gefitinib treatment; therefore, the development of preclinical tests for hepatotoxicity prior to clinical use is desirable. The present study evaluated the use of induced pluripotent stem cells (iPSCs) and iPSC-derived hepatocytes (iPSC-heps), as a platform for preclinical test development. Patient-derived iPSCs were generated by reprogramming peripheral blood mononuclear cells obtained from two groups of gefitinib-treated patients with severe hepatotoxicity [toxicity group (T group)] or mild hepatotoxicity [no clinical toxicity group (N group)]. To examine the hepatotoxicity, the iPSCs from both T and N groups were differentiated into hepatocytes to obtain iPSC-heps. Differentiation was confirmed by measuring the expression levels of hepatocyte markers, such as albumin or α-fetoprotein, via western blotting and quantitative PCR analyses. Cytotoxicity in iPSCs and iPSC-heps after gefitinib treatment was evaluated using a lactate dehydrogenase release assay. The gefitinib-induced cytotoxicity in iPSCs from the T group was significantly higher than that from the N group, whereas there were no significant differences between the groups of iPSC-heps. These results suggested that using iPSCs in preclinical assessment may be a good indicator for the prediction of gefitinib-induced cytotoxicity in clinical use.
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Affiliation(s)
- Yasuhito Fujisaka
- Department of Medical Oncology, Faculty of Medicine, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka 569-0801, Japan
| | - Takatoshi Nakagawa
- Department of Pharmacology, Faculty of Medicine, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka 569-0801, Japan
| | - Kiichiro Tomoda
- Department of Pharmacology, Faculty of Medicine, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka 569-0801, Japan
| | - Marina Watanabe
- Department of Pharmacology, Faculty of Medicine, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka 569-0801, Japan
| | - Ninso Matsunaga
- Department of Internal Medicine (I), Faculty of Medicine, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka 569-0801, Japan
| | - Yosuke Tamura
- Department of Internal Medicine (I), Faculty of Medicine, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka 569-0801, Japan
| | - Soichiro Ikeda
- Department of Internal Medicine (I), Faculty of Medicine, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka 569-0801, Japan
| | - Akihisa Imagawa
- Department of Internal Medicine (I), Faculty of Medicine, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka 569-0801, Japan
| | - Michio Asahi
- Department of Pharmacology, Faculty of Medicine, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka 569-0801, Japan
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15
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James EA, Joglekar AV, Linnemann AK, Russ HA, Kent SC. The beta cell-immune cell interface in type 1 diabetes (T1D). Mol Metab 2023; 78:101809. [PMID: 37734713 PMCID: PMC10622886 DOI: 10.1016/j.molmet.2023.101809] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 09/01/2023] [Accepted: 09/15/2023] [Indexed: 09/23/2023] Open
Abstract
BACKGROUND T1D is an autoimmune disease in which pancreatic islets of Langerhans are infiltrated by immune cells resulting in the specific destruction of insulin-producing islet beta cells. Our understanding of the factors leading to islet infiltration and the interplay of the immune cells with target beta cells is incomplete, especially in human disease. While murine models of T1D have provided crucial information for both beta cell and autoimmune cell function, the translation of successful therapies in the murine model to human disease has been a challenge. SCOPE OF REVIEW Here, we discuss current state of the art and consider knowledge gaps concerning the interface of the islet beta cell with immune infiltrates, with a focus on T cells. We discuss pancreatic and immune cell phenotypes and their impact on cell function in health and disease, which we deem important to investigate further to attain a more comprehensive understanding of human T1D disease etiology. MAJOR CONCLUSIONS The last years have seen accelerated development of approaches that allow comprehensive study of human T1D. Critically, recent studies have contributed to our revised understanding that the pancreatic beta cell assumes an active role, rather than a passive position, during autoimmune disease progression. The T cell-beta cell interface is a critical axis that dictates beta cell fate and shapes autoimmune responses. This includes the state of the beta cell after processing internal and external cues (e.g., stress, inflammation, genetic risk) that that contributes to the breaking of tolerance by hyperexpression of human leukocyte antigen (HLA) class I with presentation of native and neoepitopes and secretion of chemotactic factors to attract immune cells. We anticipate that emerging insights about the molecular and cellular aspects of disease initiation and progression processes will catalyze the development of novel and innovative intervention points to provide additional therapies to individuals affected by T1D.
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Affiliation(s)
- Eddie A James
- Center for Translational Immunology, Benaroya Research Institute, Seattle, WA, USA
| | - Alok V Joglekar
- Center for Systems Immunology and Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Amelia K Linnemann
- Center for Diabetes and Metabolic Diseases, and Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Holger A Russ
- Diabetes Institute, University of Florida, Gainesville, FL, USA; Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, USA
| | - Sally C Kent
- Diabetes Center of Excellence, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
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16
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Li Y, He C, Liu R, Xiao Z, Sun B. Stem cells therapy for diabetes: from past to future. Cytotherapy 2023; 25:1125-1138. [PMID: 37256240 DOI: 10.1016/j.jcyt.2023.04.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 04/05/2023] [Accepted: 04/24/2023] [Indexed: 06/01/2023]
Abstract
Diabetes mellitus is a chronic disease of carbohydrate metabolism characterized by uncontrolled hyperglycemia due to the body's impaired ability to produce or respond to insulin. Oral or injectable exogenous insulin and its analogs cannot mimic endogenous insulin secreted by healthy individuals, and pancreatic and islet transplants face a severe shortage of sources and transplant complications, all of which limit the widespread use of traditional strategies in diabetes treatment. We are now in the era of stem cells and their potential in ameliorating human disease. At the same time, the rapid development of gene editing and cell-encapsulation technologies has added to the wings of stem cell therapy. However, there are still many unanswered questions before stem cell therapy can be applied clinically to patients with diabetes. In this review, we discuss the progress of strategies to obtain insulin-producing cells from different types of stem cells, the application of gene editing in stem cell therapy for diabetes, as well as summarize the current advanced cell encapsulation technologies in diabetes therapy and look forward to the future development of stem cell therapy in diabetes.
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Affiliation(s)
- Yumin Li
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China
| | - Cong He
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China; Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital,The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Rui Liu
- Department of Genetic Engineering, College of Natural Science, University of Suwon, Kyunggi-Do, Republic of Korea
| | - Zhongdang Xiao
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China.
| | - Bo Sun
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China.
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17
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Augsornworawat P, Hogrebe NJ, Ishahak M, Schmidt MD, Marquez E, Maestas MM, Veronese-Paniagua DA, Gale SE, Miller JR, Velazco-Cruz L, Millman JR. Single-nucleus multi-omics of human stem cell-derived islets identifies deficiencies in lineage specification. Nat Cell Biol 2023; 25:904-916. [PMID: 37188763 PMCID: PMC10264244 DOI: 10.1038/s41556-023-01150-8] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 04/17/2023] [Indexed: 05/17/2023]
Abstract
Insulin-producing β cells created from human pluripotent stem cells have potential as a therapy for insulin-dependent diabetes, but human pluripotent stem cell-derived islets (SC-islets) still differ from their in vivo counterparts. To better understand the state of cell types within SC-islets and identify lineage specification deficiencies, we used single-nucleus multi-omic sequencing to analyse chromatin accessibility and transcriptional profiles of SC-islets and primary human islets. Here we provide an analysis that enabled the derivation of gene lists and activity for identifying each SC-islet cell type compared with primary islets. Within SC-islets, we found that the difference between β cells and awry enterochromaffin-like cells is a gradient of cell states rather than a stark difference in identity. Furthermore, transplantation of SC-islets in vivo improved cellular identities overtime, while long-term in vitro culture did not. Collectively, our results highlight the importance of chromatin and transcriptional landscapes during islet cell specification and maturation.
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Affiliation(s)
- Punn Augsornworawat
- Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, MSC 8127-057-08, St. Louis, MO, USA
- Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, USA
| | - Nathaniel J Hogrebe
- Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, MSC 8127-057-08, St. Louis, MO, USA
| | - Matthew Ishahak
- Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, MSC 8127-057-08, St. Louis, MO, USA
| | - Mason D Schmidt
- Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, MSC 8127-057-08, St. Louis, MO, USA
| | - Erica Marquez
- Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, MSC 8127-057-08, St. Louis, MO, USA
| | - Marlie M Maestas
- Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, MSC 8127-057-08, St. Louis, MO, USA
| | - Daniel A Veronese-Paniagua
- Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, MSC 8127-057-08, St. Louis, MO, USA
| | - Sarah E Gale
- Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, MSC 8127-057-08, St. Louis, MO, USA
| | - Julia R Miller
- Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, MSC 8127-057-08, St. Louis, MO, USA
- Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, USA
| | - Leonardo Velazco-Cruz
- Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, MSC 8127-057-08, St. Louis, MO, USA
| | - Jeffrey R Millman
- Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, MSC 8127-057-08, St. Louis, MO, USA.
- Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, USA.
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18
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Eisen B, Binah O. Modeling Duchenne Muscular Dystrophy Cardiomyopathy with Patients' Induced Pluripotent Stem-Cell-Derived Cardiomyocytes. Int J Mol Sci 2023; 24:ijms24108657. [PMID: 37240001 DOI: 10.3390/ijms24108657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 05/05/2023] [Accepted: 05/10/2023] [Indexed: 05/28/2023] Open
Abstract
Duchenne muscular dystrophy (DMD) is an X-linked progressive muscle degenerative disease caused by mutations in the dystrophin gene, resulting in death by the end of the third decade of life at the latest. A key aspect of the DMD clinical phenotype is dilated cardiomyopathy, affecting virtually all patients by the end of the second decade of life. Furthermore, despite respiratory complications still being the leading cause of death, with advancements in medical care in recent years, cardiac involvement has become an increasing cause of mortality. Over the years, extensive research has been conducted using different DMD animal models, including the mdx mouse. While these models present certain important similarities to human DMD patients, they also have some differences which pose a challenge to researchers. The development of somatic cell reprograming technology has enabled generation of human induced pluripotent stem cells (hiPSCs) which can be differentiated into different cell types. This technology provides a potentially endless pool of human cells for research. Furthermore, hiPSCs can be generated from patients, thus providing patient-specific cells and enabling research tailored to different mutations. DMD cardiac involvement has been shown in animal models to include changes in gene expression of different proteins, abnormal cellular Ca2+ handling, and other aberrations. To gain a better understanding of the disease mechanisms, it is imperative to validate these findings in human cells. Furthermore, with the recent advancements in gene-editing technology, hiPSCs provide a valuable platform for research and development of new therapies including the possibility of regenerative medicine. In this article, we review the DMD cardiac-related research performed so far using human hiPSCs-derived cardiomyocytes (hiPSC-CMs) carrying DMD mutations.
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Affiliation(s)
- Binyamin Eisen
- Cardiac Research Laboratory, Department of Physiology, Biophysics and Systems Biology, Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa 3200003, Israel
| | - Ofer Binah
- Cardiac Research Laboratory, Department of Physiology, Biophysics and Systems Biology, Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa 3200003, Israel
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19
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Giarrizzo M, LaComb JF, Bialkowska AB. The Role of Krüppel-like Factors in Pancreatic Physiology and Pathophysiology. Int J Mol Sci 2023; 24:ijms24108589. [PMID: 37239940 DOI: 10.3390/ijms24108589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 05/04/2023] [Accepted: 05/06/2023] [Indexed: 05/28/2023] Open
Abstract
Krüppel-like factors (KLFs) belong to the family of transcription factors with three highly conserved zinc finger domains in the C-terminus. They regulate homeostasis, development, and disease progression in many tissues. It has been shown that KLFs play an essential role in the endocrine and exocrine compartments of the pancreas. They are necessary to maintain glucose homeostasis and have been implicated in the development of diabetes. Furthermore, they can be a vital tool in enabling pancreas regeneration and disease modeling. Finally, the KLF family contains proteins that act as tumor suppressors and oncogenes. A subset of members has a biphasic function, being upregulated in the early stages of oncogenesis and stimulating its progression and downregulated in the late stages to allow for tumor dissemination. Here, we describe KLFs' function in pancreatic physiology and pathophysiology.
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Affiliation(s)
- Michael Giarrizzo
- Department of Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY 11794, USA
| | - Joseph F LaComb
- Department of Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY 11794, USA
| | - Agnieszka B Bialkowska
- Department of Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY 11794, USA
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20
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Beydag-Tasöz BS, Yennek S, Grapin-Botton A. Towards a better understanding of diabetes mellitus using organoid models. Nat Rev Endocrinol 2023; 19:232-248. [PMID: 36670309 PMCID: PMC9857923 DOI: 10.1038/s41574-022-00797-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/19/2022] [Indexed: 01/22/2023]
Abstract
Our understanding of diabetes mellitus has benefited from a combination of clinical investigations and work in model organisms and cell lines. Organoid models for a wide range of tissues are emerging as an additional tool enabling the study of diabetes mellitus. The applications for organoid models include studying human pancreatic cell development, pancreatic physiology, the response of target organs to pancreatic hormones and how glucose toxicity can affect tissues such as the blood vessels, retina, kidney and nerves. Organoids can be derived from human tissue cells or pluripotent stem cells and enable the production of human cell assemblies mimicking human organs. Many organ mimics relevant to diabetes mellitus are already available, but only a few relevant studies have been performed. We discuss the models that have been developed for the pancreas, liver, kidney, nerves and vasculature, how they complement other models, and their limitations. In addition, as diabetes mellitus is a multi-organ disease, we highlight how a merger between the organoid and bioengineering fields will provide integrative models.
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Affiliation(s)
- Belin Selcen Beydag-Tasöz
- The Novo Nordisk Foundation Center for Stem Cell Biology, Copenhagen, Denmark
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
| | - Siham Yennek
- The Novo Nordisk Foundation Center for Stem Cell Biology, Copenhagen, Denmark
| | - Anne Grapin-Botton
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
- Paul Langerhans Institute Dresden, Dresden, Germany.
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21
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Fontcuberta-PiSunyer M, García-Alamán A, Prades È, Téllez N, Alves-Figueiredo H, Ramos-Rodríguez M, Enrich C, Fernandez-Ruiz R, Cervantes S, Clua L, Ramón-Azcón J, Broca C, Wojtusciszyn A, Montserrat N, Pasquali L, Novials A, Servitja JM, Vidal J, Gomis R, Gasa R. Direct reprogramming of human fibroblasts into insulin-producing cells using transcription factors. Commun Biol 2023; 6:256. [PMID: 36964318 PMCID: PMC10039074 DOI: 10.1038/s42003-023-04627-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 02/24/2023] [Indexed: 03/26/2023] Open
Abstract
Direct lineage reprogramming of one somatic cell into another without transitioning through a progenitor stage has emerged as a strategy to generate clinically relevant cell types. One cell type of interest is the pancreatic insulin-producing β cell whose loss and/or dysfunction leads to diabetes. To date it has been possible to create β-like cells from related endodermal cell types by forcing the expression of developmental transcription factors, but not from more distant cell lineages like fibroblasts. In light of the therapeutic benefits of choosing an accessible cell type as the cell of origin, in this study we set out to analyze the feasibility of transforming human skin fibroblasts into β-like cells. We describe how the timed-introduction of five developmental transcription factors (Neurog3, Pdx1, MafA, Pax4, and Nkx2-2) promotes conversion of fibroblasts toward a β-cell fate. Reprogrammed cells exhibit β-cell features including β-cell gene expression and glucose-responsive intracellular calcium mobilization. Moreover, reprogrammed cells display glucose-induced insulin secretion in vitro and in vivo. This work provides proof-of-concept of the capacity to make insulin-producing cells from human fibroblasts via transcription factor-mediated direct reprogramming.
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Affiliation(s)
| | - Ainhoa García-Alamán
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain
| | - Èlia Prades
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Noèlia Téllez
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain
- Faculty of Medicine of University of Vic, Central University of Catalonia (UVic-UCC), Vic, Spain
- Institute of Health Research and Innovation at Central Catalonia (IRIS-CC), Vic, Spain
| | - Hugo Alves-Figueiredo
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Tecnológico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, N.L., México
| | | | - Carlos Enrich
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Faculty of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, Spain
| | - Rebeca Fernandez-Ruiz
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain
| | - Sara Cervantes
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Laura Clua
- Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Technology (BIST), Barcelona, Spain
| | - Javier Ramón-Azcón
- Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Technology (BIST), Barcelona, Spain
- Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain
| | - Christophe Broca
- CHU Montpellier, Laboratory of Cell Therapy for Diabetes (LTCD), Hospital St-Eloi, Montpellier, France
| | - Anne Wojtusciszyn
- CHU Montpellier, Laboratory of Cell Therapy for Diabetes (LTCD), Hospital St-Eloi, Montpellier, France
- Service of Endocrinology, Diabetes and Metabolism, Lausanne University Hospital, Lausanne, Switzerland
| | - Nuria Montserrat
- Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Technology (BIST), Barcelona, Spain
- Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain
- CIBER de Bioingeniería, Biomateriales y Nanomedicina, Instituto de Salud Carlos III, Madrid, Spain
| | - Lorenzo Pasquali
- Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain
| | - Anna Novials
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain
| | - Joan-Marc Servitja
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain
| | - Josep Vidal
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain
- Faculty of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, Spain
- Endocrinology and Nutrition Department, Hospital Clinic of Barcelona, Barcelona, Spain
| | - Ramon Gomis
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain
- Faculty of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, Spain
| | - Rosa Gasa
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain.
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22
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Halliez C, Ibrahim H, Otonkoski T, Mallone R. In vitro beta-cell killing models using immune cells and human pluripotent stem cell-derived islets: Challenges and opportunities. Front Endocrinol (Lausanne) 2023; 13:1076683. [PMID: 36726462 PMCID: PMC9885197 DOI: 10.3389/fendo.2022.1076683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Accepted: 12/23/2022] [Indexed: 01/19/2023] Open
Abstract
Type 1 diabetes (T1D) is a disease of both autoimmunity and β-cells. The β-cells play an active role in their own demise by mounting defense mechanisms that are insufficient at best, and that can become even deleterious in the long term. This complex crosstalk is important to understanding the physiological defense mechanisms at play in healthy conditions, their alterations in the T1D setting, and therapeutic agents that may boost such mechanisms. Robust protocols to develop stem-cell-derived islets (SC-islets) from human pluripotent stem cells (hPSCs), and islet-reactive cytotoxic CD8+ T-cells from peripheral blood mononuclear cells offer unprecedented opportunities to study this crosstalk. Challenges to develop in vitro β-cell killing models include the cluster morphology of SC-islets, the relatively weak cytotoxicity of most autoimmune T-cells and the variable behavior of in vitro expanded CD8+ T-cells. These challenges may however be highly rewarding in light of the opportunities offered by such models. Herein, we discuss these opportunities including: the β-cell/immune crosstalk in an islet microenvironment; the features that make β-cells more sensitive to autoimmunity; therapeutic agents that may modulate β-cell vulnerability; and the possibility to perform analyses in an autologous setting, i.e., by generating T-cell effectors and SC-islets from the same donor.
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Affiliation(s)
- Clémentine Halliez
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
- Assistance Publique Hôpitaux de Paris, Service de Diabétologie et Immunologie Clinique, Cochin Hospital, Paris, France
| | - Hazem Ibrahim
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Timo Otonkoski
- Assistance Publique Hôpitaux de Paris, Service de Diabétologie et Immunologie Clinique, Cochin Hospital, Paris, France
- Department of Pediatrics, Helsinki University Hospital, Helsinki, Finland
| | - Roberto Mallone
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
- Assistance Publique Hôpitaux de Paris, Service de Diabétologie et Immunologie Clinique, Cochin Hospital, Paris, France
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23
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Bele S, Wokasch AS, Gannon M. Epigenetic modulation of cell fate during pancreas development. TRENDS IN DEVELOPMENTAL BIOLOGY 2023; 16:1-27. [PMID: 38873037 PMCID: PMC11173269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Indexed: 06/15/2024]
Abstract
Epigenetic modifications to DNA and its associated proteins affect cell plasticity and cell fate restrictions throughout embryonic development. Development of the vertebrate pancreas is characterized by initial is an over-lapping expression of a set of transcriptional regulators in a defined region of the posterior foregut endoderm that collectively promote pancreas progenitor specification and proliferation. As development progresses, these transcription factors segregate into distinct pancreatic lineages, with some being maintained in specific subsets of terminally differentiated pancreas cell types throughout adulthood. Here we describe the progressive stages and cell fate restrictions that occur during pancreas development and the relevant known epigenetic regulatory events that drive the dynamic expression patterns of transcription factors that regulate pancreas development. In addition, we highlight how changes in epigenetic marks can affect susceptibility to pancreas diseases (such as diabetes), adult pancreas cell plasticity, and the ability to derive replacement insulin-producing β cells for the treatment of diabetes.
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Affiliation(s)
- Shilpak Bele
- Department of Medicine, Vanderbilt University Medical Center, 2213 Garland Avenue, Nashville, TN, 37232, USA
| | - Anthony S. Wokasch
- Department of Cell and Developmental Biology, Vanderbilt University, 2213 Garland Avenue, Nashville, TN, 37232, USA
| | - Maureen Gannon
- Department of Medicine, Vanderbilt University Medical Center, 2213 Garland Avenue, Nashville, TN, 37232, USA
- Department of Cell and Developmental Biology, Vanderbilt University, 2213 Garland Avenue, Nashville, TN, 37232, USA
- Department of Veterans Affairs Tennessee Valley Authority, Research Division, 1310 24 Avenue South, Nashville, TN, 37212, USA
- Department of Molecular Physiology and Biophysics, 2213 Garland Avenue, Nashville, TN, 37232, USA
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24
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Leavens KF, Alvarez-Dominguez JR, Vo LT, Russ HA, Parent AV. Stem cell-based multi-tissue platforms to model human autoimmune diabetes. Mol Metab 2022; 66:101610. [PMID: 36209784 PMCID: PMC9587366 DOI: 10.1016/j.molmet.2022.101610] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 09/20/2022] [Accepted: 10/04/2022] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Type 1 diabetes (T1D) is an autoimmune disease in which pancreatic insulin-producing β cells are specifically destroyed by the immune system. Understanding the initiation and progression of human T1D has been hampered by the lack of appropriate models that can reproduce the complexity and heterogeneity of the disease. The development of platforms combining multiple human pluripotent stem cell (hPSC) derived tissues to model distinct aspects of T1D has the potential to provide critical novel insights into the etiology and pathogenesis of the human disease. SCOPE OF REVIEW In this review, we summarize the state of hPSC differentiation approaches to generate cell types and tissues relevant to T1D, with a particular focus on pancreatic islet cells, T cells, and thymic epithelium. We present current applications as well as limitations of using these hPSC-derived cells for disease modeling and discuss efforts to optimize platforms combining multiple cell types to model human T1D. Finally, we outline remaining challenges and emphasize future improvements needed to accelerate progress in this emerging field of research. MAJOR CONCLUSIONS Recent advances in reprogramming approaches to create patient-specific induced pluripotent stem cell lines (iPSCs), genome engineering technologies to efficiently modify DNA of hPSCs, and protocols to direct their differentiation into mature cell types have empowered the use of stem cell derivatives to accurately model human disease. While challenges remain before complex interactions occurring in human T1D can be modeled with these derivatives, experiments combining hPSC-derived β cells and immune cells are already providing exciting insight into how these cells interact in the context of T1D, supporting the viability of this approach.
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Affiliation(s)
- Karla F Leavens
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania and Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Juan R Alvarez-Dominguez
- Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Linda T Vo
- Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA
| | - Holger A Russ
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Audrey V Parent
- Diabetes Center, University of California San Francisco, San Francisco, CA, USA.
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25
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Challenges with Cell-based Therapies for Type 1 Diabetes Mellitus. Stem Cell Rev Rep 2022; 19:601-624. [PMID: 36434300 DOI: 10.1007/s12015-022-10482-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/13/2022] [Indexed: 11/27/2022]
Abstract
Type 1 diabetes (T1D) is a chronic, lifelong metabolic disease. It is characterised by the autoimmune-mediated loss of insulin-producing pancreatic β cells in the islets of Langerhans (β-islets), resulting in disrupted glucose homeostasis. Administration of exogenous insulin is the most common management method for T1D, but this requires lifelong reliance on insulin injections and invasive blood glucose monitoring. Replacement therapies with beta cells are being developed as an advanced curative treatment for T1D. Unfortunately, this approach is limited by the lack of donated pancreatic tissue, the difficulties in beta cell isolation and viability maintenance, the longevity of the transplanted cells in vivo, and consequently high costs. Emerging approaches to address these limitations are under intensive investigations, including the production of insulin-producing beta cells from various stem cells, and the development of bioengineered devices including nanotechnologies for improving islet transplantation efficacy without the need for recipients taking toxic anti-rejection drugs. These emerging approaches present promising prospects, while the challenges with the new techniques need to be tackled for ultimately clinical treatment of T1D. This review discussed the benefits and limitations of the cell-based therapies for beta cell replacement as potential curative treatment for T1D, and the applications of bioengineered devices including nanotechnology to overcome the challenges associated with beta cell transplantation.
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26
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Padovano M, Scopetti M, Manetti F, Morena D, Radaelli D, D'Errico S, Di Fazio N, Frati P, Fineschi V. Pancreatic transplant surgery and stem cell therapy: Finding the balance between therapeutic advances and ethical principles. World J Stem Cells 2022; 14:577-586. [PMID: 36157914 PMCID: PMC9453273 DOI: 10.4252/wjsc.v14.i8.577] [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: 03/18/2022] [Revised: 05/24/2022] [Accepted: 08/01/2022] [Indexed: 02/07/2023] Open
Abstract
The latest achievements in the field of pancreas transplantation and stem cell therapy require an effort by the scientific community to clarify the ethical implications of pioneering treatments, often characterized by high complexity from a surgical point of view, due to transplantation of multiple organs at the same time or at different times, and from an immunological point of view for stem cell therapy. The fundamental value in the field of organ transplants is, of course, a solidarity principle, namely that of protecting the health and life of people for whom transplantation is a condition of functional recovery, or even of survival. The nature of this value is that of a concept to which the legal discipline of transplants entrusts its own ethical dignity and for which it has ensured a constitutional recognition in different systems. The general principle of respect for human life, both of the donor and of the recipient, evokes the need not to put oneself and one's neighbor in dangerous conditions. The present ethical reflection aims to find a balance between the latest therapeutic advances and several concepts including the idea of the person, the respect due to the dead, the voluntary nature of the donation and the consent to the same, the gratuitousness of the donation, the scientific progress and the development of surgical techniques, and the policies of health promotion.
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Affiliation(s)
- Martina Padovano
- Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Rome 00185, Italy
| | - Matteo Scopetti
- Department of Medical Surgical Sciences and Translational Medicine, Sapienza University of Rome, Rome 00189, Italy
| | - Federico Manetti
- Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Rome 00185, Italy
| | - Donato Morena
- Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Rome 00185, Italy
| | - Davide Radaelli
- Department of Medicine, Surgery and Health, University of Trieste, Trieste 34149, Italy
| | - Stefano D'Errico
- Department of Medicine, Surgery and Health, University of Trieste, Trieste 34149, Italy
| | - Nicola Di Fazio
- Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Rome 00185, Italy
| | - Paola Frati
- Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Rome 00185, Italy
| | - Vittorio Fineschi
- Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Rome 00185, Italy.
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27
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Silva IBB, Kimura CH, Colantoni VP, Sogayar MC. Stem cells differentiation into insulin-producing cells (IPCs): recent advances and current challenges. Stem Cell Res Ther 2022; 13:309. [PMID: 35840987 PMCID: PMC9284809 DOI: 10.1186/s13287-022-02977-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Accepted: 06/19/2022] [Indexed: 11/10/2022] Open
Abstract
Type 1 diabetes mellitus (T1D) is a chronic disease characterized by an autoimmune destruction of insulin-producing β-pancreatic cells. Although many advances have been achieved in T1D treatment, current therapy strategies are often unable to maintain perfect control of glycemic levels. Several studies are searching for new and improved methodologies for expansion of β-cell cultures in vitro to increase the supply of these cells for pancreatic islets replacement therapy. A promising approach consists of differentiation of stem cells into insulin-producing cells (IPCs) in sufficient number and functional status to be transplanted. Differentiation protocols have been designed using consecutive cytokines or signaling modulator treatments, at specific dosages, to activate or inhibit the main signaling pathways that control the differentiation of induced pluripotent stem cells (iPSCs) into pancreatic β-cells. Here, we provide an overview of the current approaches and achievements in obtaining stem cell-derived β-cells and the numerous challenges, which still need to be overcome to achieve this goal. Clinical translation of stem cells-derived β-cells for efficient maintenance of long-term euglycemia remains a major issue. Therefore, research efforts have been directed to the final steps of in vitro differentiation, aiming at production of functional and mature β-cells and integration of interdisciplinary fields to generate efficient cell therapy strategies capable of reversing the clinical outcome of T1D.
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Affiliation(s)
- Isaura Beatriz Borges Silva
- Cell and Molecular Therapy Center (NUCEL), School of Medicine, University of São Paulo, São Paulo, SP, 05360-130, Brazil.,Department of Biochemistry, Chemistry Institute, University of São Paulo, São Paulo, SP, 05508-000, Brazil
| | - Camila Harumi Kimura
- Cell and Molecular Therapy Center (NUCEL), School of Medicine, University of São Paulo, São Paulo, SP, 05360-130, Brazil
| | - Vitor Prado Colantoni
- Cell and Molecular Therapy Center (NUCEL), School of Medicine, University of São Paulo, São Paulo, SP, 05360-130, Brazil.,Department of Biochemistry, Chemistry Institute, University of São Paulo, São Paulo, SP, 05508-000, Brazil
| | - Mari Cleide Sogayar
- Cell and Molecular Therapy Center (NUCEL), School of Medicine, University of São Paulo, São Paulo, SP, 05360-130, Brazil. .,Department of Biochemistry, Chemistry Institute, University of São Paulo, São Paulo, SP, 05508-000, Brazil.
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28
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Habeeb MA, Vishwakarma SK, Habeeb S, Khan AA. Current progress and emerging technologies for generating extrapancreatic functional insulin-producing cells. World J Transl Med 2022; 10:1-13. [DOI: 10.5528/wjtm.v10.i1.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 03/05/2022] [Accepted: 06/03/2022] [Indexed: 02/06/2023] Open
Affiliation(s)
- Md Aejaz Habeeb
- Centre for Liver Research and Diagnostics, Deccan College of Medical Sciences, Hyderabad 500058, Telangana, India
| | - Sandeep Kumar Vishwakarma
- Centre for Liver Research and Diagnostics, Deccan College of Medical Sciences, Hyderabad 500058, Telangana, India
| | - Safwaan Habeeb
- Centre for Liver Research and Diagnostics, Deccan College of Medical Sciences, Hyderabad 500058, Telangana, India
| | - Aleem Ahmed Khan
- Centre for Liver Research and Diagnostics, Deccan College of Medical Sciences, Hyderabad 500058, Telangana, India
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29
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Regeneration of insulin-producing cells from iPS cells using functionalized scaffolds and solid lipid nanoparticles. J Taiwan Inst Chem Eng 2022. [DOI: 10.1016/j.jtice.2022.104387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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30
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Wan XX, Zhang DY, Khan MA, Zheng SY, Hu XM, Zhang Q, Yang RH, Xiong K. Stem Cell Transplantation in the Treatment of Type 1 Diabetes Mellitus: From Insulin Replacement to Beta-Cell Replacement. Front Endocrinol (Lausanne) 2022; 13:859638. [PMID: 35370989 PMCID: PMC8972968 DOI: 10.3389/fendo.2022.859638] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 02/16/2022] [Indexed: 12/19/2022] Open
Abstract
Type 1 diabetes mellitus (T1DM) is an autoimmune disease that attacks pancreatic β-cells, leading to the destruction of insulitis-related islet β-cells. Islet β-cell transplantation has been proven as a curative measure in T1DM. However, a logarithmic increase in the global population with diabetes, limited donor supply, and the need for lifelong immunosuppression restrict the widespread use of β-cell transplantation. Numerous therapeutic approaches have been taken to search for substitutes of β-cells, among which stem cell transplantation is one of the most promising alternatives. Stem cells have demonstrated the potential efficacy to treat T1DM by reconstitution of immunotolerance and preservation of islet β-cell function in recent research. cGMP-grade stem cell products have been used in human clinical trials, showing that stem cell transplantation has beneficial effects on T1DM, with no obvious adverse reactions. To better achieve remission of T1DM by stem cell transplantation, in this work, we explain the progression of stem cell transplantation such as mesenchymal stem cells (MSCs), human embryonic stem cells (hESCs), and bone marrow hematopoietic stem cells (BM-HSCs) to restore the immunotolerance and preserve the islet β-cell function of T1DM in recent years. This review article provides evidence of the clinical applications of stem cell therapy in the treatment of T1DM.
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Affiliation(s)
- Xin-Xing Wan
- Department of Endocrinology, Third Xiangya Hospital, Central South University, Changsha, China
| | - Dan-Yi Zhang
- Clinical Medicine Eight-Year Program, Xiangya School of Medicine, Central South University, Changsha, China
| | - Md. Asaduzzaman Khan
- The Research Centre for Preclinical Medicine, Southwest Medical University, Luzhou, China
| | - Sheng-Yuan Zheng
- Clinical Medicine Eight-Year Program, Xiangya School of Medicine, Central South University, Changsha, China
| | - Xi-Min Hu
- Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha, China
| | - Qi Zhang
- Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha, China
| | - Rong-Hua Yang
- Department of Burn and Plastic Surgery, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Kun Xiong
- Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha, China
- Hunan Key Laboratory of Ophthalmology, Changsha, China
- Key Laboratory of Emergency and Trauma, Ministry of Education, College of Emergency and Trauma, Hainan Medical University, Haikou, China
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31
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Adipose-Derived Stem Cells Preincubated with Green Tea EGCG Enhance Pancreatic Tissue Regeneration in Rats with Type 1 Diabetes through ROS/Sirt1 Signaling Regulation. Int J Mol Sci 2022; 23:ijms23063165. [PMID: 35328586 PMCID: PMC8951845 DOI: 10.3390/ijms23063165] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 03/09/2022] [Accepted: 03/09/2022] [Indexed: 02/04/2023] Open
Abstract
Type 1 diabetes stem-cell-based therapy is one of the best therapeutic approaches for pancreatic damage treatment due to stem cell tissue regeneration. Epigallocatechin gallate (EGCG) is one of the active components found in green tea. Experimental results suggest that EGCG shows beneficial effects on cell protection. This study explores whether a better pancreatic regeneration therapeutic effect could be found in mesenchymal stem cells pretreated with EGCG compared to stem cells without EGCG pretreatment. A cell model confirmed that adipose-derived stem cells (ADSC) incubated with EGCG increase cell viability under high-glucose (HG) stress. This is due to survival marker p-Akt expression. In an animal model, type 1 diabetes induced the activation of several pathological signals, including islet size reduction, extracellular fibrotic collagen deposition, oxidative stress elevation, survival pathway suppression, apoptosis signaling induction, and Sirt1 antioxidant pathway downregulation. Ordinary ADSC transplantation slightly improved the above pathological signals. Further, EGCG-pretreated ADSC transplantation significantly improved the above pathological conditions. Taken together, EGCG-pretreated ADSCs show clinical potential in the treatment of patients with type 1 diabetes through the regeneration of damaged pancreatic tissues.
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32
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Zhou Z, Zhu X, Huang H, Xu Z, Jiang J, Chen B, Zhu H. Recent Progress of Research Regarding the Applications of Stem Cells for Treating Diabetes Mellitus. Stem Cells Dev 2022; 31:102-110. [PMID: 35072537 DOI: 10.1089/scd.2021.0083] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
At present, the number of diabetes patients has exceeded 537 million worldwide and this number continues to increase. Stem cell therapy represents a new direction for the treatment of diabetes; the use of stem cells overcomes some shortcomings associated with traditional therapies. Functional β-cells play an important role in the pathogenesis of diabetes. As therapeutic targets, functional β-cells are restored by a variety of stem cells, including pluripotent stem cells, mesenchymal cells, and urine-derived stem cells. Although all types of stem cells have their own characteristics, they mainly promote the repair and regeneration of β-cells through directional differentiation, immunomodulation, and paracrine signaling after homing to the injured site. However, stem cell therapy still faces many obstacles, such as low long-term cell survival rate after transplantation, low maintenance time of blood glucose homeostasis, immune rejection, and tumorigenesis. Recently, genetically edited pluripotent stem cells and the co-transplantation of mesenchymal stem cells and islet cells have made significant progress in improving the efficacy of stem cell transplantation processes, also providing powerful tools for the study of the mechanisms underlying diabetes and disease modeling. In this review, we first focused on: (1) stem cells as a pool for the differentiation of insulin-producing cells; (2) stem cells as a source for regenerative repair of damaged islets and as a potential co-transplanted population with islets; (3) the potential of combining gene editing with stem cell therapy; and (4) selection of the stem cell transplantation approach. Based on these topics, we discuss the challenges within the field of adapting stem cell-supported and stem cell-derived transplantations, and the promising routes for overcoming these problems.
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Affiliation(s)
- Zijun Zhou
- The First Affiliated Hospital of Wenzhou Medical University, 89657, Endocrinology, Wenzhou, Zhejiang, China, 325000;
| | - Xiandong Zhu
- Wenzhou Medical University First Affiliated Hospital, 89657, Wenzhou, China, 325000;
| | - Hongjian Huang
- Wenzhou Medical College First Affiliated Hospital, 89657, Wenzhou, China, 325000;
| | - Zeru Xu
- The First Affiliated Hospital of Wenzhou Medical University, 89657, Wenzhou, China, 325000;
| | - Jiahong Jiang
- The First Affiliated Hospital of Wenzhou Medical University, 89657, endocrinology, Wenzhou, Zhejiang, China, 325000;
| | - Bicheng Chen
- Wenzhou Medical University First Affiliated Hospital, 89657, Wenzhou, China, 325000;
| | - Hong Zhu
- The First Affiliated Hospital of Wenzhou Medical University, 89657, Endocrinology, Wenzhou, Zhejiang, China, 325000;
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33
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Kuo YC, Tsao CW, Rajesh R. Dual-sized inverted colloidal crystal scaffolds grafted with GDF-8 and Wnt3a for enhancing differentiation of iPS cells toward islet β-cells. J Taiwan Inst Chem Eng 2021. [DOI: 10.1016/j.jtice.2021.07.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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34
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Agrawal A, Narayan G, Gogoi R, Thummer RP. Recent Advances in the Generation of β-Cells from Induced Pluripotent Stem Cells as a Potential Cure for Diabetes Mellitus. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1347:1-27. [PMID: 34426962 DOI: 10.1007/5584_2021_653] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Diabetes mellitus (DM) is a group of metabolic disorders characterized by high blood glucose levels due to insufficient insulin secretion, insulin action, or both. The present-day solution to diabetes mellitus includes regular administration of insulin, which brings about many medical complications in diabetic patients. Although islet transplantation from cadaveric subjects was proposed to be a permanent cure, the increased risk of infections, the need for immunosuppressive drugs, and their unavailability had restricted its use. To overcome this, the generation of renewable and transplantable β-cells derived from autologous induced pluripotent stem cells (iPSCs) has gained enormous interest as a potential therapeutic strategy to treat diabetes mellitus permanently. To date, extensive research has been undertaken to derive transplantable insulin-producing β-cells (iβ-cells) from iPSCs in vitro by recapitulating the in vivo developmental process of the pancreas. This in vivo developmental process relies on transcription factors, signaling molecules, growth factors, and culture microenvironment. This review highlights the various factors facilitating the generation of mature β-cells from iPSCs. Moreover, this review also describes the generation of pancreatic progenitors and β-cells from diabetic patient-specific iPSCs, exploring the potential of the diabetes disease model and drug discovery. In addition, the applications of genome editing strategies have also been discussed to achieve patient-specific diabetes cell therapy. Last, we have discussed the current challenges and prospects of iPSC-derived β-cells to improve the relative efficacy of the available treatment of diabetes mellitus.
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Affiliation(s)
- Akriti Agrawal
- Laboratory for Stem Cell Engineering and Regenerative Medicine, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Gloria Narayan
- Laboratory for Stem Cell Engineering and Regenerative Medicine, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Ranadeep Gogoi
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research Guwahati, Changsari, Guwahati, Assam, India
| | - Rajkumar P Thummer
- Laboratory for Stem Cell Engineering and Regenerative Medicine, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India.
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35
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Maxwell KG, Augsornworawat P, Velazco-Cruz L, Kim MH, Asada R, Hogrebe NJ, Morikawa S, Urano F, Millman JR. Gene-edited human stem cell-derived β cells from a patient with monogenic diabetes reverse preexisting diabetes in mice. Sci Transl Med 2021; 12:12/540/eaax9106. [PMID: 32321868 DOI: 10.1126/scitranslmed.aax9106] [Citation(s) in RCA: 124] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 10/11/2019] [Accepted: 03/29/2020] [Indexed: 12/13/2022]
Abstract
Differentiation of insulin-producing pancreatic β cells from induced pluripotent stem cells (iPSCs) derived from patients with diabetes promises to provide autologous cells for diabetes cell replacement therapy. However, current approaches produce patient iPSC-derived β (SC-β) cells with poor function in vitro and in vivo. Here, we used CRISPR-Cas9 to correct a diabetes-causing pathogenic variant in Wolfram syndrome 1 (WFS1) in iPSCs derived from a patient with Wolfram syndrome (WS). After differentiation to β cells with our recent six-stage differentiation strategy, corrected WS SC-β cells performed robust dynamic insulin secretion in vitro in response to glucose and reversed preexisting streptozocin-induced diabetes after transplantation into mice. Single-cell transcriptomics showed that corrected SC-β cells displayed increased insulin and decreased expression of genes associated with endoplasmic reticulum stress. CRISPR-Cas9 correction of a diabetes-inducing gene variant thus allows for robust differentiation of autologous SC-β cells that can reverse severe diabetes in an animal model.
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Affiliation(s)
- Kristina G Maxwell
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.,Department of Biomedical Engineering, Washington University in St. Louis, 1 Brookings Drive, St. Louis, MO 63130, USA
| | - Punn Augsornworawat
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.,Department of Biomedical Engineering, Washington University in St. Louis, 1 Brookings Drive, St. Louis, MO 63130, USA
| | - Leonardo Velazco-Cruz
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA
| | - Michelle H Kim
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA
| | - Rie Asada
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA
| | - Nathaniel J Hogrebe
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA
| | - Shuntaro Morikawa
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA
| | - Fumihiko Urano
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA. .,Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA
| | - Jeffrey R Millman
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA. .,Department of Biomedical Engineering, Washington University in St. Louis, 1 Brookings Drive, St. Louis, MO 63130, USA
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Jiang M, Kuang Z, He Y, Cao Y, Yu T, Cheng J, Liu W, Wang W. SNAPIN Regulates Cell Cycle Progression to Promote Pancreatic β Cell Growth. Front Endocrinol (Lausanne) 2021; 12:624309. [PMID: 34194388 DOI: 10.3389/fendo.2021.624309] [cited] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Accepted: 05/13/2021] [Indexed: 01/26/2025] Open
Abstract
In diabetes mellitus, death of β cell in the pancreas occurs throughout the development of the disease, with loss of insulin production. The maintenance of β cell number is essential to maintaining normoglycemia. SNAPIN has been found to regulate insulin secretion, but whether it induces β cell proliferation remains to be elucidated. This study aimed to explore the physiological roles of SNAPIN in β cell proliferation. SNAPIN expression increases with the age of mice and SNAPIN is down-regulated in diabetes. KEGG pathway and GO analysis showed that SNAPIN- interacting proteins were enriched in cell cycle regulation. B cell cycle was arrested in the S phase, and cell proliferation was inhibited after SNAPIN knockdown. The expression of CDK2, CDK4 and CCND1 proteins in the S phase of the cell cycle were reduced after SNAPIN knockdown, whereas they were increased after overexpression of SNAPIN. In addition, insulin protein and mRNA levels also increased or decreased after SNAPIN knockdown or overexpression, respectively. Conclusions: Our data indicate that SNAPIN mediates β cells proliferation and insulin secretion, and provide evidences that SNAPIN might be a pharmacotherapeutic target for diabetes mellitus.
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Affiliation(s)
- Mengxue Jiang
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Zhijian Kuang
- Fujian Provincial KeyLaboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Yaohui He
- Fujian Provincial KeyLaboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Yin Cao
- Fujian Provincial KeyLaboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Tingyan Yu
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Jidong Cheng
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Wen Liu
- Fujian Provincial KeyLaboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Wei Wang
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
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37
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George MN, Leavens KF, Gadue P. Genome Editing Human Pluripotent Stem Cells to Model β-Cell Disease and Unmask Novel Genetic Modifiers. Front Endocrinol (Lausanne) 2021; 12:682625. [PMID: 34149620 PMCID: PMC8206553 DOI: 10.3389/fendo.2021.682625] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 05/13/2021] [Indexed: 01/21/2023] Open
Abstract
A mechanistic understanding of the genetic basis of complex diseases such as diabetes mellitus remain elusive due in large part to the activity of genetic disease modifiers that impact the penetrance and/or presentation of disease phenotypes. In the face of such complexity, rare forms of diabetes that result from single-gene mutations (monogenic diabetes) can be used to model the contribution of individual genetic factors to pancreatic β-cell dysfunction and the breakdown of glucose homeostasis. Here we review the contribution of protein coding and non-protein coding genetic disease modifiers to the pathogenesis of diabetes subtypes, as well as how recent technological advances in the generation, differentiation, and genome editing of human pluripotent stem cells (hPSC) enable the development of cell-based disease models. Finally, we describe a disease modifier discovery platform that utilizes these technologies to identify novel genetic modifiers using induced pluripotent stem cells (iPSC) derived from patients with monogenic diabetes caused by heterozygous mutations.
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Affiliation(s)
- Matthew N. George
- Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States
| | - Karla F. Leavens
- Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
- Division of Endocrinology and Diabetes, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States
| | - Paul Gadue
- Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States
- Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States
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Pushp P, Nogueira DES, Rodrigues CAV, Ferreira FC, Cabral JMS, Gupta MK. A Concise Review on Induced Pluripotent Stem Cell-Derived Cardiomyocytes for Personalized Regenerative Medicine. Stem Cell Rev Rep 2021; 17:748-776. [PMID: 33098306 DOI: 10.1007/s12015-020-10061-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/16/2020] [Indexed: 02/07/2023]
Abstract
The induced pluripotent stem cells (iPSCs) are derived from somatic cells by using reprogramming factors such as Oct4, Sox2, Klf4, and c-Myc (OSKM) or Oct4, Sox2, Nanog and Lin28 (OSNL). They resemble embryonic stem cells (ESCs) and have the ability to differentiate into cell lineage of all three germ-layer, including cardiomyocytes (CMs). The CMs can be generated from iPSCs by inducing embryoid bodies (EBs) formation and treatment with activin A, bone morphogenic protein 4 (BMP4), and inhibitors of Wnt signaling. However, these iPSC-derived CMs are a heterogeneous population of cells and require purification and maturation to mimic the in vivo CMs. The matured CMs can be used for various therapeutic purposes in regenerative medicine by cardiomyoplasty or through the development of tissue-engineered cardiac patches. In recent years, significant advancements have been made in the isolation of iPSC and their differentiation, purification, and maturation into clinically usable CMs. Newer small molecules have also been identified to substitute the reprogramming factors for iPSC generation as well as for direct differentiation of somatic cells into CMs without an intermediary pluripotent state. This review provides a concise update on the generation of iPSC-derived CMs and their application in personalized cardiac regenerative medicine. It also discusses the current limitations and challenges in the application of iPSC-derived CMs. Graphical abstract.
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Affiliation(s)
- Pallavi Pushp
- Department of Biotechnology, Institute of Engineering and Technology (IET), Bundelkhand University, Jhansi, Uttar Pradesh, 284128, India
- Department of Biotechnology and Medical Engineering, National Institute of Technology, Rourkela, Odisha, 769 008, India
| | - Diogo E S Nogueira
- Department of Bioengineering, and iBB - Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
| | - Carlos A V Rodrigues
- Department of Bioengineering, and iBB - Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
| | - Frederico C Ferreira
- Department of Bioengineering, and iBB - Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal
| | - Joaquim M S Cabral
- Department of Bioengineering, and iBB - Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal.
| | - Mukesh Kumar Gupta
- Department of Biotechnology and Medical Engineering, National Institute of Technology, Rourkela, Odisha, 769 008, India.
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Boscari F, Avogaro A. Current treatment options and challenges in patients with Type 1 diabetes: Pharmacological, technical advances and future perspectives. Rev Endocr Metab Disord 2021; 22:217-240. [PMID: 33755854 PMCID: PMC7985920 DOI: 10.1007/s11154-021-09635-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/09/2021] [Indexed: 12/14/2022]
Abstract
Type 1 diabetes mellitus imposes a significant burden of complications and mortality, despite important advances in treatment: subjects affected by this disease have also a worse quality of life-related to disease management. To overcome these challenges, different new approaches have been proposed, such as new insulin formulations or innovative devices. The introduction of insulin pumps allows a more physiological insulin administration with a reduction of HbA1c level and hypoglycemic risk. New continuous glucose monitoring systems with better accuracy have allowed, not only better glucose control, but also the improvement of the quality of life. Integration of these devices with control algorithms brought to the creation of the first artificial pancreas, able to independently gain metabolic control without the risk of hypo- and hyperglycemic crisis. This approach has revolutionized the management of diabetes both in terms of quality of life and glucose control. However, complete independence from exogenous insulin will be obtained only by biological approaches that foresee the replacement of functional beta cells obtained from stem cells: this will be a major challenge but the biggest hope for the subjects with type 1 diabetes. In this review, we will outline the current scenario of innovative diabetes management both from a technological and biological point of view, and we will also forecast some cutting-edge approaches to reduce the challenges that hamper the definitive cure of diabetes.
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Affiliation(s)
- Federico Boscari
- Department of Medicine, Unit of Metabolic Diseases, University of Padova, Padova, Italy.
| | - Angelo Avogaro
- Department of Medicine, Unit of Metabolic Diseases, University of Padova, Padova, Italy
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Heller S, Melzer MK, Azoitei N, Julier C, Kleger A. Human Pluripotent Stem Cells Go Diabetic: A Glimpse on Monogenic Variants. Front Endocrinol (Lausanne) 2021; 12:648284. [PMID: 34079523 PMCID: PMC8166226 DOI: 10.3389/fendo.2021.648284] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 04/13/2021] [Indexed: 12/17/2022] Open
Abstract
Diabetes, as one of the major diseases in industrial countries, affects over 350 million people worldwide. Type 1 (T1D) and type 2 diabetes (T2D) are the most common forms with both types having invariable genetic influence. It is accepted that a subset of all diabetes patients, generally estimated to account for 1-2% of all diabetic cases, is attributed to mutations in single genes. As only a subset of these genes has been identified and fully characterized, there is a dramatic need to understand the pathophysiological impact of genetic determinants on β-cell function and pancreatic development but also on cell replacement therapies. Pluripotent stem cells differentiated along the pancreatic lineage provide a valuable research platform to study such genes. This review summarizes current perspectives in applying this platform to study monogenic diabetes variants.
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Affiliation(s)
- Sandra Heller
- Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany
| | - Michael Karl Melzer
- Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany
- Department of Urology, Ulm University Hospital, Ulm, Germany
| | - Ninel Azoitei
- Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany
| | - Cécile Julier
- Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR-8104, Paris, France
| | - Alexander Kleger
- Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany
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Joshi K, Cameron F, Tiwari S, Mannering SI, Elefanty AG, Stanley EG. Modeling Type 1 Diabetes Using Pluripotent Stem Cell Technology. Front Endocrinol (Lausanne) 2021; 12:635662. [PMID: 33868170 PMCID: PMC8047192 DOI: 10.3389/fendo.2021.635662] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 03/03/2021] [Indexed: 12/26/2022] Open
Abstract
Induced pluripotent stem cell (iPSC) technology is increasingly being used to create in vitro models of monogenic human disorders. This is possible because, by and large, the phenotypic consequences of such genetic variants are often confined to a specific and known cell type, and the genetic variants themselves can be clearly identified and controlled for using a standardized genetic background. In contrast, complex conditions such as autoimmune Type 1 diabetes (T1D) have a polygenic inheritance and are subject to diverse environmental influences. Moreover, the potential cell types thought to contribute to disease progression are many and varied. Furthermore, as HLA matching is critical for cell-cell interactions in disease pathogenesis, any model that seeks to test the involvement of particular cell types must take this restriction into account. As such, creation of an in vitro model of T1D will require a system that is cognizant of genetic background and enables the interaction of cells representing multiple lineages to be examined in the context of the relevant environmental disease triggers. In addition, as many of the lineages critical to the development of T1D cannot be easily generated from iPSCs, such models will likely require combinations of cell types derived from in vitro and in vivo sources. In this review we imagine what an ideal in vitro model of T1D might look like and discuss how the required elements could be feasibly assembled using existing technologies. We also examine recent advances towards this goal and discuss potential uses of this technology in contributing to our understanding of the mechanisms underlying this autoimmune condition.
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Affiliation(s)
- Kriti Joshi
- Department of Endocrinology and Metabolism, All India Institute of Medical Sciences Rishikesh, Uttarakhand, India
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
- Department of Cell Biology, Murdoch Children’s Research Institute, Parkville, Vic, Australia
| | - Fergus Cameron
- Department of Cell Biology, Murdoch Children’s Research Institute, Parkville, Vic, Australia
- Department of Endocrinology and Diabetes, The Royal Children’s Hospital, Parkville, Vic, Australia
- Department of Paediatrics, University of Melbourne, Parkville, Vic, Australia
| | - Swasti Tiwari
- Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Stuart I. Mannering
- Immunology and Diabetes Unit, St. Vincent’s Institute of Medical Research, Fitzroy, Vic, Australia
| | - Andrew G. Elefanty
- Department of Cell Biology, Murdoch Children’s Research Institute, Parkville, Vic, Australia
- Department of Paediatrics, University of Melbourne, Parkville, Vic, Australia
- Department of Anatomy and Developmental Biology, Monash University, Clayton, Vic, Australia
| | - Edouard G. Stanley
- Department of Cell Biology, Murdoch Children’s Research Institute, Parkville, Vic, Australia
- Department of Paediatrics, University of Melbourne, Parkville, Vic, Australia
- Department of Anatomy and Developmental Biology, Monash University, Clayton, Vic, Australia
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Generation of high yield insulin-producing cells (IPCs) from various sources of stem cells. VITAMINS AND HORMONES 2021; 116:235-268. [PMID: 33752820 DOI: 10.1016/bs.vh.2021.02.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Type 1 diabetes mellitus occurs when beta cell mass is reduced to less than 20% of the normal level due to immune system destruction of beta cell resulting in an inability to secrete enough insulin. The prevalence of diabetes is expanding according to the American Diabetes Association and the World Health Organization (WHO), foretold to exceed 350 million by 2030. The current treatment does not cure many of the serious complications associated with the disease such as neuropathy, nephropathy, dyslipidemia, retinopathy and cardiovascular disease. Whole pancreas or isolated pancreatic islet transplantation as an alternative therapy can prevent or reduce some of the complications of diabetes. However, the shortage of matched organ or islets cells donor and alloimmune responses limit this therapeutic strategy. Recently, several reports have raised extremely promising results to use different sources of stem cells to differentiate insulin-producing cells and focus on the expansion of these alternative sources. Stem cells, due to their potential for multiple differentiation and self-renewal can differentiate into all cell types, including insulin-producing cells (IPCs). Generation of new beta cells can be achieved from various stem cell sources, including embryonic stem cells (ESCs), adult stem cells, such as mesenchymal stem cells (MSCs) and induced pluripotent stem cells (iPSCs). Thus, this chapter discusses on the assistance of cellular reprogramming of various stem cells as candidates for the generation of IPCs using transcription factors/miRNA, cytokines/small molecules and tissue engineering.
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Abdelalim EM. Modeling different types of diabetes using human pluripotent stem cells. Cell Mol Life Sci 2021; 78:2459-2483. [PMID: 33242105 PMCID: PMC11072720 DOI: 10.1007/s00018-020-03710-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 10/19/2020] [Accepted: 11/11/2020] [Indexed: 12/22/2022]
Abstract
Diabetes mellitus (DM) is a metabolic disease characterized by chronic hyperglycemia as a result of progressive loss of pancreatic β cells, which could lead to several debilitating complications. Different paths, triggered by several genetic and environmental factors, lead to the loss of pancreatic β cells and/or function. Understanding these many paths to β cell damage or dysfunction could help in identifying therapeutic approaches specific for each path. Most of our knowledge about diabetes pathophysiology has been obtained from studies on animal models, which do not fully recapitulate human diabetes phenotypes. Currently, human pluripotent stem cell (hPSC) technology is a powerful tool for generating in vitro human models, which could provide key information about the disease pathogenesis and provide cells for personalized therapies. The recent progress in generating functional hPSC-derived β cells in combination with the rapid development in genomic and genome-editing technologies offer multiple options to understand the cellular and molecular mechanisms underlying the development of different types of diabetes. Recently, several in vitro hPSC-based strategies have been used for studying monogenic and polygenic forms of diabetes. This review summarizes the current knowledge about different hPSC-based diabetes models and how these models improved our current understanding of the pathophysiology of distinct forms of diabetes. Also, it highlights the progress in generating functional β cells in vitro, and discusses the current challenges and future perspectives related to the use of the in vitro hPSC-based strategies.
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Affiliation(s)
- Essam M Abdelalim
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar.
- College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Education City, Doha, Qatar.
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Marfil-Garza BA, Shapiro AMJ, Kin T. Clinical islet transplantation: Current progress and new frontiers. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2021; 28:243-254. [PMID: 33417749 DOI: 10.1002/jhbp.891] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 12/12/2020] [Accepted: 12/28/2020] [Indexed: 02/05/2023]
Abstract
Islet transplantation (IT) is now a robust treatment for selected patients with type 1 diabetes suffering from recurrent hypoglycemia and impaired awareness of hypoglycemia. A global soar of clinical islet transplant programs attests to the commitment of many institutions and researchers to advance IT as a potential cure for this devastating disease. However, many challenges limiting the widespread applicability of clinical IT remain. In this review, we will touch on the milestones in the history of IT and its path to clinical success, discuss the current challenges around IT, propose some possible solutions, and elaborate on the frontiers envisioned in the future of clinical IT.
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Affiliation(s)
| | - Andrew Mark James Shapiro
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
| | - Tatsuya Kin
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
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45
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DGK and DZHK position paper on genome editing: basic science applications and future perspective. Basic Res Cardiol 2021; 116:2. [PMID: 33449167 PMCID: PMC7810637 DOI: 10.1007/s00395-020-00839-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 12/09/2020] [Indexed: 12/18/2022]
Abstract
For a long time, gene editing had been a scientific concept, which was limited to a few applications. With recent developments, following the discovery of TALEN zinc-finger endonucleases and in particular the CRISPR/Cas system, gene editing has become a technique applicable in most laboratories. The current gain- and loss-of function models in basic science are revolutionary as they allow unbiased screens of unprecedented depth and complexity and rapid development of transgenic animals. Modifications of CRISPR/Cas have been developed to precisely interrogate epigenetic regulation or to visualize DNA complexes. Moreover, gene editing as a clinical treatment option is rapidly developing with first trials on the way. This article reviews the most recent progress in the field, covering expert opinions gathered during joint conferences on genome editing of the German Cardiac Society (DGK) and the German Center for Cardiovascular Research (DZHK). Particularly focusing on the translational aspect and the combination of cellular and animal applications, the authors aim to provide direction for the development of the field and the most frequent applications with their problems.
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46
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Jiang M, Kuang Z, He Y, Cao Y, Yu T, Cheng J, Liu W, Wang W. SNAPIN Regulates Cell Cycle Progression to Promote Pancreatic β Cell Growth. Front Endocrinol (Lausanne) 2021; 12:624309. [PMID: 34194388 PMCID: PMC8237857 DOI: 10.3389/fendo.2021.624309] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Accepted: 05/13/2021] [Indexed: 02/05/2023] Open
Abstract
In diabetes mellitus, death of β cell in the pancreas occurs throughout the development of the disease, with loss of insulin production. The maintenance of β cell number is essential to maintaining normoglycemia. SNAPIN has been found to regulate insulin secretion, but whether it induces β cell proliferation remains to be elucidated. This study aimed to explore the physiological roles of SNAPIN in β cell proliferation. SNAPIN expression increases with the age of mice and SNAPIN is down-regulated in diabetes. KEGG pathway and GO analysis showed that SNAPIN- interacting proteins were enriched in cell cycle regulation. B cell cycle was arrested in the S phase, and cell proliferation was inhibited after SNAPIN knockdown. The expression of CDK2, CDK4 and CCND1 proteins in the S phase of the cell cycle were reduced after SNAPIN knockdown, whereas they were increased after overexpression of SNAPIN. In addition, insulin protein and mRNA levels also increased or decreased after SNAPIN knockdown or overexpression, respectively. Conclusions: Our data indicate that SNAPIN mediates β cells proliferation and insulin secretion, and provide evidences that SNAPIN might be a pharmacotherapeutic target for diabetes mellitus.
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Affiliation(s)
- Mengxue Jiang
- Department of Endocrinology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Zhijian Kuang
- Fujian Provincial KeyLaboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Yaohui He
- Fujian Provincial KeyLaboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Yin Cao
- Fujian Provincial KeyLaboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Tingyan Yu
- Department of Endocrinology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
| | - Jidong Cheng
- Department of Endocrinology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- *Correspondence: Jidong Cheng, ; Wen Liu, ; Wei Wang,
| | - Wen Liu
- Fujian Provincial KeyLaboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
- *Correspondence: Jidong Cheng, ; Wen Liu, ; Wei Wang,
| | - Wei Wang
- Department of Endocrinology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China
- *Correspondence: Jidong Cheng, ; Wen Liu, ; Wei Wang,
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47
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Elnashar M, Vaccarezza M, Al-Salami H. Cutting-edge biotechnological advancement in islet delivery using pancreatic and cellular approaches. Future Sci OA 2020; 7:FSO660. [PMID: 33552541 PMCID: PMC7849926 DOI: 10.2144/fsoa-2020-0105] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
There are approximately 1 billion prediabetic people worldwide, and the global cost for diabetes mellitus (DM) is estimated to be $825 billion. In regard to Type 1 DM, transplanting a whole pancreas or its islets has gained the attention of researchers in the last few decades. Recent studies showed that islet transplantation (ILT) containing insulin-producing β cells is the most notable advancement cure for Type 1 DM. However, this procedure has been hindered by shortage and lack of sufficient islet donors and the need for long-term immunosuppression of any potential graft rejection. The strategy of encapsulation may avoid the rejection of stem-cell-derived allogeneic islets or xenogeneic islets. This review article describes various biotechnology features in encapsulation-of-islet-cell therapy for humans, including the use of bile acids.
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Affiliation(s)
- Magdy Elnashar
- Biotechnology & Drug Development Research Laboratory, School of Pharmacy & Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia.,Centre of Excellence, Department of Polymers, National Research Centre, Cairo, Egypt
| | - Mauro Vaccarezza
- School of Pharmacy & Biomedical Science, Faculty of Health Sciences, Curtin University, Bentley, Perth, WA 6102, Australia
| | - Hani Al-Salami
- Biotechnology & Drug Development Research Laboratory, School of Pharmacy & Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia
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48
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Insulin/Glucose-Responsive Cells Derived from Induced Pluripotent Stem Cells: Disease Modeling and Treatment of Diabetes. Cells 2020; 9:cells9112465. [PMID: 33198288 PMCID: PMC7696367 DOI: 10.3390/cells9112465] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 11/03/2020] [Accepted: 11/09/2020] [Indexed: 12/21/2022] Open
Abstract
Type 2 diabetes, characterized by dysfunction of pancreatic β-cells and insulin resistance in peripheral organs, accounts for more than 90% of all diabetes. Despite current developments of new drugs and strategies to prevent/treat diabetes, there is no ideal therapy targeting all aspects of the disease. Restoration, however, of insulin-producing β-cells, as well as insulin-responsive cells, would be a logical strategy for the treatment of diabetes. In recent years, generation of transplantable cells derived from stem cells in vitro has emerged as an important research area. Pluripotent stem cells, either embryonic or induced, are alternative and feasible sources of insulin-secreting and glucose-responsive cells. This notwithstanding, consistent generation of robust glucose/insulin-responsive cells remains challenging. In this review, we describe basic concepts of the generation of induced pluripotent stem cells and subsequent differentiation of these into pancreatic β-like cells, myotubes, as well as adipocyte- and hepatocyte-like cells. Use of these for modeling of human disease is now feasible, while development of replacement therapies requires continued efforts.
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Abstract
OBJECTIVES We aimed to determine whether responsive insulin-producing cells (IPCs) could be generated from adipose-derived stem cells (ADSCs) isolated from patients with type 1 diabetes mellitus (T1DM). METHODS We isolated ADSCs from adipose tissue of 4 patients (one patient with T1DM and 3 nondiabetic patients), who underwent surgery and differentiated them into IPCs with using a 2-step xeno-antigen free, 3-dimensional culture method. Characteristics of isolated ADSCs, in vitro cell quality, programmed cell death ligand-1 (PDL-1) expression, and transplantation into streptozotocin induced diabetic nude mice were investigated. RESULTS Adipose-derived stem cells from T1DM patients and commercially obtained ADSCs showed the same surface markers; CD31CD34CD45CD90CD105CD146. Moreover, the generated IPCs at day 21 demonstrated appropriate autonomous insulin secretion (stimulation index, 3.5; standard deviation, 0.8). Nonfasting blood glucose concentrations of IPC-transplanted mice were normal at 30 days. The normalized rate of IPC-transplanted mice was significantly higher than that of the sham-operated group (P < 0.05). Insulin-producing cells generated from T1DM adipose tissue expressed high levels of PDL-1. CONCLUSIONS Insulin-producing cells obtained from adipose tissue of T1DM patients are capable of secreting insulin long-term and achieve normoglycemia after transplantation. Expression of PDL-1 suggests the potential for immune circumvention.
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Paniza T, Deshpande M, Wang N, O’Neil R, Zuccaro MV, Smith ME, Madireddy A, James D, Ecker J, Rosenwaks Z, Egli D, Gerhardt J. Pluripotent stem cells with low differentiation potential contain incompletely reprogrammed DNA replication. J Cell Biol 2020; 219:e201909163. [PMID: 32673399 PMCID: PMC7480103 DOI: 10.1083/jcb.201909163] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 02/26/2020] [Accepted: 05/13/2020] [Indexed: 12/20/2022] Open
Abstract
Reprogrammed pluripotent stem cells (PSCs) are valuable for research and potentially for cell replacement therapy. However, only a fraction of reprogrammed PSCs are developmentally competent. Genomic stability and accurate DNA synthesis are fundamental for cell development and critical for safety. We analyzed whether defects in DNA replication contribute to genomic instability and the diverse differentiation potentials of reprogrammed PSCs. Using a unique single-molecule approach, we visualized DNA replication in isogenic PSCs generated by different reprogramming approaches, either somatic cell nuclear transfer (NT-hESCs) or with defined factors (iPSCs). In PSCs with lower differentiation potential, DNA replication was incompletely reprogrammed, and genomic instability increased during replicative stress. Reprogramming of DNA replication did not correlate with DNA methylation. Instead, fewer replication origins and a higher frequency of DNA breaks in PSCs with incompletely reprogrammed DNA replication were found. Given the impact of error-free DNA synthesis on the genomic integrity and differentiation proficiency of PSCs, analyzing DNA replication may be a useful quality control tool.
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Affiliation(s)
- Theodore Paniza
- The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medicine, New York, NY
| | - Madhura Deshpande
- The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medicine, New York, NY
| | - Ning Wang
- Department of Pediatrics, Columbia University, New York, NY
| | - Ryan O’Neil
- Plant Molecular and Cellular Biology Laboratory, Salk Institute, La Jolla, CA
| | - Michael V. Zuccaro
- Department of Pediatrics, Columbia University, New York, NY
- Department of Physiology and Cellular Biophysics, Columbia University Vagelos College of Physicians and Surgeons, New York, NY
| | | | - Advaitha Madireddy
- Department of Pediatric Hematology/Oncology, Rutgers University, New Brunswick, NJ
| | - Daylon James
- The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medicine, New York, NY
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY
| | - Joseph Ecker
- Plant Molecular and Cellular Biology Laboratory, Salk Institute, La Jolla, CA
| | - Zev Rosenwaks
- The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medicine, New York, NY
| | - Dieter Egli
- Department of Pediatrics, Columbia University, New York, NY
| | - Jeannine Gerhardt
- The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medicine, New York, NY
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY
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