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Grygoryev D, Ekstrom T, Manalo E, Link JM, Alshaikh A, Keith D, Allen-Petersen BL, Sheppard B, Morgan T, Soufi A, Sears RC, Kim J. Sendai virus is robust and consistent in delivering genes into human pancreatic cancer cells. Heliyon 2024; 10:e27221. [PMID: 38463758 PMCID: PMC10923719 DOI: 10.1016/j.heliyon.2024.e27221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Revised: 02/22/2024] [Accepted: 02/26/2024] [Indexed: 03/12/2024] Open
Abstract
Background Pancreatic ductal adenocarcinoma (PDAC) is a highly intratumorally heterogeneous disease that includes several subtypes and is highly plastic. Effective gene delivery to all PDAC cells is essential for modulating gene expression and identifying potential gene-based therapeutic targets in PDAC. Most current gene delivery systems for pancreatic cells are optimized for islet or acinar cells. Lentiviral vectors are the current main gene delivery vectors for PDAC, but their transduction efficiencies vary depending on pancreatic cell type, and are especially poor for the classical subtype of PDAC cells from both primary tumors and cell lines. Methods We systemically compare transduction efficiencies of glycoprotein G of vesicular stomatitis virus (VSV-G)-pseudotyped lentiviral and Sendai viral vectors in human normal pancreatic ductal and PDAC cells. Results We find that the Sendai viral vector gives the most robust gene delivery efficiency regardless of PDAC cell type. Therefore, we propose using Sendai viral vectors to transduce ectopic genes into PDAC cells.
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Affiliation(s)
- Dmytro Grygoryev
- Cancer Early Detection Advanced Research Center at Knight Cancer Institute, Oregon Health & Science University School of Medicine, USA
| | - Taelor Ekstrom
- Cancer Early Detection Advanced Research Center at Knight Cancer Institute, Oregon Health & Science University School of Medicine, USA
| | - Elise Manalo
- Cancer Early Detection Advanced Research Center at Knight Cancer Institute, Oregon Health & Science University School of Medicine, USA
| | - Jason M. Link
- Department of Molecular and Medical Genetics, Oregon Health & Science University School of Medicine, USA
- Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University School of Medicine, USA
| | - Amani Alshaikh
- The University of Edinburgh, Centre for Regenerative Medicine, Institute of Regeneration and Repair, Institute of Stem Cell Research, Edinburgh, UK
- King Abdulaziz City for Science and Technology, Health Sector (KACST), Riyadh, Saudi Arabia
| | - Dove Keith
- Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University School of Medicine, USA
| | - Brittany L. Allen-Petersen
- Department of Molecular and Medical Genetics, Oregon Health & Science University School of Medicine, USA
- Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University School of Medicine, USA
| | - Brett Sheppard
- Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University School of Medicine, USA
- Department of Surgery, Oregon Health & Science University School of Medicine, USA
| | - Terry Morgan
- Cancer Early Detection Advanced Research Center at Knight Cancer Institute, Oregon Health & Science University School of Medicine, USA
- Department of Pathology, Oregon Health & Science University School of Medicine, USA
- Cancer Biology Research Program, Knight Cancer Institute, Oregon Health & Science University School of Medicine, Portland, OR, 97201, USA
| | - Abdenour Soufi
- The University of Edinburgh, Centre for Regenerative Medicine, Institute of Regeneration and Repair, Institute of Stem Cell Research, Edinburgh, UK
| | - Rosalie C. Sears
- Department of Molecular and Medical Genetics, Oregon Health & Science University School of Medicine, USA
- Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University School of Medicine, USA
- Cancer Biology Research Program, Knight Cancer Institute, Oregon Health & Science University School of Medicine, Portland, OR, 97201, USA
| | - Jungsun Kim
- Cancer Early Detection Advanced Research Center at Knight Cancer Institute, Oregon Health & Science University School of Medicine, USA
- Department of Molecular and Medical Genetics, Oregon Health & Science University School of Medicine, USA
- Cancer Biology Research Program, Knight Cancer Institute, Oregon Health & Science University School of Medicine, Portland, OR, 97201, USA
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2
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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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3
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Memon B, Abdelalim EM. OUP accepted manuscript. Stem Cells Transl Med 2022; 11:704-714. [PMID: 35640144 PMCID: PMC9299517 DOI: 10.1093/stcltm/szac030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Accepted: 04/09/2022] [Indexed: 11/14/2022] Open
Abstract
Although genome profiling provides important genetic and phenotypic details for applying precision medicine to diabetes, it is imperative to integrate in vitro human cell models, accurately recapitulating the genetic alterations associated with diabetes. The absence of the appropriate preclinical human models and the unavailability of genetically relevant cells substantially limit the progress in developing personalized treatment for diabetes. Human pluripotent stem cells (hPSCs) provide a scalable source for generating diabetes-relevant cells carrying the genetic signatures of the patients. Remarkably, allogenic hPSC-derived pancreatic progenitors and β cells are being used in clinical trials with promising preliminary results. Autologous hiPSC therapy options exist for those with monogenic and type 2 diabetes; however, encapsulation or immunosuppression must be accompanied with in the case of type 1 diabetes. Furthermore, genome-wide association studies-identified candidate variants can be introduced in hPSCs for deciphering the associated molecular defects. The hPSC-based disease models serve as excellent resources for drug development facilitating personalized treatment. Indeed, hPSC-based diabetes models have successfully provided valuable knowledge by modeling different types of diabetes, which are discussed in this review. Herein, we also evaluate their strengths and shortcomings in dissecting the underlying pathogenic molecular mechanisms and discuss strategies for improving hPSC-based disease modeling investigations.
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Affiliation(s)
- Bushra Memon
- College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Education City, Doha, Qatar
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
| | - Essam M Abdelalim
- Corresponding author: Essam M. Abdelalim, Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa, University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar. Tel: +974 445 46432; Fax: +974 445 41770;
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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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5
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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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Vieira CP, McCarrel TM, Grant MB. Novel Methods to Mobilize, Isolate, and Expand Mesenchymal Stem Cells. Int J Mol Sci 2021; 22:ijms22115728. [PMID: 34072061 PMCID: PMC8197893 DOI: 10.3390/ijms22115728] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 05/12/2021] [Accepted: 05/20/2021] [Indexed: 12/11/2022] Open
Abstract
Numerous studies demonstrate the essential role of mesenchymal stem cells (MSCs) in the treatment of metabolic and inflammatory diseases, as these cells are known to modulate humoral and cellular immune responses. In this manuscript, we efficiently present two novel approaches to obtain MSCs from equine or human sources. In our first approach, we used electro-acupuncture as previously described by our group to mobilize MSCs into the peripheral blood of horses. For equine MSC collection, culture, and expansion, we used the Miltenyi Biotec CliniMACS Prodigy system of automated cell manufacturing. Using this system, we were able to generate appoximately 100 MSC colonies that exhibit surface marker expression of CD105 (92%), CD90 (85%), and CD73 (88%) within seven days of blood collection. Our second approach utilized the iPSC embryoid bodies from healthy or diabetic subjects where the iPSCs were cultured in standard media (endothelial + mesoderm basal media). After 21 days, the cells were FACS sorted and exhibited surface marker expression of CD105, CD90, and CD73. Both the equine cells and the human iPSC-derived MSCs were able to differentiate into adipogenic, osteogenic, and chondrogenic lineages. Both methods described simple and highly efficient methods to produce cells with surface markers phenotypically considered as MSCs and may, in the future, facilitate rapid production of MSCs with therapeutic potential.
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Affiliation(s)
- Cristiano P. Vieira
- Department of Ophthalmology and Visual Sciences, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
| | - Taralyn M. McCarrel
- College of Veterinary Medicine, University of Florida, Gainesville, FL 32611, USA;
| | - Maria B. Grant
- Department of Ophthalmology and Visual Sciences, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
- Correspondence:
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7
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Abstract
Improved stem cell-derived pancreatic islet (SC-islet) differentiation protocols robustly generate insulin-secreting β cells from patient induced pluripotent stem cells (iPSCs). These advances are enabling in vitro disease modeling studies and the development of an autologous diabetes cell replacement therapy. SC-islet technology elucidates key features of human pancreas development and diabetes disease progression through the generation of pancreatic progenitors, endocrine progenitors, and β cells derived from diabetic and nondiabetic iPSCs. Combining disease modeling with gene editing and next-generation sequencing reveals the impact of diabetes-causing mutations and diabetic phenotypes on multiple islet cell types. In addition, the supply of SC-islets, containing β and other islet cell types, is unlimited, presenting an opportunity for personalized medicine and overcoming several disadvantages posed by donor islets. This review highlights relevant studies involving iPSC-β cells and progenitors, encompassing new conclusions involving cells from patients with diabetes and the therapeutic potential of iPSC-β cells.
Improved differentiation protocols generate pancreatic islet from patient stem cells Diabetic stem cell-derived islet studies identified key markers for cell function Gene editing aims to address unmet needs for stem cell therapy field Stem cell-derived islets are a promising source for diabetes stem cell therapy
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8
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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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9
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Elsayed AK, Vimalraj S, Nandakumar M, Abdelalim EM. Insulin resistance in diabetes: The promise of using induced pluripotent stem cell technology. World J Stem Cells 2021; 13:221-235. [PMID: 33815671 PMCID: PMC8006014 DOI: 10.4252/wjsc.v13.i3.221] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 02/07/2021] [Accepted: 03/11/2021] [Indexed: 02/06/2023] Open
Abstract
Insulin resistance (IR) is associated with several metabolic disorders, including type 2 diabetes (T2D). The development of IR in insulin target tissues involves genetic and acquired factors. Persons at genetic risk for T2D tend to develop IR several years before glucose intolerance. Several rodent models for both IR and T2D are being used to study the disease pathogenesis; however, these models cannot recapitulate all the aspects of this complex disorder as seen in each individual. Human pluripotent stem cells (hPSCs) can overcome the hurdles faced with the classical mouse models for studying IR. Human induced pluripotent stem cells (hiPSCs) can be generated from the somatic cells of the patients without the need to destroy a human embryo. Therefore, patient-specific hiPSCs can generate cells genetically identical to IR individuals, which can help in distinguishing between genetic and acquired defects in insulin sensitivity. Combining the technologies of genome editing and hiPSCs may provide important information about the genetic factors underlying the development of different forms of IR. Further studies are required to fill the gaps in understanding the pathogenesis of IR and diabetes. In this review, we summarize the factors involved in the development of IR in the insulin-target tissues leading to diabetes. Also, we highlight the use of hPSCs to understand the mechanisms underlying the development of IR.
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Affiliation(s)
- Ahmed K Elsayed
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha 34110, Qatar
| | | | - Manjula Nandakumar
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha 34110, Qatar
| | - Essam M Abdelalim
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha 34110, Qatar
- College of Health and Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Doha 34110, Qatar
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10
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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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11
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Antao AM, Karapurkar JK, Lee DR, Kim KS, Ramakrishna S. Disease modeling and stem cell immunoengineering in regenerative medicine using CRISPR/Cas9 systems. Comput Struct Biotechnol J 2020; 18:3649-3665. [PMID: 33304462 PMCID: PMC7710510 DOI: 10.1016/j.csbj.2020.11.026] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 11/16/2020] [Accepted: 11/16/2020] [Indexed: 12/14/2022] Open
Abstract
CRISPR/Cas systems are popular genome editing tools that belong to a class of programmable nucleases and have enabled tremendous progress in the field of regenerative medicine. We here outline the structural and molecular frameworks of the well-characterized type II CRISPR system and several computational tools intended to facilitate experimental designs. The use of CRISPR tools to generate disease models has advanced research into the molecular aspects of disease conditions, including unraveling the molecular basis of immune rejection. Advances in regenerative medicine have been hindered by major histocompatibility complex-human leukocyte antigen (HLA) genes, which pose a major barrier to cell- or tissue-based transplantation. Based on progress in CRISPR, including in recent clinical trials, we hypothesize that the generation of universal donor immune-engineered stem cells is now a realistic approach to tackling a multitude of disease conditions.
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Affiliation(s)
- Ainsley Mike Antao
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea
| | | | - Dong Ryul Lee
- Department of Biomedical Science, College of Life Science, CHA University, Seoul, South Korea
- CHA Stem Cell Institute, CHA University, Seoul, South Korea
| | - Kye-Seong Kim
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea
- College of Medicine, Hanyang University, Seoul, South Korea
| | - Suresh Ramakrishna
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea
- College of Medicine, Hanyang University, Seoul, South Korea
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12
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Walsh P, Truong V, Nayak S, Saldías Montivero M, Low WC, Parr AM, Dutton JR. Accelerated differentiation of human pluripotent stem cells into neural lineages via an early intermediate ectoderm population. Stem Cells 2020; 38:1400-1408. [PMID: 32745311 PMCID: PMC7693041 DOI: 10.1002/stem.3260] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 06/17/2020] [Accepted: 07/10/2020] [Indexed: 12/22/2022]
Abstract
Differentiation of human pluripotent stem cells (hPSCs) into ectoderm provides neurons and glia useful for research, disease modeling, drug discovery, and potential cell therapies. In current protocols, hPSCs are traditionally differentiated into an obligate rostro-dorsal ectodermal fate expressing PAX6 after 6 to 12 days in vitro when protected from mesendoderm inducers. This rate-limiting step has performed a long-standing role in hindering the development of rapid differentiation protocols for ectoderm-derived cell types, as any protocol requires 6 to 10 days in vitro to simply initiate. Here, we report efficient differentiation of hPSCs into a naive early ectodermal intermediate within 24 hours using combined inhibition of bone morphogenic protein and fibroblast growth factor signaling. The induced population responds immediately to morphogen gradients to upregulate rostro-caudal neurodevelopmental landmark gene expression in a generally accelerated fashion. This method can serve as a new platform for the development of novel, rapid, and efficient protocols for the manufacture of hPSC-derived neural lineages.
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Affiliation(s)
- Patrick Walsh
- Stem Cell InstituteUniversity of MinnesotaMinneapolisMinnesotaUSA
- Department of Genetics, Cell Biology and DevelopmentUniversity of MinnesotaMinneapolisMinnesotaUSA
| | - Vincent Truong
- Stem Cell InstituteUniversity of MinnesotaMinneapolisMinnesotaUSA
- Department of Ophthalmology and Visual NeurosciencesUniversity of MinnesotaMinneapolisMinnesotaUSA
| | - Sushmita Nayak
- Stem Cell InstituteUniversity of MinnesotaMinneapolisMinnesotaUSA
| | | | - Walter C. Low
- Stem Cell InstituteUniversity of MinnesotaMinneapolisMinnesotaUSA
- Department of NeurosurgeryUniversity of MinnesotaMinneapolisMinnesotaUSA
| | - Ann M. Parr
- Stem Cell InstituteUniversity of MinnesotaMinneapolisMinnesotaUSA
- Department of NeurosurgeryUniversity of MinnesotaMinneapolisMinnesotaUSA
| | - James R. Dutton
- Stem Cell InstituteUniversity of MinnesotaMinneapolisMinnesotaUSA
- Department of Genetics, Cell Biology and DevelopmentUniversity of MinnesotaMinneapolisMinnesotaUSA
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13
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Nasser MI, Qi X, Zhu S, He Y, Zhao M, Guo H, Zhu P. Current situation and future of stem cells in cardiovascular medicine. Biomed Pharmacother 2020; 132:110813. [PMID: 33068940 DOI: 10.1016/j.biopha.2020.110813] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 09/22/2020] [Accepted: 09/25/2020] [Indexed: 12/21/2022] Open
Abstract
Cardiovascular disease (CVD) is one of the leading causes of death worldwide. Currently, many methods have been proposed by researchers for the prevention and treatment of CVD; among them, stem cell-based therapies are the most promising. As the cells of origin for various mature cells, stem cells have the ability to self-renew and differentiate. Stem cells have a powerful ability to regenerate biologically, self-repair, and enhance damaged functional tissues or organs. Allogeneic stem cells and somatic stem cells are two types of cells that can be used for cardiac repair. Theoretically, dilated cardiomyopathy and acute myocardial infarction can be treated with such cells. In addition, stem cell transplantation procedures, including intravenous, epicardial, cardiac, and endocardial injections, have been reported to provide significant benefits in clinical practice; however, there are still a number of issues that need further study and consideration, such as the form and quantity of transplanted cells and post-transplantation health. The goal of this analysis was to summarize the recent advances in stem cell-based therapies and their efficacy in cardiovascular regenerative medicine.
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Affiliation(s)
- M I Nasser
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510100, China. Address: 106 Zhongshan Er Road, Guangzhou, 510080, PR China
| | - Xiao Qi
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510100, China. Address: 106 Zhongshan Er Road, Guangzhou, 510080, PR China
| | - Shuoji Zhu
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510100, China. Address: 106 Zhongshan Er Road, Guangzhou, 510080, PR China
| | - Yin He
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510100, China. Address: 106 Zhongshan Er Road, Guangzhou, 510080, PR China
| | - Mingyi Zhao
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510100, China. Address: 106 Zhongshan Er Road, Guangzhou, 510080, PR China
| | - Huiming Guo
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510100, China. Address: 106 Zhongshan Er Road, Guangzhou, 510080, PR China
| | - Ping Zhu
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510100, China. Address: 106 Zhongshan Er Road, Guangzhou, 510080, PR China.
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14
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New insights into human beta cell biology using human pluripotent stem cells. Semin Cell Dev Biol 2020; 103:31-40. [DOI: 10.1016/j.semcdb.2019.11.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 10/21/2019] [Accepted: 11/05/2019] [Indexed: 12/18/2022]
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15
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Chang Y, Kim J, Park H, Choi H, Kim J. Modelling neurodegenerative diseases with 3D brain organoids. Biol Rev Camb Philos Soc 2020; 95:1497-1509. [PMID: 32568450 DOI: 10.1111/brv.12626] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 05/25/2020] [Accepted: 05/28/2020] [Indexed: 02/06/2023]
Abstract
Neurodegenerative diseases are incurable and debilitating conditions characterized by the deterioration of brain function. Most brain disease models rely on human post-mortem brain tissue, non-human primate tissue, or in vitro two-dimensional (2D) experiments. Resource limitations and the complexity of the human brain are some of the reasons that make suitable human neurodegenerative disease models inaccessible. However, recently developed three-dimensional (3D) brain organoids derived from pluripotent stem cells (PSCs), including embryonic stem cells and induced PSCs, may provide suitable models for the study of the pathological features of neurodegenerative diseases. In this review, we provide an overview of existing 3D brain organoid models and discuss recent advances in organoid technology that have increased our understanding of brain development. Moreover, we explain how 3D organoid models recapitulate aspects of specific neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, and explore the utility of these models, for therapeutic applications.
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Affiliation(s)
- Yujung Chang
- Department of Biomedical Engineering, Dongguk University, Seoul, 04620, Republic of Korea
| | - Junyeop Kim
- Department of Biomedical Engineering, Dongguk University, Seoul, 04620, Republic of Korea
| | - Hanseul Park
- Department of Biomedical Engineering, Dongguk University, Seoul, 04620, Republic of Korea
| | - Hwan Choi
- Department of Biomedical Engineering, Dongguk University, Seoul, 04620, Republic of Korea
| | - Jongpil Kim
- Department of Biomedical Engineering, Dongguk University, Seoul, 04620, Republic of Korea.,Department of Chemistry, Dongguk University, Seoul, 04620, Republic of Korea
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16
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Komatsu Y, Takeuchi D, Tokunaga T, Sakurai H, Makino A, Honda T, Ikeda Y, Tomonaga K. RNA Virus-Based Episomal Vector with a Fail-Safe Switch Facilitating Efficient Genetic Modification and Differentiation of iPSCs. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 2019; 14:47-55. [PMID: 31309127 PMCID: PMC6606997 DOI: 10.1016/j.omtm.2019.05.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 05/15/2019] [Indexed: 12/24/2022]
Abstract
A gene delivery system that allows efficient and safe stem cell modification is critical for next-generation stem cell therapies. An RNA virus-based episomal vector (REVec) is a gene transfer system developed based on Borna disease virus (BoDV), which facilitates persistent intranuclear RNA transgene delivery without integrating into the host genome. In this study, we analyzed susceptibility of human induced pluripotent stem cell (iPSC) lines from different somatic cell sources to REVec, along with commonly used viral vectors, and demonstrated highly efficient REVec transduction of iPSCs. Using REVec encoding myogenic transcription factor MyoD1, we further demonstrated potential application of the REVec system for inducing differentiation of iPSCs into skeletal muscle cells. Of note, treatment with a small molecule, T-705, completely eliminated REVec in persistently transduced cells. Thus, the REVec system offers a versatile toolbox for stable, integration-free iPSC modification and trans-differentiation, with a unique switch-off mechanism.
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Affiliation(s)
- Yumiko Komatsu
- Laboratory of RNA Viruses, Department of Virus Research, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.,The Keihanshin Consortium for Fostering the Next Generation of Global Leaders in Research (K-CONNEX), Kyoto University, Kyoto 606-8501, Japan
| | - Dan Takeuchi
- Section of Bacterial Drug Resistance Research, Thailand-Japan Research Collaboration Center, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
| | - Tomoya Tokunaga
- Laboratory of RNA Viruses, Department of Virus Research, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
| | - Hidetoshi Sakurai
- Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan
| | - Akiko Makino
- Laboratory of RNA Viruses, Department of Virus Research, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.,Department of Mammalian Regulatory Network, Graduate School of Biostudies, Kyoto University, Kyoto 606-8507, Japan
| | - Tomoyuki Honda
- Division of Virology, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Yasuhiro Ikeda
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | - Keizo Tomonaga
- Laboratory of RNA Viruses, Department of Virus Research, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.,Department of Mammalian Regulatory Network, Graduate School of Biostudies, Kyoto University, Kyoto 606-8507, Japan.,Department of Molecular Virology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
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17
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Wang Q, Vossen A, Ikeda Y, Devaux P. Measles vector as a multigene delivery platform facilitating iPSC reprogramming. Gene Ther 2019; 26:151-164. [PMID: 30718755 PMCID: PMC8228481 DOI: 10.1038/s41434-019-0058-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Revised: 12/07/2018] [Accepted: 01/09/2019] [Indexed: 01/19/2023]
Abstract
Induced pluripotent stem cells (iPSCs) provide a unique platform for individualized cell therapy approaches. Currently, episomal DNA, mRNA, and Sendai virus-based RNA reprogramming systems are widely used to generate iPSCs. However, they all rely on the use of multiple (three to six) components (vectors/plasmids/mRNAs) leading to the production of partially reprogrammed cells, reducing the efficiency of the systems. We produced a one-cycle measles virus (MV) vector by substituting the viral attachment protein gene with the green fluorescent protein (GFP) gene. Here, we present a highly efficient multi-transgene delivery system based on a vaccine strain of MV, a non-integrating RNA virus that has a long-standing safety record in humans. Introduction of the four reprogramming factors OCT4, SOX2, KLF4, and cMYC via a single, "one-cycle" MV vector efficiently reprogrammed human somatic cells into iPSCs, whereas MV vector genomes are rapidly eliminated in derived iPSCs. Our MV vector system offers a new reprogramming platform for genomic modification-free iPSCs amenable for clinical translation.
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Affiliation(s)
- Qi Wang
- Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA
| | - Alanna Vossen
- Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA
| | - Yasuhiro Ikeda
- Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA
- Virology and Gene Therapy Graduate Track, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA
| | - Patricia Devaux
- Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.
- Virology and Gene Therapy Graduate Track, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.
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18
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Rogal J, Zbinden A, Schenke-Layland K, Loskill P. Stem-cell based organ-on-a-chip models for diabetes research. Adv Drug Deliv Rev 2019; 140:101-128. [PMID: 30359630 DOI: 10.1016/j.addr.2018.10.010] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Revised: 09/10/2018] [Accepted: 10/19/2018] [Indexed: 12/22/2022]
Abstract
Diabetes mellitus (DM) ranks among the severest global health concerns of the 21st century. It encompasses a group of chronic disorders characterized by a dysregulated glucose metabolism, which arises as a consequence of progressive autoimmune destruction of pancreatic beta-cells (type 1 DM), or as a result of beta-cell dysfunction combined with systemic insulin resistance (type 2 DM). Human cohort studies have provided evidence of genetic and environmental contributions to DM; yet, these studies are mostly restricted to investigating statistical correlations between DM and certain risk factors. Mechanistic studies, on the other hand, aimed at re-creating the clinical picture of human DM in animal models. A translation to human biology is, however, often inadequate owing to significant differences between animal and human physiology, including the species-specific glucose regulation. Thus, there is an urgent need for the development of advanced human in vitro models with the potential to identify novel treatment options for DM. This review provides an overview of the technological advances in research on DM-relevant stem cells and their integration into microphysiological environments as provided by the organ-on-a-chip technology.
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Affiliation(s)
- Julia Rogal
- Department of Women's Health, Research Institute for Women's Health, Eberhard Karls University, Silcherstrasse 7/1, 72076 Tübingen, Germany; Fraunhofer Institute for Interfacial Engineering and Biotechnology IGB, Nobelstrasse 12, 70569 Stuttgart, Germany
| | - Aline Zbinden
- Department of Women's Health, Research Institute for Women's Health, Eberhard Karls University, Silcherstrasse 7/1, 72076 Tübingen, Germany
| | - Katja Schenke-Layland
- Department of Women's Health, Research Institute for Women's Health, Eberhard Karls University, Silcherstrasse 7/1, 72076 Tübingen, Germany; The Natural and Medical Sciences Institute (NMI) at the University of Tübingen, Markwiesenstr. 55, 72770 Reutlingen, Germany; Department of Medicine/Cardiology, Cardiovascular Research Laboratories, David Geffen School of Medicine at UCLA, 675 Charles E. Young Drive South, MRL 3645, Los Angeles, CA, USA.
| | - Peter Loskill
- Department of Women's Health, Research Institute for Women's Health, Eberhard Karls University, Silcherstrasse 7/1, 72076 Tübingen, Germany; Fraunhofer Institute for Interfacial Engineering and Biotechnology IGB, Nobelstrasse 12, 70569 Stuttgart, Germany
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19
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Acquisition of Dynamic Function in Human Stem Cell-Derived β Cells. Stem Cell Reports 2019; 12:351-365. [PMID: 30661993 PMCID: PMC6372986 DOI: 10.1016/j.stemcr.2018.12.012] [Citation(s) in RCA: 270] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Revised: 12/12/2018] [Accepted: 12/14/2018] [Indexed: 02/07/2023] Open
Abstract
Recent advances in human pluripotent stem cell (hPSC) differentiation protocols have generated insulin-producing cells resembling pancreatic β cells. While these stem cell-derived β (SC-β) cells are capable of undergoing glucose-stimulated insulin secretion (GSIS), insulin secretion per cell remains low compared with islets and cells lack dynamic insulin release. Herein, we report a differentiation strategy focused on modulating transforming growth factor β (TGF-β) signaling, controlling cellular cluster size, and using an enriched serum-free media to generate SC-β cells that express β cell markers and undergo GSIS with first- and second-phase dynamic insulin secretion. Transplantation of these cells into mice greatly improves glucose tolerance. These results reveal that specific time frames for inhibiting and permitting TGF-β signaling are required during SC-β cell differentiation to achieve dynamic function. The capacity of these cells to undergo GSIS with dynamic insulin release makes them a promising cell source for diabetes cellular therapy.
Development of differentiation protocol to β-like cells with enhanced function TGF-β signaling promotes acquisition of dynamic function in maturing β-like cells Transplanted cells rapidly restore glucose tolerance in mice
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20
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Jacobson EF, Tzanakakis ES. Who Will Win: Induced Pluripotent Stem Cells Versus Embryonic Stem Cells for β Cell Replacement and Diabetes Disease Modeling? Curr Diab Rep 2018; 18:133. [PMID: 30343423 DOI: 10.1007/s11892-018-1109-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
PURPOSE OF REVIEW Ever since the reprogramming of human fibroblasts to induced pluripotent stem cells (hiPSCs), scientists have been trying to determine if hiPSCs can give rise to progeny akin to native terminally differentiated cells as human embryonic stem cells (hESCs) do. Many different somatic cell types have been successfully reprogrammed via a variety of methods. In this review, we will discuss recent studies comparing hiPSCs and hESCs and their ability to differentiate to desired cell types as well as explore diabetes disease models. RECENT FINDINGS Both somatic cell origin and the reprogramming method are important to the epigenetic state of the hiPSCs; however, genetic background contributes the most to differences seen between hiPSCs and hESCs. Based on our review of the relevant literature, hiPSCs display differences compared to hESCs, including a higher propensity for specification toward particular cell types based on memory retained from the somatic cell of origin. Moreover, hiPSCs provide a unique opportunity for creating diabetes disease models.
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Affiliation(s)
- Elena F Jacobson
- Department of Chemical and Biological Engineering, Tufts University, Science and Technology Center, Room 276A, Medford, MA, 02155, USA
| | - Emmanuel S Tzanakakis
- Department of Chemical and Biological Engineering, Tufts University, Science and Technology Center, Room 276A, Medford, MA, 02155, USA.
- Clinical and Translational Science Institute, Tufts Medical Center, Boston, MA, 02111, USA.
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21
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Kondo Y, Toyoda T, Inagaki N, Osafune K. iPSC technology-based regenerative therapy for diabetes. J Diabetes Investig 2018; 9:234-243. [PMID: 28609558 PMCID: PMC5835458 DOI: 10.1111/jdi.12702] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Revised: 06/01/2017] [Accepted: 06/04/2017] [Indexed: 12/28/2022] Open
Abstract
The directed differentiation of human pluripotent stem cells, such as embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs), into pancreatic endocrine lineages has been vigorously examined by reproducing the in vivo developmental processes of the pancreas. Recent advances in this research field have enabled the generation from hESCs/iPSCs of functionally mature β-like cells in vitro that show glucose-responsive insulin secretion ability. The therapeutic potentials of hESC/iPSC-derived pancreatic cells have been evaluated using diabetic animal models, and transplantation methods including immunoprotective devices that prevent immune responses from hosts to the implanted pancreatic cells have been investigated towards the development of regenerative therapies against diabetes. These efforts led to the start of a clinical trial that involves the implantation of hESC-derived pancreatic progenitors into type 1 diabetes patients. In addition, patient-derived iPSCs have been generated from diabetes-related disorders towards the creation of novel in vitro disease models and drug discovery, although few reports so far have analyzed the disease mechanisms. Considering recent advances in differentiation methods that generate pancreatic endocrine lineages, we will see the development of novel cell therapies and therapeutic drugs against diabetes based on iPSC technology-based research in the next decade.
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Affiliation(s)
- Yasushi Kondo
- Center for iPS Cell Research and Application (CiRA)Kyoto UniversityKyotoJapan
- Department of Diabetes, Endocrinology and NutritionKyoto University Graduate School of MedicineKyotoJapan
| | - Taro Toyoda
- Center for iPS Cell Research and Application (CiRA)Kyoto UniversityKyotoJapan
| | - Nobuya Inagaki
- Department of Diabetes, Endocrinology and NutritionKyoto University Graduate School of MedicineKyotoJapan
| | - Kenji Osafune
- Center for iPS Cell Research and Application (CiRA)Kyoto UniversityKyotoJapan
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Human Induced Pluripotent Stem Cells in the Curative Treatment of Diabetes and Potential Impediments Ahead. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1144:25-35. [PMID: 30569414 DOI: 10.1007/5584_2018_305] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The successful landmark discovery of mouse and human inducible pluripotential stem cells (iPSC's) by Takahashi and Yamanaka in 2006 and 2007 has triggered a revolution in the potential generation of self-compatible cells for regenerative medicine, and further opened up a new avenue for "disease in dish" drug screening of self-target cells (Neofytou et al. 2015). The introduction of four 'Yamanaka' transcription factors through viral or other transfection of mature cells can induce pluripotency and acquired plasticity. These factors include transduction with octamer-binding transcription factor-4 (Oct-4), nanog homeobox (Nanog), sex-determining region Y-box-2 (Sox-2) and MYC protooncogene (cMyc). Such cells become iPSC's (Takahashi and Yamanaka 2006). These reprogrammed cells exhibit increased telomerase activity and have a hypomethylated gene promotor region similar to embryonic stem cells (ESC's). These milestone discoveries have generated immense hope that diseases such as diabetes could be treated and effectively cured by transplantation of self-compatible, personalized autologous stem cell transplantation of β-cells that release physiological insulin under glycemic control (Maehr et al. 2009; Park et al. 2008) (Fig. 1). Diabetes is a profligate disease of disordered glucose metabolism resulting from an absolute or relative deficiency of insulin, the consequences of which lead to immense socio-economic societal burden. While there are many different types of diabetes, the two major types (type 1 diabetes (T1DM) and type 2 diabetes (T2DM) are caused respectively by immune-mediated destruction (T1DM) or malfunctioning (T2DM) insulin-producing β-cells within the endocrine pancreas, the islets of Langerhans (Atkinson et al. 2011; Holman et al. 2015; You and Henneberg 2016). Almost 425 million people are affected by the global burden of diabetes, and this is predicted to increase by 48% (629 million) by 2045 (International Diabetes Federation Atlas 8th Ed 2018). Whole pancreas or islet cell transplantation offer an effective alternative to injected insulin, but both require lifelong potent immunosuppression to control both allo-and autoimmunity. Whole pancreas transplantation involves invasive complex surgery and is associated with greater morbidity and occasional mortality, while islet transplantation involves a minimally invasive intraportal hepatic infusion. Generally, whole pancreas transplantation provides greater metabolic reserve, but this may be matched by cumulative multiple islet infusions to achieve insulin independence. An additional challenge of islet transplantation is progressive loss of complete insulin independence over time, which may be multifactorial, the dominant factor however being ineffective control of autoimmunity. Both whole pancreas and islet transplantation are restricted to patients at risk of severe hypoglycemia that cannot be stabilized by alternate means, or in recipients that are already immunosuppressed in order to sustain a kidney or other solid organ transplant. The risks of chronic immunosuppression and the scarcity of human organ donors mean that both of these transplantation therapies cannot presently be extended to the broader diabetic population (Shapiro 2011; Shapiro et al. 2006). Recent progress in xenotransplantation of multiple knock-out 'humanized' pig islets could offer one potential solution, perhaps aided by clustered regularly interspaced short palindromic repeats/CRISPR associated-9 (CRISPR/Cas-9) gene editing approaches, but this remains to be proven in practice. Human stem cell derived new β-cell products could effectively address the global supply challenge for broad application across all forms of diabetes, but recurrent autoimmunity may still remain an insurmountable challenge. Considerable progress in the generation of human stem cell derived SC-β cells from ESC, iPS and other adult cell sources such as mesenchymal stem cells (MSCs) offer huge hope that a personalized, 'syngeneic' cell could be transplanted without risk of alloimmunity, thereby securing sufficient supply to meet future global demand (Cito et al. 2018).
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23
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Establishment of integration-free induced pluripotent stem cells from human recessive dystrophic epidermolysis bullosa keratinocytes. J Dermatol Sci 2017; 89:263-271. [PMID: 29229433 DOI: 10.1016/j.jdermsci.2017.11.017] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Revised: 11/15/2017] [Accepted: 11/27/2017] [Indexed: 11/21/2022]
Abstract
BACKGROUND Induced pluripotent stem cell (iPSC) technology enables patient-specific pluripotent stem cells to be derived from adult somatic cells without the use of an embryonic cell source. To date, recessive dystrophic epidermolysis bullosa (RDEB)-specific iPSCs have been generated from patients using integrating retroviral vectors. However, vector integration into the host genome can endanger the biosafety and differentiation propensities of iPSCs. Although various integration-free reprogramming systems have been reported, their utility in reprogramming somatic cells from patients remains largely undetermined. OBJECTIVE Our study aims to establish safe iPSCs from keratinocytes of RDEB patients using non-integration vector. METHOD We optimized and infected non-integrating Sendai viral vectors to reprogram keratinocytes from healthy volunteers and RDEB patients. RESULTS Sendai vector infection led to the reproducible generation of genomic modification-free iPSCs from these keratinocytes, which was proved by immunohistochemistry, reverse transcription polymerase chain reaction, methylation assay, teratoma assay and embryoid body formation assay. Furthermore, we confirmed that these iPSCs have the potential to differentiate into dermal fibroblasts and epidermal keratinocytes. CONCLUSION This is the first report to prove that the Sendai vector system facilitates the reliable reprogramming of patient keratinocytes into transgene-free iPSCs, providing another pluripotent platform for personalized diagnostic and therapeutic approaches to RDEB.
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Cnop M, Toivonen S, Igoillo-Esteve M, Salpea P. Endoplasmic reticulum stress and eIF2α phosphorylation: The Achilles heel of pancreatic β cells. Mol Metab 2017; 6:1024-1039. [PMID: 28951826 PMCID: PMC5605732 DOI: 10.1016/j.molmet.2017.06.001] [Citation(s) in RCA: 198] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Revised: 05/19/2017] [Accepted: 06/01/2017] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Pancreatic β cell dysfunction and death are central in the pathogenesis of most if not all forms of diabetes. Understanding the molecular mechanisms underlying β cell failure is important to develop β cell protective approaches. SCOPE OF REVIEW Here we review the role of endoplasmic reticulum stress and dysregulated endoplasmic reticulum stress signaling in β cell failure in monogenic and polygenic forms of diabetes. There is substantial evidence for the presence of endoplasmic reticulum stress in β cells in type 1 and type 2 diabetes. Direct evidence for the importance of this stress response is provided by an increasing number of monogenic forms of diabetes. In particular, mutations in the PERK branch of the unfolded protein response provide insight into its importance for human β cell function and survival. The knowledge gained from different rodent models is reviewed. More disease- and patient-relevant models, using human induced pluripotent stem cells differentiated into β cells, will further advance our understanding of pathogenic mechanisms. Finally, we review the therapeutic modulation of endoplasmic reticulum stress and signaling in β cells. MAJOR CONCLUSIONS Pancreatic β cells are sensitive to excessive endoplasmic reticulum stress and dysregulated eIF2α phosphorylation, as indicated by transcriptome data, monogenic forms of diabetes and pharmacological studies. This should be taken into consideration when devising new therapeutic approaches for diabetes.
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Key Words
- ATF, activating transcription factor
- CHOP, C/EBP homologous protein
- CRISPR, clustered regularly interspaced short palindromic repeats
- CReP, constitutive repressor of eIF2α phosphorylation
- Diabetes
- ER, endoplasmic reticulum
- ERAD, ER-associated degradation
- Endoplasmic reticulum stress
- GCN2, general control non-derepressible-2
- GIP, glucose-dependent insulinotropic polypeptide
- GLP-1, glucagon-like peptide 1
- GWAS, genome-wide association study
- HNF1A, hepatocyte nuclear factor 1-α
- HRI, heme-regulated inhibitor kinase
- IAPP, islet amyloid polypeptide
- IER3IP1, immediate early response-3 interacting protein-1
- IRE1, inositol-requiring protein-1
- ISR, integrated stress response
- Insulin
- Islet
- MEHMO, mental retardation, epilepsy, hypogonadism and -genitalism, microcephaly and obesity
- MODY, maturity-onset diabetes of the young
- NRF2, nuclear factor, erythroid 2 like 2
- PBA, 4-phenyl butyric acid
- PERK, PKR-like ER kinase
- PKR, protein kinase RNA
- PP1, protein phosphatase 1
- PPA, phenylpropenoic acid glucoside
- Pancreatic β cell
- Pdx1, pancreatic duodenal homeobox 1
- RIDD, regulated IRE1-dependent decay
- RyR2, type 2 ryanodine receptor/Ca2+ release channel
- SERCA, sarcoendoplasmic reticulum Ca2+ ATPase
- TUDCA, taurine-conjugated ursodeoxycholic acid derivative
- UPR, unfolded protein response
- WFS, Wolfram syndrome
- XBP1, X-box binding protein 1
- eIF2, eukaryotic translation initiation factor 2
- eIF2α
- hESC, human embryonic stem cell
- hPSC, human pluripotent stem cell
- hiPSC, human induced pluripotent stem cell
- uORF, upstream open reading frame
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Affiliation(s)
- Miriam Cnop
- ULB Center for Diabetes Research, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium
- Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Sanna Toivonen
- ULB Center for Diabetes Research, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium
| | - Mariana Igoillo-Esteve
- ULB Center for Diabetes Research, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium
| | - Paraskevi Salpea
- ULB Center for Diabetes Research, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium
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Carcamo-Orive I, Huang NF, Quertermous T, Knowles JW. Induced Pluripotent Stem Cell-Derived Endothelial Cells in Insulin Resistance and Metabolic Syndrome. Arterioscler Thromb Vasc Biol 2017; 37:2038-2042. [PMID: 28729365 DOI: 10.1161/atvbaha.117.309291] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Accepted: 07/10/2017] [Indexed: 02/06/2023]
Abstract
Insulin resistance leads to a number of metabolic and cellular abnormalities including endothelial dysfunction that increase the risk of vascular disease. Although it has been particularly challenging to study the genetic determinants that predispose to abnormal function of the endothelium in insulin-resistant states, the possibility of deriving endothelial cells from induced pluripotent stem cells generated from individuals with detailed clinical phenotyping, including accurate measurements of insulin resistance accompanied by multilevel omic data (eg, genetic and genomic characterization), has opened new avenues to study this relationship. Unfortunately, several technical barriers have hampered these efforts. In the present review, we summarize the current status of induced pluripotent stem cell-derived endothelial cells for modeling endothelial dysfunction associated with insulin resistance and discuss the challenges to overcoming these limitations.
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Affiliation(s)
- Ivan Carcamo-Orive
- From the Department of Medicine and Cardiovascular Institute (I.C.-O., T.Q., J.W.K.) and Department of Cardiothoracic Surgery and Cardiovascular Institute (N.F.H.), Stanford University School of Medicine, CA; and Veterans Affairs Palo Alto Health Care System, CA (N.F.H.).
| | - Ngan F Huang
- From the Department of Medicine and Cardiovascular Institute (I.C.-O., T.Q., J.W.K.) and Department of Cardiothoracic Surgery and Cardiovascular Institute (N.F.H.), Stanford University School of Medicine, CA; and Veterans Affairs Palo Alto Health Care System, CA (N.F.H.)
| | - Thomas Quertermous
- From the Department of Medicine and Cardiovascular Institute (I.C.-O., T.Q., J.W.K.) and Department of Cardiothoracic Surgery and Cardiovascular Institute (N.F.H.), Stanford University School of Medicine, CA; and Veterans Affairs Palo Alto Health Care System, CA (N.F.H.)
| | - Joshua W Knowles
- From the Department of Medicine and Cardiovascular Institute (I.C.-O., T.Q., J.W.K.) and Department of Cardiothoracic Surgery and Cardiovascular Institute (N.F.H.), Stanford University School of Medicine, CA; and Veterans Affairs Palo Alto Health Care System, CA (N.F.H.)
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Berezin AE. New Trends in Stem Cell Transplantation in Diabetes Mellitus Type I and Type II. ACTA ACUST UNITED AC 2017. [DOI: 10.1007/978-3-319-55687-1_3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Millman JR, Pagliuca FW. Autologous Pluripotent Stem Cell-Derived β-Like Cells for Diabetes Cellular Therapy. Diabetes 2017; 66:1111-1120. [PMID: 28507211 DOI: 10.2337/db16-1406] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Accepted: 02/10/2017] [Indexed: 11/13/2022]
Abstract
Development of stem cell technologies for cell replacement therapy has progressed rapidly in recent years. Diabetes has long been seen as one of the first applications for stem cell-derived cells because of the loss of only a single cell type-the insulin-producing β-cell. Recent reports have detailed strategies that overcome prior hurdles to generate functional β-like cells from human pluripotent stem cells in vitro, including from human induced pluripotent stem cells (hiPSCs). Even with this accomplishment, addressing immunological barriers to transplantation remains a major challenge for the field. The development of clinically relevant hiPSC derivation methods from patients and demonstration that these cells can be differentiated into β-like cells presents a new opportunity to treat diabetes without immunosuppression or immunoprotective encapsulation or with only targeted protection from autoimmunity. This review focuses on the current status in generating and transplanting autologous β-cells for diabetes cell therapy, highlighting the unique advantages and challenges of this approach.
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Affiliation(s)
- Jeffrey R Millman
- Division of Endocrinology, Metabolism and Lipid Research, Department of Medicine, Washington University School of Medicine in St. Louis, and Department of Biomedical Engineering, School of Engineering & Applied Science, Washington University in St. Louis, St. Louis, MO
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Samuel R, Duda DG, Fukumura D, Jain RK. Vascular diseases await translation of blood vessels engineered from stem cells. Sci Transl Med 2016; 7:309rv6. [PMID: 26468328 DOI: 10.1126/scitranslmed.aaa1805] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The discovery of human induced pluripotent stem cells (hiPSCs) might pave the way toward a long-sought solution for obtaining sufficient numbers of autologous cells for tissue engineering. Several methods exist for generating endothelial cells or perivascular cells from hiPSCs in vitro for use in the building of vascular tissue. We discuss current developments in the generation of vascular progenitor cells from hiPSCs and the assessment of their functional capacity in vivo, opportunities and challenges for the clinical translation of engineered vascular tissue, and modeling of vascular diseases using hiPSC-derived vascular progenitor cells.
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Affiliation(s)
- Rekha Samuel
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Centre for Stem Cell Research, Christian Medical College, Bagayam, Vellore 632002, Tamil Nadu, India
| | - Dan G Duda
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Dai Fukumura
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Rakesh K Jain
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
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Kahraman S, Okawa ER, Kulkarni RN. Is Transforming Stem Cells to Pancreatic Beta Cells Still the Holy Grail for Type 2 Diabetes? Curr Diab Rep 2016; 16:70. [PMID: 27313072 PMCID: PMC5877461 DOI: 10.1007/s11892-016-0764-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Diabetes is a progressive disease affecting millions of people worldwide. There are several medications and treatment options to improve the life quality of people with diabetes. One of the strategies for the treatment of diabetes could be the use of human pluripotent stem cells or induced pluripotent stem cells. The recent advances in differentiation of stem cells into insulin-secreting beta-like cells in vitro make the transplantation of the stem cell-derived beta-like cells an attractive approach for treatment of type 1 and type 2 diabetes. While stem cell-derived beta-like cells provide an unlimited cell source for beta cell replacement therapies, these cells can also be used as a platform for drug screening or modeling diseases.
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Affiliation(s)
- Sevim Kahraman
- Section of Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center and Harvard Medical School, Boston, MA, 02215, USA
| | - Erin R Okawa
- Section of Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center and Harvard Medical School, Boston, MA, 02215, USA
- Division of Endocrinology, Department of Medicine, Boston Children's Hospital, Boston, MA, 02215, USA
| | - Rohit N Kulkarni
- Section of Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center and Harvard Medical School, Boston, MA, 02215, USA.
- Harvard Stem Cell Institute, Boston, MA, 02215, USA.
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30
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El Khatib MM, Ohmine S, Jacobus EJ, Tonne JM, Morsy SG, Holditch SJ, Schreiber CA, Uetsuka K, Fusaki N, Wigle DA, Terzic A, Kudva YC, Ikeda Y. Tumor-Free Transplantation of Patient-Derived Induced Pluripotent Stem Cell Progeny for Customized Islet Regeneration. Stem Cells Transl Med 2016; 5:694-702. [PMID: 26987352 PMCID: PMC4835241 DOI: 10.5966/sctm.2015-0017] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Accepted: 09/23/2015] [Indexed: 01/27/2023] Open
Abstract
UNLABELLED Human induced pluripotent stem cells (iPSCs) and derived progeny provide invaluable regenerative platforms, yet their clinical translation has been compromised by their biosafety concern. Here, we assessed the safety of transplanting patient-derived iPSC-generated pancreatic endoderm/progenitor cells. Transplantation of progenitors from iPSCs reprogrammed by lentiviral vectors (LV-iPSCs) led to the formation of invasive teratocarcinoma-like tumors in more than 90% of immunodeficient mice. Moreover, removal of primary tumors from LV-iPSC progeny-transplanted hosts generated secondary and metastatic tumors. Combined transgene-free (TGF) reprogramming and elimination of residual pluripotent cells by enzymatic dissociation ensured tumor-free transplantation, ultimately enabling regeneration of type 1 diabetes-specific human islet structures in vivo. The incidence of tumor formation in TGF-iPSCs was titratable, depending on the oncogenic load, with reintegration of the cMYC expressing vector abolishing tumor-free transplantation. Thus, transgene-free cMYC-independent reprogramming and elimination of residual pluripotent cells are mandatory steps in achieving transplantation of iPSC progeny for customized and safe islet regeneration in vivo. SIGNIFICANCE Pluripotent stem cell therapy for diabetes relies on the safety as well as the quality of derived insulin-producing cells. Data from this study highlight prominent tumorigenic risks of induced pluripotent stem cell (iPSC) products, especially when reprogrammed with integrating vectors. Two major underlying mechanisms in iPSC tumorigenicity are residual pluripotent cells and cMYC overload by vector integration. This study also demonstrated that combined transgene-free reprogramming and enzymatic dissociation allows teratoma-free transplantation of iPSC progeny in the mouse model in testing the tumorigenicity of iPSC products. Further safety assessment and improvement in iPSC specification into a mature β cell phenotype would lead to safe islet replacement therapy for diabetes.
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Affiliation(s)
| | - Seiga Ohmine
- Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Egon J Jacobus
- Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Jason M Tonne
- Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Salma G Morsy
- Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Sara J Holditch
- Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Claire A Schreiber
- Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Koji Uetsuka
- Laboratory of Animal Health and Hygiene, Department of Biological Production Science, College of Agriculture, Ibaraki University, Ibaraki, Japan
| | - Noemi Fusaki
- PRESTO, Japan Science and Technology Agency, Saitama, Japan Ophthalmology, Keio University School of Medicine, Tokyo, Japan
| | - Dennis A Wigle
- Center for Regenerative Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Andre Terzic
- Center for Regenerative Medicine, Mayo Clinic, Rochester, Minnesota, USA Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA Department of Medical Genetics, Mayo Clinic, Rochester, Minnesota, USA
| | - Yogish C Kudva
- Division of Endocrinology, Mayo Clinic, Rochester, Minnesota, USA
| | - Yasuhiro Ikeda
- Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA Center for Regenerative Medicine, Mayo Clinic, Rochester, Minnesota, USA
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31
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Hayek A, King CC. Brief review: cell replacement therapies to treat type 1 diabetes mellitus. Clin Diabetes Endocrinol 2016; 2:4. [PMID: 28702240 PMCID: PMC5471705 DOI: 10.1186/s40842-016-0023-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Accepted: 02/19/2016] [Indexed: 12/22/2022] Open
Abstract
Human embryonic stem cells (hESCs) and induced pluripotent cells (iPSCs) have the potential to differentiate into any somatic cell, making them ideal candidates for cell replacement therapies to treat a number of human diseases and regenerate damaged or non-functional tissues and organs. Key to the promise of regenerative medicine is developing standardized protocols that can safely be applied in patients. Progress towards this goal has occurred in a number of fields, including type 1 diabetes mellitus (T1D). During the past 10 years, significant technological advances in hESC/iPSC biochemistry have provided a roadmap to generate sufficient quantities of glucose-responsive, insulin-producing cells capable of eliminating diabetes in rodents. Although many of the molecular mechanisms underlying the genesis of these cells remain to be elucidated, the field of cell-based therapeutics to treat T1D has advanced to the point where the first Phase I/II trials in humans have begun. Here, we provide a concise review of the history of cell replacement therapies to treat T1D from islet transplantations and xenotranplantation, to current work in hESC/iPSC. We also highlight the latest advances in efforts to employ insulin-producing, glucose-responsive β-like cells derived from hESC as therapeutics.
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Affiliation(s)
- Alberto Hayek
- Scripps Whittier Diabetes Institute, La Jolla, CA 92037 USA
| | - Charles C King
- Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093 USA
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Bartlett ST, Markmann JF, Johnson P, Korsgren O, Hering BJ, Scharp D, Kay TWH, Bromberg J, Odorico JS, Weir GC, Bridges N, Kandaswamy R, Stock P, Friend P, Gotoh M, Cooper DKC, Park CG, O'Connell P, Stabler C, Matsumoto S, Ludwig B, Choudhary P, Kovatchev B, Rickels MR, Sykes M, Wood K, Kraemer K, Hwa A, Stanley E, Ricordi C, Zimmerman M, Greenstein J, Montanya E, Otonkoski T. Report from IPITA-TTS Opinion Leaders Meeting on the Future of β-Cell Replacement. Transplantation 2016; 100 Suppl 2:S1-44. [PMID: 26840096 PMCID: PMC4741413 DOI: 10.1097/tp.0000000000001055] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2015] [Accepted: 10/07/2015] [Indexed: 12/11/2022]
Affiliation(s)
- Stephen T. Bartlett
- Department of Surgery, University of Maryland School of Medicine, Baltimore MD
| | - James F. Markmann
- Division of Transplantation, Massachusetts General Hospital, Boston MA
| | - Paul Johnson
- Nuffield Department of Surgical Sciences and Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Oxford, United Kingdom
| | - Olle Korsgren
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Bernhard J. Hering
- Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, MN
| | - David Scharp
- Prodo Laboratories, LLC, Irvine, CA
- The Scharp-Lacy Research Institute, Irvine, CA
| | - Thomas W. H. Kay
- Department of Medicine, St. Vincent’s Hospital, St. Vincent's Institute of Medical Research and The University of Melbourne Victoria, Australia
| | - Jonathan Bromberg
- Division of Transplantation, Massachusetts General Hospital, Boston MA
| | - Jon S. Odorico
- Division of Transplantation, Department of Surgery, School of Medicine and Public Health, University of Wisconsin, Madison, WI
| | - Gordon C. Weir
- Joslin Diabetes Center and Harvard Medical School, Boston, MA
| | - Nancy Bridges
- National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
| | - Raja Kandaswamy
- Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, MN
| | - Peter Stock
- Division of Transplantation, University of San Francisco Medical Center, San Francisco, CA
| | - Peter Friend
- Nuffield Department of Surgical Sciences and Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Oxford, United Kingdom
| | - Mitsukazu Gotoh
- Department of Surgery, Fukushima Medical University, Fukushima, Japan
| | - David K. C. Cooper
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA
| | - Chung-Gyu Park
- Xenotransplantation Research Center, Department of Microbiology and Immunology, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
| | - Phillip O'Connell
- The Center for Transplant and Renal Research, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, NSW, Australia
| | - Cherie Stabler
- Diabetes Research Institute, School of Medicine, University of Miami, Coral Gables, FL
| | - Shinichi Matsumoto
- National Center for Global Health and Medicine, Tokyo, Japan
- Otsuka Pharmaceutical Factory inc, Naruto Japan
| | - Barbara Ludwig
- Department of Medicine III, Technische Universität Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden of Helmholtz Centre Munich at University Clinic Carl Gustav Carus of TU Dresden and DZD-German Centre for Diabetes Research, Dresden, Germany
| | - Pratik Choudhary
- Diabetes Research Group, King's College London, Weston Education Centre, London, United Kingdom
| | - Boris Kovatchev
- University of Virginia, Center for Diabetes Technology, Charlottesville, VA
| | - Michael R. Rickels
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - Megan Sykes
- Columbia Center for Translational Immunology, Coulmbia University Medical Center, New York, NY
| | - Kathryn Wood
- Nuffield Department of Surgical Sciences and Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Oxford, United Kingdom
| | - Kristy Kraemer
- National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
| | - Albert Hwa
- Juvenile Diabetes Research Foundation, New York, NY
| | - Edward Stanley
- Murdoch Children's Research Institute, Parkville, VIC, Australia
- Monash University, Melbourne, VIC, Australia
| | - Camillo Ricordi
- Diabetes Research Institute, School of Medicine, University of Miami, Coral Gables, FL
| | - Mark Zimmerman
- BetaLogics, a business unit in Janssen Research and Development LLC, Raritan, NJ
| | - Julia Greenstein
- Discovery Research, Juvenile Diabetes Research Foundation New York, NY
| | - Eduard Montanya
- Bellvitge Biomedical Research Institute (IDIBELL), Hospital Universitari Bellvitge, CIBER of Diabetes and Metabolic Diseases (CIBERDEM), University of Barcelona, Barcelona, Spain
| | - Timo Otonkoski
- Children's Hospital and Biomedicum Stem Cell Center, University of Helsinki, Helsinki, Finland
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Miere C, Devito L, Ilic D. Sendai Virus-Based Reprogramming of Mesenchymal Stromal/Stem Cells from Umbilical Cord Wharton's Jelly into Induced Pluripotent Stem Cells. Methods Mol Biol 2016; 1357:33-44. [PMID: 26246353 DOI: 10.1007/7651_2014_163] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
In an attempt to bring pluripotent stem cell biology closer to reaching its full potential, many groups have focused on improving reprogramming protocols over the past several years. The episomal modified Sendai virus-based vector has emerged as one of the most practical ones. Here we describe reprogramming of mesenchymal stromal/stem cells (MSC) derived from umbilical cord Wharton's Jelly into induced pluripotent stem cells (iPSC) using genome non-integrating Sendai virus-based vectors. The detailed protocols of iPSC colony cryopreservation (vitrification) and adaption to feeder-free culture conditions are also included.
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Affiliation(s)
- Cristian Miere
- Stem Cell Laboratories, Assisted Conception Unit, Guy's Hospital, London, UK
| | - Liani Devito
- Stem Cell Laboratories, Assisted Conception Unit, Guy's Hospital, London, UK
| | - Dusko Ilic
- Stem Cell Laboratories, Assisted Conception Unit, Guy's Hospital, London, UK
- Kings College London, Strand, London, WC2R2LS, UK
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Abdelalim EM, Emara MM. Pluripotent Stem Cell-Derived Pancreatic β Cells: From In Vitro Maturation to Clinical Application. RECENT ADVANCES IN STEM CELLS 2016. [DOI: 10.1007/978-3-319-33270-3_6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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35
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Freedman BS. Modeling Kidney Disease with iPS Cells. Biomark Insights 2015; 10:153-69. [PMID: 26740740 PMCID: PMC4689367 DOI: 10.4137/bmi.s20054] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Revised: 07/19/2015] [Accepted: 07/21/2015] [Indexed: 12/14/2022] Open
Abstract
Induced pluripotent stem cells (iPSCs) are somatic cells that have been transcriptionally reprogrammed to an embryonic stem cell (ESC)-like state. iPSCs are a renewable source of diverse somatic cell types and tissues matching the original patient, including nephron-like kidney organoids. iPSCs have been derived representing several kidney disorders, such as ADPKD, ARPKD, Alport syndrome, and lupus nephritis, with the goals of generating replacement tissue and ‘disease in a dish’ laboratory models. Cellular defects in iPSCs and derived kidney organoids provide functional, personalized biomarkers, which can be correlated with genetic and clinical information. In proof of principle, disease-specific phenotypes have been described in iPSCs and ESCs with mutations linked to polycystic kidney disease or focal segmental glomerulosclerosis. In addition, these cells can be used to model nephrotoxic chemical injury. Recent advances in directed differentiation and CRISPR genome editing enable more specific iPSC models and present new possibilities for diagnostics, disease modeling, therapeutic screens, and tissue regeneration using human cells. This review outlines growth opportunities and design strategies for this rapidly expanding and evolving field.
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Affiliation(s)
- Benjamin S Freedman
- Division of Nephrology, Kidney Research Institute, and Institute for Stem Cell and Regenerative Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA
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A novel intranuclear RNA vector system for long-term stem cell modification. Gene Ther 2015; 23:256-62. [PMID: 26632671 PMCID: PMC4777691 DOI: 10.1038/gt.2015.108] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2015] [Accepted: 11/05/2015] [Indexed: 11/29/2022]
Abstract
Genetically modified stem and progenitor cells have emerged as a promising regenerative platform in the treatment of genetic and degenerative disorders, highlighted by their successful therapeutic use in inherent immunodeficiencies. However, biosafety concerns over insertional mutagenesis resulting from integrating recombinant viral vectors have overshadowed the widespread clinical applications of genetically modified stem cells. Here, we report an RNA-based episomal vector system, amenable for long-term transgene expression in stem cells. Specifically, we used a unique intranuclear RNA virus, Borna disease virus (BDV), as the gene transfer vehicle, capable of persistent infections in various cell types. BDV-based vectors allowed for long-term transgene expression in mesenchymal stem cells (MSCs) without affecting cellular morphology, cell surface CD105 expression, or the adipogenicity of MSCs. Similarly, replication-defective BDV vectors achieved long-term transduction of human induced pluripotent stem cells (iPSCs), while maintaining the ability to differentiate into three embryonic germ layers. Thus, the BDV-based vectors offer a genomic modification-free, episomal RNA delivery system for sustained stem cell transduction.
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37
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Quiskamp N, Bruin JE, Kieffer TJ. Differentiation of human pluripotent stem cells into β-cells: Potential and challenges. Best Pract Res Clin Endocrinol Metab 2015; 29:833-47. [PMID: 26696513 DOI: 10.1016/j.beem.2015.10.011] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) hold great potential as the basis for cell-based therapies of degenerative diseases, including diabetes. Current insulin-based therapies for diabetes do not prevent hyperglycaemia or the associated long-term organ damage. While transplantation of pancreatic islets can achieve insulin independence and improved glycemic control, it is limited by donor tissue scarcity, challenges of purifying islets from the pancreas, and the need for immunosuppression to prevent rejection of transplants. Large-scale production of β-cells from stem cells is a promising alternative. Recent years have seen considerable progress in the optimization of in vitro differentiation protocols to direct hESCs/iPSCs into mature insulin-secreting β-cells and clinical trials are now under way to test the safety and efficiency of hESC-derived pancreatic progenitor cells in patients with type 1 diabetes. Here, we discuss key milestones leading up to these trials in addition to recent developments and challenges for hESC/iPSC-based diabetes therapies and disease modeling.
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Affiliation(s)
- Nina Quiskamp
- Laboratory of Molecular and Cellular Medicine, Department of Cellular & Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.
| | - Jennifer E Bruin
- Laboratory of Molecular and Cellular Medicine, Department of Cellular & Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.
| | - Timothy J Kieffer
- Laboratory of Molecular and Cellular Medicine, Department of Cellular & Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada; Department of Surgery, University of British Columbia, Vancouver, BC, Canada.
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38
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Pellegrini S, Ungaro F, Mercalli A, Melzi R, Sebastiani G, Dotta F, Broccoli V, Piemonti L, Sordi V. Human induced pluripotent stem cells differentiate into insulin-producing cells able to engraft in vivo. Acta Diabetol 2015; 52:1025-35. [PMID: 25733399 DOI: 10.1007/s00592-015-0726-z] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2014] [Accepted: 02/12/2015] [Indexed: 12/31/2022]
Abstract
AIMS New sources of insulin-secreting cells are strongly required for the cure of diabetes. Recent successes in differentiating embryonic stem cells, in combination with the discovery that it is possible to derive human induced pluripotent stem cells (iPSCs) from somatic cells, have raised the possibility that patient-specific beta cells might be derived from patients through cell reprogramming and differentiation. In this study, we aimed to obtain insulin-producing cells from human iPSCs and test their ability to secrete insulin in vivo. METHODS Human iPSCs, derived from both fetal and adult fibroblasts, were differentiated in vitro into pancreas-committed cells and then transplanted into immunodeficient mice at two different stages of differentiation (posterior foregut and endocrine cells). RESULTS IPSCs were shown to differentiate in insulin-producing cells in vitro, following the stages of pancreatic organogenesis. At the end of the differentiation, the production of INSULIN mRNA was highly increased and 5 ± 2.9 % of the cell population became insulin-positive. Terminally differentiated cells also produced C-peptide in vitro in both basal and stimulated conditions. In vivo, mice transplanted with pancreatic cells secreted human C-peptide in response to glucose stimulus, but transplanted cells were observed to lose insulin secretion capacity during the time. At histological evaluation, the grafts resulted to be composed of a mixed population of cells containing mature pancreatic cells, but also pluripotent and some neuronal cells. CONCLUSION These data overall suggest that human iPSCs have the potential to generate insulin-producing cells and that these differentiated cells can engraft and secrete insulin in vivo.
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Affiliation(s)
- Silvia Pellegrini
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132, Milan, Italy
| | - Federica Ungaro
- Stem Cells and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy
| | - Alessia Mercalli
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132, Milan, Italy
| | - Raffaella Melzi
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132, Milan, Italy
| | - Guido Sebastiani
- Diabetes Unit, Department of Medicine, Surgery and Neuroscience, University of Siena, 53100, Siena, Italy
- Fondazione Umberto Di Mario ONLUS, c/o Toscana Life Sciences, 53100, Siena, Italy
| | - Francesco Dotta
- Diabetes Unit, Department of Medicine, Surgery and Neuroscience, University of Siena, 53100, Siena, Italy
- Fondazione Umberto Di Mario ONLUS, c/o Toscana Life Sciences, 53100, Siena, Italy
| | - Vania Broccoli
- Stem Cells and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy
| | - Lorenzo Piemonti
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132, Milan, Italy.
| | - Valeria Sordi
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132, Milan, Italy.
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The Use of Patient-Specific Induced Pluripotent Stem Cells (iPSCs) to Identify Osteoclast Defects in Rare Genetic Bone Disorders. J Clin Med 2015; 3:1490-510. [PMID: 25621177 PMCID: PMC4300535 DOI: 10.3390/jcm3041490] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
More than 500 rare genetic bone disorders have been described, but for many of them only limited treatment options are available. Challenges for studying these bone diseases come from a lack of suitable animal models and unavailability of skeletal tissues for studies. Effectors for skeletal abnormalities of bone disorders may be abnormal bone formation directed by osteoblasts or anomalous bone resorption by osteoclasts, or both. Patient-specific induced pluripotent stem cells (iPSCs) can be generated from somatic cells of various tissue sources and in theory can be differentiated into any desired cell type. However, successful differentiation of hiPSCs into functional bone cells is still a challenge. Our group focuses on the use of human iPSCs (hiPSCs) to identify osteoclast defects in craniometaphyseal dysplasia. In this review, we describe the impact of stem cell technology on research for better treatment of such disorders, the generation of hiPSCs from patients with rare genetic bone disorders and current protocols for differentiating hiPSCs into osteoclasts.
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Teo AKK, Gupta MK, Doria A, Kulkarni RN. Dissecting diabetes/metabolic disease mechanisms using pluripotent stem cells and genome editing tools. Mol Metab 2015; 4:593-604. [PMID: 26413465 PMCID: PMC4563028 DOI: 10.1016/j.molmet.2015.06.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2015] [Revised: 06/09/2015] [Accepted: 06/12/2015] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Diabetes and metabolic syndromes are chronic, devastating diseases with increasing prevalence. Human pluripotent stem cells are gaining popularity in their usage for human in vitro disease modeling. With recent rapid advances in genome editing tools, these cells can now be genetically manipulated with relative ease to study how genes and gene variants contribute to diabetes and metabolic syndromes. SCOPE OF REVIEW We highlight the diabetes and metabolic genes and gene variants, which could potentially be studied, using two powerful technologies - human pluripotent stem cells (hPSCs) and genome editing tools - to aid the elucidation of yet elusive mechanisms underlying these complex diseases. MAJOR CONCLUSIONS hPSCs and the advancing genome editing tools appear to be a timely and potent combination for probing molecular mechanism(s) underlying diseases such as diabetes and metabolic syndromes. The knowledge gained from these hiPSC-based disease modeling studies can potentially be translated into the clinics by guiding clinicians on the appropriate type of medication to use for each condition based on the mechanism of action of the disease.
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Affiliation(s)
- Adrian Kee Keong Teo
- Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02215, USA ; Discovery Research Division, Institute of Molecular and Cell Biology, Proteos, Singapore 138673, Singapore ; School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore ; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117596, Singapore
| | - Manoj K Gupta
- Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02215, USA
| | - Alessandro Doria
- Section of Epidemiology and Genetics, Joslin Diabetes Center, Department of Epidemiology, Harvard School of Public Health, Boston, MA 02215, USA
| | - Rohit N Kulkarni
- Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02215, USA
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De Assuncao TM, Sun Y, Jalan-Sakrikar N, Drinane M, Huang BQ, Li Y, Davila JI, Wang R, O’Hara SP, Lomberk GA, Urrutia RA, Ikeda Y, Huebert RC. Development and characterization of human-induced pluripotent stem cell-derived cholangiocytes. J Transl Med 2015; 95:684-96. [PMID: 25867762 PMCID: PMC4447567 DOI: 10.1038/labinvest.2015.51] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2014] [Revised: 01/26/2015] [Accepted: 02/04/2015] [Indexed: 12/25/2022] Open
Abstract
Cholangiocytes are the target of a heterogeneous group of liver diseases known as the cholangiopathies. An evolving understanding of the mechanisms driving biliary development provides the theoretical underpinnings for rational development of induced pluripotent stem cell (iPSC)-derived cholangiocytes (iDCs). Therefore, the aims of this study were to develop an approach to generate iDCs and to fully characterize the cells in vitro and in vivo. Human iPSC lines were generated by forced expression of the Yamanaka pluripotency factors. We then pursued a stepwise differentiation strategy toward iDCs, using precise temporal exposure to key biliary morphogens, and we characterized the cells, using a variety of morphologic, molecular, cell biologic, functional, and in vivo approaches. Morphology shows a stepwise phenotypic change toward an epithelial monolayer. Molecular analysis during differentiation shows appropriate enrichment in markers of iPSC, definitive endoderm, hepatic specification, hepatic progenitors, and ultimately cholangiocytes. Immunostaining, western blotting, and flow cytometry demonstrate enrichment of multiple functionally relevant biliary proteins. RNA sequencing reveals that the transcriptome moves progressively toward that of human cholangiocytes. iDCs generate intracellular calcium signaling in response to ATP, form intact primary cilia, and self-assemble into duct-like structures in three-dimensional culture. In vivo, the cells engraft within mouse liver, following retrograde intrabiliary infusion. In summary, we have developed a novel approach to generate mature cholangiocytes from iPSCs. In addition to providing a model of biliary differentiation, iDCs represent a platform for in vitro disease modeling, pharmacologic testing, and individualized, cell-based, regenerative therapies for the cholangiopathies.
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Affiliation(s)
- Thiago M. De Assuncao
- Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN,Gastroenterology Research Unit, Mayo Clinic and Foundation, Rochester, MN
| | - Yan Sun
- Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN,Gastroenterology Research Unit, Mayo Clinic and Foundation, Rochester, MN
| | - Nidhi Jalan-Sakrikar
- Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN,Gastroenterology Research Unit, Mayo Clinic and Foundation, Rochester, MN
| | - Mary Drinane
- Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN,Gastroenterology Research Unit, Mayo Clinic and Foundation, Rochester, MN
| | - Bing Q. Huang
- Center for Basic Research in Digestive Diseases, Mayo Clinic and Foundation, Rochester, MN
| | - Ying Li
- Division of Biomedical Statistics and Informatics, Mayo Clinic and Foundation, Rochester, MN
| | - Jaime I. Davila
- Division of Biomedical Statistics and Informatics, Mayo Clinic and Foundation, Rochester, MN
| | - Ruisi Wang
- Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN,Gastroenterology Research Unit, Mayo Clinic and Foundation, Rochester, MN
| | - Steven P. O’Hara
- Center for Basic Research in Digestive Diseases, Mayo Clinic and Foundation, Rochester, MN
| | - Gwen A. Lomberk
- Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN,Gastroenterology Research Unit, Mayo Clinic and Foundation, Rochester, MN,Center for Cell Signaling in Gastroenterology, Mayo Clinic and Foundation, Rochester, MN
| | - Raul A. Urrutia
- Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN,Gastroenterology Research Unit, Mayo Clinic and Foundation, Rochester, MN,Center for Cell Signaling in Gastroenterology, Mayo Clinic and Foundation, Rochester, MN
| | - Yasuhiro Ikeda
- Department of Molecular Medicine; Mayo Clinic and Foundation, Rochester, MN
| | - Robert C. Huebert
- Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN,Gastroenterology Research Unit, Mayo Clinic and Foundation, Rochester, MN,Center for Cell Signaling in Gastroenterology, Mayo Clinic and Foundation, Rochester, MN
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Hew M, O'Connor K, Edel MJ, Lucas M. The Possible Future Roles for iPSC-Derived Therapy for Autoimmune Diseases. J Clin Med 2015; 4:1193-206. [PMID: 26239553 PMCID: PMC4484994 DOI: 10.3390/jcm4061193] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Revised: 04/29/2015] [Accepted: 05/11/2015] [Indexed: 02/06/2023] Open
Abstract
The ability to generate inducible pluripotent stem cells (iPSCs) and the potential for their use in treatment of human disease is of immense interest. Autoimmune diseases, with their limited treatment choices are a potential target for the clinical application of stem cell and iPSC technology. IPSCs provide three potential ways of treating autoimmune disease; (i) providing pure replacement of lost cells (immuno-reconstitution); (ii) through immune-modulation of the disease process in vivo; and (iii) for the purposes of disease modeling in vitro. In this review, we will use examples of systemic, system-specific and organ-specific autoimmunity to explore the potential applications of iPSCs for treatment of autoimmune diseases and review the evidence of iPSC technology in auto-immunity to date.
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Affiliation(s)
- Meilyn Hew
- Department of Clinical Immunology, Pathwest Laboratory Medicine, Queen Elizabeth II Medical Centre, Perth 6009, Western Australia, Australia.
| | - Kevin O'Connor
- Department of Clinical Immunology, Royal Perth Hospital, Perth 6000, Western Australia, Australia.
| | - Michael J Edel
- Control of Pluripotency Laboratory, Department of Physiological Sciences I, Faculty of Medicine, University of Barcelona, Hospital Clinic, Casanova 143, Barcelona 08036, Spain.
- Victor Chang Cardiac Research Institute, Sydney, 2010, New South Wales, Australia.
- School of Medicine and Pharmacology, Anatomy, Physiology and Human Biology, CCTRM, University of Western Australia, Perth, 6009, Western Australia, Australia.
| | - Michaela Lucas
- Department of Clinical Immunology, Pathwest Laboratory Medicine, Queen Elizabeth II Medical Centre, Perth 6009, Western Australia, Australia.
- School of Medicine and Pharmacology and School of Pathology and Laboratory Medicine, The University of Western Australia, Harry Perkins Institute of Medical Research, Perth, 6009, Western Australia, Australia.
- Institute for Immunology and Infectious Diseases, Murdoch University, Perth, 6150, Western Australia.
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Giannoukakis N, Trucco M. Cellular therapies based on stem cells and their insulin-producing surrogates: a 2015 reality check. Pediatr Diabetes 2015; 16:151-63. [PMID: 25652322 DOI: 10.1111/pedi.12259] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2015] [Accepted: 01/12/2015] [Indexed: 12/27/2022] Open
Abstract
Stem cell technology has recently gained a substantial amount of interest as one method to create a potentially limitless supply of transplantable insulin-producing cells to treat, and possibly cure diabetes mellitus. In this review, we summarize the state-of-the art of stem cell technology and list the potential sources of stem cells that have been shown to be useful as insulin-expressing surrogates. We also discuss the milestones that have been reached and those that remain to be addressed to generate bona fide beta cell-similar, insulin-producing surrogates. The caveats, limitations, and realistic expectations are also considered for current and future technology. In spite of the tremendous technical advances realized in the past decade, especially in the field of reprogramming adult somatic cells to become stem cells, the state-of-the art still relies on lengthy and cumbersome in vitro culture methods that yield cell populations that are not particularly glucose-responsive when transplanted into diabetic hosts. Despite the current impediments toward clinical translation, including the potential for immune rejection, the availability of technology to generate patient-specific reprogrammable stem cells has, and will be critical for, important insights into the genetics, epigenetics, biology, and physiology of insulin-producing cells in normal and pathologic states. This knowledge could accelerate the time to reach the desired breakthrough for safe and efficacious beta cell surrogates.
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Affiliation(s)
- Nick Giannoukakis
- Institute of Cellular Therapeutics, Allegheny Health Network, Pittsburgh, PA, USA
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Abstract
Diabetes is a common multisystem disease that results in hyperglycemia due to a relative or absolute insulin deficiency. Improved glycemic control decreases the risk of development and progression of microvascular and, to a lesser extent, macrovascular complications and prevents symptomatic hyperglycemia. However, complex treatment regimens aimed at improving glycemic control are associated with an increased incidence of hypoglycemia. On paper at least, cellular therapies arising from reprogramed stem cells or other somatic cell types would provide ideal therapy for diabetes and the prevention of its complications. This hypothesis has led to intensive efforts to grow β cells from various sources. In this review, we provide an overview of β-cell development as well as the efforts reported to date in terms of cellular therapy for diabetes. Engineering β-cell replacement therapy requires an understanding of how β cells respond to other metabolites such as amino acids, free fatty acids, and ketones. Indeed, efforts thus far have been characterized by an inability of cellular replacement products to adequately respond to metabolites that normally couple the metabolic state to β-cell function and insulin secretion. Efforts to date intended to capitalize on current knowledge of islet cell development and stimulus-secretion coupling of the β cell are encouraging but as yet of little clinical relevance.
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Affiliation(s)
- Aleksey Matveyenko
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN
| | - Adrian Vella
- Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, MN.
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Driscoll CB, Tonne JM, El Khatib M, Cattaneo R, Ikeda Y, Devaux P. Nuclear reprogramming with a non-integrating human RNA virus. Stem Cell Res Ther 2015; 6:48. [PMID: 25889591 PMCID: PMC4415226 DOI: 10.1186/s13287-015-0035-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2014] [Revised: 09/10/2014] [Accepted: 03/03/2015] [Indexed: 01/10/2023] Open
Abstract
INTRODUCTION Advances in the field of stem cells have led to novel avenues for generating induced pluripotent stem cells (iPSCs) from differentiated somatic cells. iPSCs are typically obtained by the introduction of four factors--OCT4, SOX2, KLF4, and cMYC--via integrating vectors. Here, we report the feasibility of a novel reprogramming process based on vectors derived from the non-integrating vaccine strain of measles virus (MV). METHODS We produced a one-cycle MV vector by substituting the viral attachment protein gene with the green fluorescent protein (GFP) gene. This vector was further engineered to encode for OCT4 in an additional transcription unit. RESULTS After verification of OCT4 expression, we assessed the ability of iPSC reprogramming. The reprogramming vector cocktail with the OCT4-expressing MV vector and SOX2-, KLF4-, and cMYC-expressing lentiviral vectors efficiently transduced human skin fibroblasts and formed iPSC colonies. Reverse transcription-polymerase chain reaction and immunostaining confirmed induction of endogenous pluripotency-associated marker genes, such as SSEA-4, TRA-1-60, and Nanog. Pluripotency of derived clones was confirmed by spontaneous differentiation into three germ layers, teratoma formation, and guided differentiation into beating cardiomyocytes. CONCLUSIONS MV vectors can induce efficient nuclear reprogramming. Given the excellent safety record of MV vaccines and the translational capabilities recently developed to produce MV-based vectors now used for cancer clinical trials, our MV vector system provides an RNA-based, non-integrating gene transfer platform for nuclear reprogramming that is amenable for immediate clinical translation.
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Affiliation(s)
- Christopher B Driscoll
- Department of Molecular Medicine, and Virology and Gene Therapy Graduate Track, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN, 55905, USA.
| | - Jason M Tonne
- Department of Molecular Medicine, and Virology and Gene Therapy Graduate Track, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN, 55905, USA.
| | - Moustafa El Khatib
- Department of Molecular Medicine, and Virology and Gene Therapy Graduate Track, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN, 55905, USA.
| | - Roberto Cattaneo
- Department of Molecular Medicine, and Virology and Gene Therapy Graduate Track, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN, 55905, USA.
| | - Yasuhiro Ikeda
- Department of Molecular Medicine, and Virology and Gene Therapy Graduate Track, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN, 55905, USA.
| | - Patricia Devaux
- Department of Molecular Medicine, and Virology and Gene Therapy Graduate Track, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN, 55905, USA.
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Stepniewski J, Kachamakova-Trojanowska N, Ogrocki D, Szopa M, Matlok M, Beilharz M, Dyduch G, Malecki MT, Jozkowicz A, Dulak J. Induced pluripotent stem cells as a model for diabetes investigation. Sci Rep 2015; 5:8597. [PMID: 25716801 PMCID: PMC4341212 DOI: 10.1038/srep08597] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2014] [Accepted: 01/27/2015] [Indexed: 12/15/2022] Open
Abstract
Mouse and human induced pluripotent stem cells (iPSCs) may represent a novel approach for modeling diabetes. Taking this into consideration, the aim of this study was to generate and evaluate differentiation potential of iPSCs from lepdb/db (db/db) mice, the model of diabetes type 2 as well as from patients with Maturity Onset Diabetes of the Young 3 (HNF1A MODY). Murine iPSC colonies from both wild type and db/db mice were positive for markers of pluripotency: Oct3/4A, Nanog, SSEA1, CDy1 and alkaline phosphatase and differentiated in vitro and in vivo into cells originating from three germ layers. However, our results suggest impaired differentiation of db/db cells into endothelial progenitor-like cells expressing CD34 and Tie2 markers and their reduced angiogenic potential. Human control and HNF1A MODY reprogrammed cells also expressed pluripotency markers: OCT3/4A, SSEA4, TRA-1–60, TRA-1-81, formed embryoid bodies (EBs) and differentiated into cells of three germ layers. Additionally, insulin expressing cells were obtained from those partially reprogrammed cells with direct as well as EB-mediated differentiation method. Our findings indicate that disease-specific iPSCs may help to better understand the mechanisms responsible for defective insulin production or vascular dysfunction upon differentiation toward cell types affected by diabetes.
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Affiliation(s)
- J Stepniewski
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | - N Kachamakova-Trojanowska
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | - D Ogrocki
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | - M Szopa
- 1] Clinic of Metabolic Diseases, Jagiellonian University Medical College, Krakow, Poland [2] University Hospital Krakow Poland
| | - M Matlok
- II Clinic of General Surgery, Collegium Medicum, Jagiellonian University, Krakow, Poland
| | - M Beilharz
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | - G Dyduch
- Department of Clinical and Experimental Pathomorphology, Jagiellonian University Medical College, Krakow, Poland
| | - M T Malecki
- 1] Clinic of Metabolic Diseases, Jagiellonian University Medical College, Krakow, Poland [2] University Hospital Krakow Poland
| | - A Jozkowicz
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | - J Dulak
- 1] Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland [2] Malopolska Centre of Biotechnology, Jagiellonian University, Poland
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O'Reilly M, Federoff HJ, Fong Y, Kohn DB, Patterson AP, Ahmed N, Asokan A, Boye SE, Crystal RG, De Oliveira S, Gargiulo L, Harper SQ, Ikeda Y, Jambou R, Montgomery M, Prograis L, Rosenthal E, Sterman DH, Vandenberghe LH, Zoloth L, Abedi M, Adair J, Adusumilli PS, Goins WF, Gray J, Monahan P, Popplewell L, Sena-Esteves M, Tannous B, Weber T, Wierda W, Gopal-Srivastava R, McDonald CL, Rosenblum D, Corrigan-Curay J. Gene therapy: charting a future course--summary of a National Institutes of Health Workshop, April 12, 2013. Hum Gene Ther 2015; 25:488-97. [PMID: 24773122 DOI: 10.1089/hum.2014.045] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Recently, the gene therapy field has begun to experience clinical successes in a number of different diseases using various approaches and vectors. The workshop Gene Therapy: Charting a Future Course, sponsored by the National Institutes of Health (NIH) Office of Biotechnology Activities, brought together early and mid-career researchers to discuss the key scientific challenges and opportunities, ethical and communication issues, and NIH and foundation resources available to facilitate further clinical advances.
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Affiliation(s)
- Marina O'Reilly
- 1 Office of Science Policy, Office of the Director, National Institutes of Health , Bethesda, MD 20892
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Abdelalim EM, Emara MM. Advances and challenges in the differentiation of pluripotent stem cells into pancreatic β cells. World J Stem Cells 2015; 7:174-181. [PMID: 25621117 PMCID: PMC4300928 DOI: 10.4252/wjsc.v7.i1.174] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Revised: 09/16/2014] [Accepted: 09/19/2014] [Indexed: 02/06/2023] Open
Abstract
Pluripotent stem cells (PSCs) are able to differentiate into several cell types, including pancreatic β cells. Differentiation of pancreatic β cells depends on certain transcription factors, which function in a coordinated way during pancreas development. The existing protocols for in vitro differentiation produce pancreatic β cells, which are not highly responsive to glucose stimulation except after their transplantation into immune-compromised mice and allowing several weeks for further differentiation to ensure the maturation of these cells in vivo. Thus, although the substantial improvement that has been made for the differentiation of induced PSCs and embryonic stem cells toward pancreatic β cells, several challenges still hindering their full generation. Here, we summarize recent advances in the differentiation of PSCs into pancreatic β cells and discuss the challenges facing their differentiation as well as the different applications of these potential PSC-derived β cells.
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Abdelalim EM, Bonnefond A, Bennaceur-Griscelli A, Froguel P. Pluripotent stem cells as a potential tool for disease modelling and cell therapy in diabetes. Stem Cell Rev Rep 2014; 10:327-37. [PMID: 24577791 DOI: 10.1007/s12015-014-9503-6] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Diabetes mellitus is the most prevailing disease with progressive incidence worldwide. To date, the pathogenesis of diabetes is far to be understood, and there is no permanent treatment available for diabetes. One of the promising approaches to understand and cure diabetes is to use pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced PCSs (iPSCs). ESCs and iPSCs have a great potential to differentiate into all cell types, and they have a high ability to differentiate into insulin-secreting β cells. Obtaining PSCs genetically identical to the patient presenting with diabetes has been a longstanding dream for the in vitro modeling of disease and ultimately cell therapy. For several years, somatic cell nuclear transfer (SCNT) was the method of choice to generate patient-specific ESC lines. However, this technology faces ethical and practical concerns. Interestingly, the recently established iPSC technology overcomes the major problems of other stem cell types including the lack of ethical concern and no risk of immune rejection. Several iPSC lines have been recently generated from patients with different types of diabetes, and most of these cell lines are able to differentiate into insulin-secreting β cells. In this review, we summarize recent advances in the differentiation of pancreatic β cells from PSCs, and describe the challenges for their clinical use in diabetes cell therapy. Furthermore, we discuss the potential use of patient-specific PSCs as an in vitro model, providing new insights into the pathophysiology of diabetes.
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Affiliation(s)
- Essam M Abdelalim
- Qatar Biomedical Research Institute, Qatar Foundation, Education City, 5825, Doha, Qatar,
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Berezin AE. Diabetes mellitus and cellular replacement therapy: Expected clinical potential and perspectives. World J Diabetes 2014; 5:777-786. [PMID: 25512780 PMCID: PMC4265864 DOI: 10.4239/wjd.v5.i6.777] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2014] [Revised: 07/16/2014] [Accepted: 09/23/2014] [Indexed: 02/05/2023] Open
Abstract
Diabetes mellitus (DM) is the most prevailing disease with progressive incidence worldwide. Despite contemporary treatment type one DM and type two DM are frequently associated with long-term major microvascular and macrovascular complications. Currently restoration of failing β-cell function, regulation of metabolic processes with stem cell transplantation is discussed as complements to contemporary DM therapy regimens. The present review is considered paradigm of the regenerative care and the possibly effects of cell therapy in DM. Reprogramming stem cells, bone marrow-derived mononuclear cells; lineage-specified progenitor cells are considered for regenerative strategy in DM. Finally, perspective component of stem cell replacement in DM is discussed.
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