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Hu M, Liu T, Huang H, Ogi D, Tan Y, Ye K, Jin S. Extracellular matrix proteins refine microenvironments for pancreatic organogenesis from induced pluripotent stem cell differentiation. Theranostics 2025; 15:2229-2249. [PMID: 39990212 PMCID: PMC11840725 DOI: 10.7150/thno.104883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 12/30/2024] [Indexed: 02/25/2025] Open
Abstract
Rationale: The current understanding on manipulating signaling pathways to generate mature human islet organoids with all major hormone-secreting endocrine cell types (i.e., α, β, δ, and γ cells) from induced pluripotent stem cells (iPSCs) is insufficient. However, donor islet shortage necessitates that we produce functional islets in vitro. In this study, we aimed to find decellularized pancreatic extracellular matrix (dpECM) proteins that leverage signaling pathways and promote functional iPSC islet organogenesis. Methods: We performed proteomic analysis to identify key islet promoting factors from porcine and rat dpECM. With this, we identified collagen type II (COL2) as a potential biomaterial cue that endorses islet development from iPSCs. Using global transcriptome profiling, gene set enrichment analysis, immunofluorescence microscopy, flow cytometry, Western blot, and glucose-stimulated hormonal secretion analysis, we examined COL2's role in regulating iPSC pancreatic lineage specification and signaling pathways, critical to islet organogenesis and morphogenesis. Results: We discovered COL2 acts as a functional biomaterial that augments islet development from iPSCs, similar to collagen type V (COL5) as reported in our earlier study. COL2 substantially stimulates the formation of endocrine progenitors and subsequent islet organoids with significantly elevated expressions of pancreatic signature genes and proteins. Furthermore, it enhances islets' glucose sensitivity for hormonal secretion. A cluster of gene expressions associated with various signaling pathways, including but not limited to oxidative phosphorylation, insulin secretion, cell cycle, the canonical WNT, hypoxia, and interferon-γ response, were considerably affected by COL2 and COL5 cues. Conclusion: We demonstrated dpECM's crucial role in refining stem cell differentiation microenvironments for organoid development and maturation. Our findings on biomaterial-stimulated signaling for stem cell specification, organogenesis, and maturation open up a new way to increase the differentiation efficacy of endocrine tissues that can contribute to the production of biologically functional islets.
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Affiliation(s)
- Ming Hu
- Department of Biomedical Engineering, Thomas J. Watson College of Engineering and Applied Science, Binghamton University, State University of New York (SUNY), Binghamton, New York 13902, USA
| | - Tianzheng Liu
- Department of Biomedical Engineering, Thomas J. Watson College of Engineering and Applied Science, Binghamton University, State University of New York (SUNY), Binghamton, New York 13902, USA
| | - Hui Huang
- Department of Biomedical Engineering, Thomas J. Watson College of Engineering and Applied Science, Binghamton University, State University of New York (SUNY), Binghamton, New York 13902, USA
| | - Derek Ogi
- Department of Biomedical Engineering, Thomas J. Watson College of Engineering and Applied Science, Binghamton University, State University of New York (SUNY), Binghamton, New York 13902, USA
| | - Yinfei Tan
- Genomics Facility, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Kaiming Ye
- Department of Biomedical Engineering, Thomas J. Watson College of Engineering and Applied Science, Binghamton University, State University of New York (SUNY), Binghamton, New York 13902, USA
- Center of Biomanufacturing for Regenerative Medicine, Binghamton University, State University of New York (SUNY), Binghamton, New York 13902, USA
| | - Sha Jin
- Department of Biomedical Engineering, Thomas J. Watson College of Engineering and Applied Science, Binghamton University, State University of New York (SUNY), Binghamton, New York 13902, USA
- Center of Biomanufacturing for Regenerative Medicine, Binghamton University, State University of New York (SUNY), Binghamton, New York 13902, USA
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Zheng C, Wang J, Wang J, Zhang Q, Liang T. Cell of Origin of Pancreatic cancer: Novel Findings and Current Understanding. Pancreas 2024; 53:e288-e297. [PMID: 38277420 PMCID: PMC11882172 DOI: 10.1097/mpa.0000000000002301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 09/08/2023] [Indexed: 01/28/2024]
Abstract
ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) stands as one of the most lethal diseases globally, boasting a grim 5-year survival prognosis. The origin cell and the molecular signaling pathways that drive PDAC progression are not entirely understood. This review comprehensively outlines the categorization of PDAC and its precursor lesions, expounds on the creation and utility of genetically engineered mouse models used in PDAC research, compiles a roster of commonly used markers for pancreatic progenitors, duct cells, and acinar cells, and briefly addresses the mechanisms involved in the progression of PDAC. We acknowledge the value of precise markers and suitable tracing tools to discern the cell of origin, as it can facilitate the creation of more effective models for PDAC exploration. These conclusions shed light on our existing understanding of foundational genetically engineered mouse models and focus on the origin and development of PDAC.
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Affiliation(s)
- Chenlei Zheng
- From the Department of Hepatobiliary and Pancreatic Surgery
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine
| | - Jianing Wang
- From the Department of Hepatobiliary and Pancreatic Surgery
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine
| | - Junli Wang
- From the Department of Hepatobiliary and Pancreatic Surgery
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine
| | - Qi Zhang
- From the Department of Hepatobiliary and Pancreatic Surgery
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases
- The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province
- Zhejiang University Cancer Center, Hangzhou, China
| | - Tingbo Liang
- From the Department of Hepatobiliary and Pancreatic Surgery
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine
- Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases
- The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province
- Zhejiang University Cancer Center, Hangzhou, China
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3
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Kim MH, Thanuthanakhun N, Kino-Oka M. A simple tool for the synchronous differentiation of human induced pluripotent stem cells into pancreatic progenitors. Biotechnol J 2024; 19:e2300364. [PMID: 37955342 DOI: 10.1002/biot.202300364] [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: 07/28/2023] [Revised: 10/01/2023] [Accepted: 11/09/2023] [Indexed: 11/14/2023]
Abstract
Efficient differentiation of human induced pluripotent stem cells (hiPSCs) into functional pancreatic cells holds great promise for diabetes research and treatment. However, a robust culture strategy for producing pancreatic progenitors with high homogeneity is lacking. Here, we established a simple differentiation strategy for generating synchronous iPSC-derived pancreatic progenitors via a two-step method of sequential cell synchronization using botulinum hemagglutinin (HA), an E-cadherin function-blocking agent. Of the various methods tested, the first-step synchronization method with HA exposure induces a synchronous switch from E- to N-cadherin and N- to E-cadherin expression by spatially controlling heterogeneous cell distribution, subsequently improving their competency for directed differentiation into definitive endodermal cells from iPSCs. The iPSC-derived definitive endodermal cells can efficiently generate PDX1+ and NKX6.1+ pancreatic progenitor cells in high yields. The PDX1+ and PDX1+ /NKX6.1+ cell densities showed 1.6- and 2.2-fold increases, respectively, compared with those from unsynchronized cultures. The intra-run and inter-run coefficient of variation were below 10%, indicating stable and robust differentiation across different cultures and runs. Our approach is a simple and efficient strategy to produce large quantities of differentiated cells with the highest homogeneity during multistage pancreatic progenitor differentiation, providing a potential tool for guided differentiation of iPSCs to functional insulin-producing cells.
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Affiliation(s)
- Mee-Hae Kim
- Department of Biotechnology, Graduate School of Engineering, Osaka University, Suita, Osaka, Japan
| | - Naruchit Thanuthanakhun
- Department of Biotechnology, Graduate School of Engineering, Osaka University, Suita, Osaka, Japan
| | - Masahiro Kino-Oka
- Department of Biotechnology, Graduate School of Engineering, Osaka University, Suita, Osaka, Japan
- Research Base for Cell Manufacturability, Osaka University, Suita, Osaka, Japan
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4
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Aldous N, Moin ASM, Abdelalim EM. Pancreatic β-cell heterogeneity in adult human islets and stem cell-derived islets. Cell Mol Life Sci 2023; 80:176. [PMID: 37270452 DOI: 10.1007/s00018-023-04815-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 04/27/2023] [Accepted: 05/19/2023] [Indexed: 06/05/2023]
Abstract
Recent studies reported that pancreatic β-cells are heterogeneous in terms of their transcriptional profiles and their abilities for insulin secretion. Sub-populations of pancreatic β-cells have been identified based on the functionality and expression of specific surface markers. Under diabetes condition, β-cell identity is altered leading to different β-cell sub-populations. Furthermore, cell-cell contact between β-cells and other endocrine cells within the islet play an important role in regulating insulin secretion. This highlights the significance of generating a cell product derived from stem cells containing β-cells along with other major islet cells for treating patients with diabetes, instead of transplanting a purified population of β-cells. Another key question is how close in terms of heterogeneity are the islet cells derived from stem cells? In this review, we summarize the heterogeneity in islet cells of the adult pancreas and those generated from stem cells. In addition, we highlight the significance of this heterogeneity in health and disease conditions and how this can be used to design a stem cell-derived product for diabetes cell therapy.
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Affiliation(s)
- Noura Aldous
- College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Education City, Doha, Qatar
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Education City, PO Box 34110, Doha, Qatar
| | - Abu Saleh Md Moin
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Education City, PO Box 34110, Doha, Qatar
- Research Department, Royal College of Surgeons in Ireland Bahrain, Adliya, Kingdom of Bahrain
| | - Essam M Abdelalim
- College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Education City, Doha, Qatar.
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Education City, PO Box 34110, Doha, Qatar.
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5
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Aldous N, Elsayed AK, Alajez NM, Abdelalim EM. iPSC-Derived Pancreatic Progenitors Lacking FOXA2 Reveal Alterations in miRNA Expression Targeting Key Pancreatic Genes. Stem Cell Rev Rep 2023; 19:1082-1097. [PMID: 36749553 DOI: 10.1007/s12015-023-10515-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/28/2023] [Indexed: 02/08/2023]
Abstract
Recently, we reported that forkhead box A2 (FOXA2) is required for the development of human pancreatic α- and β-cells. However, whether miRNAs play a role in regulating pancreatic genes during pancreatic development in the absence of FOXA2 expression is largely unknown. Here, we aimed to capture the dysregulated miRNAs and to identify their pancreatic-specific gene targets in pancreatic progenitors (PPs) derived from wild-type induced pluripotent stem cells (WT-iPSCs) and from iPSCs lacking FOXA2 (FOXA2-/-iPSCs). To identify differentially expressed miRNAs (DEmiRs), and genes (DEGs), two different FOXA2-/-iPSC lines were differentiated into PPs. FOXA2-/- PPs showed a significant reduction in the expression of the main PP transcription factors (TFs) in comparison to WT-PPs. RNA sequencing analysis demonstrated significant reduction in the mRNA expression of genes involved in the development and function of exocrine and endocrine pancreas. Furthermore, miRNA profiling identified 107 downregulated and 111 upregulated DEmiRs in FOXA2-/- PPs compared to WT-PPs. Target prediction analysis between DEmiRs and DEGs identified 92 upregulated miRNAs, predicted to target 1498 downregulated genes in FOXA2-/- PPs. Several important pancreatic TFs essential for pancreatic development were targeted by multiple DEmiRs. Selected DEmiRs and DEGs were further validated using RT-qPCR. Our findings revealed that FOXA2 expression is crucial for pancreatic development through regulating the expression of pancreatic endocrine and exocrine genes targeted by a set of miRNAs at the pancreatic progenitor stage. These data provide novel insights of the effect of FOXA2 deficiency on miRNA-mRNA regulatory networks controlling pancreatic development and differentiation.
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Affiliation(s)
- Noura Aldous
- College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar.,Diabetes Research Center (DRC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar
| | - Ahmed K Elsayed
- Diabetes Research Center (DRC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar
| | - Nehad M Alajez
- College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar.,Translational Cancer and Immunity Center (TCIC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar
| | - Essam M Abdelalim
- College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar. .,Diabetes Research Center (DRC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar.
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6
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Jin W, Jiang W. Stepwise differentiation of functional pancreatic β cells from human pluripotent stem cells. CELL REGENERATION (LONDON, ENGLAND) 2022; 11:24. [PMID: 35909206 PMCID: PMC9339430 DOI: 10.1186/s13619-022-00125-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 07/13/2022] [Indexed: 12/15/2022]
Abstract
Pancreatic β cells differentiated from stem cells provide promise for cell replacement therapy of diabetes. Human pluripotent stem cells could be differentiated into definitive endoderm, followed by pancreatic progenitors, and then subjected to endocrinal differentiation and maturation in a stepwise fashion. Many achievements have been made in making pancreatic β cells from human pluripotent stem cells in last two decades, and a couple of phase I/II clinical trials have just been initiated. Here, we overview the major progresses in differentiating pancreatic β cells from human pluripotent stem cells with the focus on recent technical advances in each differentiation stage, and briefly discuss the current limitations as well.
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Affiliation(s)
- Wenwen Jin
- Department of Biological Repositories, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Wei Jiang
- Department of Biological Repositories, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
- Human Genetics Resource Preservation Center of Wuhan University, Wuhan, 430071, China.
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7
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Memon B, Abdelalim EM. Highly Efficient Differentiation of Human Pluripotent Stem Cells into Pancreatic Progenitors Co-expressing PDX1 and NKX6.1. Methods Mol Biol 2022; 2454:351-363. [PMID: 33190184 DOI: 10.1007/7651_2020_323] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Diabetes is a complex metabolic disorder, with no available treatment. Islet transplantation is currently practiced beta cell replacement therapy option, however, with major limitations. Human pluripotent stem cells (hPSCs) can be used as a scalable source for generation of insulin-secreting cells as hPSCs have high proliferative capacity and can differentiate into any tissue type. In vitro stepwise protocols have been designed for differentiating hPSCs into pancreatic lineages that finally give rise to beta cells; however, these hPSC-derived beta cells are dissimilar to adult human beta cells in key aspects of gene expression and functionality. Alternatively, pancreatic progenitors, when transplanted in the body, have been shown to mature into functional insulin-secreting beta cells, capable of reversing hyperglycemia. These pancreatic progenitors require the co-expression of PDX1, a transcription factor (TF) regulating pancreatic development, and NKX6.1, another TF key for beta cell maturation and function, to produce glucose-responsive beta cells. Given the crucial role played by NKX6.1, we optimized an in vitro differentiation protocol to enhance the generation of pancreatic progenitors co-expressing PDX1 and NKX6.1 by modulating cell density, matrix availability, and cellular dissociation.
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Affiliation(s)
- Bushra Memon
- College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
| | - Essam M Abdelalim
- College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar.
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar.
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Development of a 48-Well Dynamic Suspension Culture System for Pancreatic Differentiation from Human Embryonic Stem Cells. Stem Cell Rev Rep 2021; 18:1423-1433. [PMID: 34855111 DOI: 10.1007/s12015-021-10312-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/28/2021] [Indexed: 01/13/2023]
Abstract
BACKGROUND Human pluripotent stem cells (hPSCs) have started to emerge as a potential tool with application in fields of drug discovery, disease modelling and cell therapy. A variety of protocols for culturing and differentiating pluripotent stem cells into pancreatic β like cells have been published. However, small-scale dynamic suspension culture systems, which could be applied toward systematically optimizing production strategies for cell replacement therapies to accelerate the pace of their discovery and development toward the clinic, are overlooked. METHODS Human embryonic stem cell (hESC) line H9 was used to establish the novel 48-well dynamic suspension culture system. The effects of various rotational speeds and culture medium volumes on cell morphology, cell proliferation, cell viability and cell phenotype were evaluated. Effect of cell density on the pancreatic differentiation efficiency from H9 cells in 48-well plates was further investigated. In vitro the function of pancreatic β like cells was assessed by measuring glucose-stimulated insulin secretion. MAIN RESULTS A 48-well dynamic suspension culture system for hESC expansion as cell aggregates was developed. With optimized rotational speed and culture medium volume, hESCs maintained normal karyotype, viability and pluripotency. Furthermore, the system can also support the hESC aggregates subsequent differentiation into functional pancreatic β like cells after optimizing initial cell seeding density. CONCLUSION A controllable 48-well suspension culture system in microplates for hESCs maintenance, expansion and pancreatic differentiation was developed, which may provide an efficient platform for high-throughput drug screening.
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Burgos JI, Vallier L, Rodríguez-Seguí SA. Monogenic Diabetes Modeling: In Vitro Pancreatic Differentiation From Human Pluripotent Stem Cells Gains Momentum. Front Endocrinol (Lausanne) 2021; 12:692596. [PMID: 34295307 PMCID: PMC8290520 DOI: 10.3389/fendo.2021.692596] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 06/15/2021] [Indexed: 12/14/2022] Open
Abstract
The occurrence of diabetes mellitus is characterized by pancreatic β cell loss and chronic hyperglycemia. While Type 1 and Type 2 diabetes are the most common types, rarer forms involve mutations affecting a single gene. This characteristic has made monogenic diabetes an interesting disease group to model in vitro using human pluripotent stem cells (hPSCs). By altering the genotype of the original hPSCs or by deriving human induced pluripotent stem cells (hiPSCs) from patients with monogenic diabetes, changes in the outcome of the in vitro differentiation protocol can be analyzed in detail to infer the regulatory mechanisms affected by the disease-associated genes. This approach has been so far applied to a diversity of genes/diseases and uncovered new mechanisms. The focus of the present review is to discuss the latest findings obtained by modeling monogenic diabetes using hPSC-derived pancreatic cells generated in vitro. We will specifically focus on the interpretation of these studies, the advantages and limitations of the models used, and the future perspectives for improvement.
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Affiliation(s)
- Juan Ignacio Burgos
- Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), CONICET-Universidad de Buenos Aires, Ciudad Universitaria, Buenos Aires, Argentina
| | - Ludovic Vallier
- Wellcome-Medical Research Council Cambridge Stem Cell Institute and Department of Surgery, University of Cambridge, Cambridge, United Kingdom
| | - Santiago A. Rodríguez-Seguí
- Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), CONICET-Universidad de Buenos Aires, Ciudad Universitaria, Buenos Aires, Argentina
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10
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Memon B, Younis I, Abubaker F, Abdelalim EM. PDX1 - /NKX6.1 + progenitors derived from human pluripotent stem cells as a novel source of insulin-secreting cells. Diabetes Metab Res Rev 2021; 37:e3400. [PMID: 32857429 DOI: 10.1002/dmrr.3400] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 07/27/2020] [Accepted: 07/28/2020] [Indexed: 12/11/2022]
Abstract
AIM Beta cell replacement strategies are a promising alternative for diabetes treatment. Human pluripotent stem cells (hPSCs) serve as a scalable source for producing insulin-secreting cells for transplantation therapy. We recently generated novel hPSC-derived pancreatic progenitors, expressing high levels of the transcription factor NKX6.1, in the absence of PDX1 (PDX1- /NKX6.1+ ). Herein, our aim was to characterize this novel population and assess its ability to differentiate into insulin-secreting beta cells in vitro. MATERIALS AND METHODS Three different hPSC lines were differentiated into PDX1- /NKX6.1+ progenitors, which were further differentiated into insulin-secreting cells using two different protocols. The progenitors and beta cells were extensively characterized. Transcriptome analysis was performed at different stages and compared with the profiles of various pancreatic counterparts. RESULTS PDX1- /NKX6.1+ progenitors expressed high levels of nestin, a key marker of pancreatic islet-derived progenitors, in the absence of E-cadherin, similar to pancreatic mesenchymal stem cells. At progenitor stage, comparison of the two populations showed downregulation of pancreatic epithelial genes and upregulation of neuronal development genes in PDX1- /NKX6.1+ cells in comparison to the PDX1+ /NKX6.1+ cells. Interestingly, on further differentiation, PDX1- /NKX6.1+ cells generated mono-hormonal insulin+ cells and activated pancreatic key genes, such as PDX1. The transcriptome profile of PDX1- /NKX6.1+ -derived beta (3D-beta) was closely similar to those of human pancreatic islets and purified hPSC-derived beta cells. Also, the 3D-beta cells secreted C-peptide in response to increased glucose concentrations indicating their functionality. CONCLUSION These findings provide a novel source of insulin-secreting cells that can be used for beta cell therapy for diabetes.
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Affiliation(s)
- Bushra Memon
- College of Health and Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, PO Box 34110,, Qatar
| | - Ihab Younis
- Biological Sciences Program, Carnegie Mellon University in Qatar, Qatar Foundation (QF), Doha, Qatar
| | - Fadhil Abubaker
- Qatar Computing Research Institute (QCRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
| | - Essam M Abdelalim
- College of Health and Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, PO Box 34110,, Qatar
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11
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Zhang Y, Xu J, Ren Z, Meng Y, Liu W, Lu L, Zhou Z, Chen G. Nicotinamide promotes pancreatic differentiation through the dual inhibition of CK1 and ROCK kinases in human embryonic stem cells. Stem Cell Res Ther 2021; 12:362. [PMID: 34172095 PMCID: PMC8235863 DOI: 10.1186/s13287-021-02426-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 05/28/2021] [Indexed: 01/17/2023] Open
Abstract
Background Vitamin B3 (nicotinamide) plays important roles in metabolism as well as in SIRT and PARP pathways. It is also recently reported as a novel kinase inhibitor with multiple targets. Nicotinamide promotes pancreatic cell differentiation from human embryonic stem cells (hESCs). However, its molecular mechanism is still unclear. In order to understand the molecular mechanism involved in pancreatic cell fate determination, we analyzed the downstream pathways of nicotinamide in the derivation of NKX6.1+ pancreatic progenitors from hESCs. Methods We applied downstream modulators of nicotinamide during the induction from posterior foregut to pancreatic progenitors, including niacin, PARP inhibitor, SIRT inhibitor, CK1 inhibitor and ROCK inhibitor. The impact of those treatments was evaluated by quantitative real-time PCR, flow cytometry and immunostaining of pancreatic markers. Furthermore, CK1 isoforms were knocked down to validate CK1 function in the induction of pancreatic progenitors. Finally, RNA-seq was used to demonstrate pancreatic induction on the transcriptomic level. Results First, we demonstrated that nicotinamide promoted pancreatic progenitor differentiation in chemically defined conditions, but it did not act through either niacin-associated metabolism or the inhibition of PARP and SIRT pathways. In contrast, nicotinamide modulated differentiation through CK1 and ROCK inhibition. We demonstrated that CK1 inhibitors promoted the generation of PDX1/NKX6.1 double-positive pancreatic progenitor cells. shRNA knockdown revealed that the inhibition of CK1α and CK1ε promoted pancreatic progenitor differentiation. We then showed that nicotinamide also improved pancreatic progenitor differentiation through ROCK inhibition. Finally, RNA-seq data showed that CK1 and ROCK inhibition led to pancreatic gene expression, similar to nicotinamide treatment. Conclusions In this report, we revealed that nicotinamide promotes generation of pancreatic progenitors from hESCs through CK1 and ROCK inhibition. Furthermore, we discovered the novel role of CK1 in pancreatic cell fate determination. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02426-2.
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Affiliation(s)
- Yumeng Zhang
- Centre of Reproduction, Development and Aging, Faculty of Health Sciences, University of Macau, Macau SAR, China.,Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau SAR, China
| | - Jiaqi Xu
- Centre of Reproduction, Development and Aging, Faculty of Health Sciences, University of Macau, Macau SAR, China.,Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau SAR, China
| | - Zhili Ren
- Centre of Reproduction, Development and Aging, Faculty of Health Sciences, University of Macau, Macau SAR, China.,Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau SAR, China
| | - Ya Meng
- Centre of Reproduction, Development and Aging, Faculty of Health Sciences, University of Macau, Macau SAR, China.,Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau SAR, China.,Zhuhai Precision Medical Center, Zhuhai People's Hospital, Jinan University, Zhuhai, Guangdong, China
| | - Weiwei Liu
- Centre of Reproduction, Development and Aging, Faculty of Health Sciences, University of Macau, Macau SAR, China.,Bioimaging and Stem Cell Core Facility, Faculty of Health Sciences, University of Macau, Macau SAR, China
| | - Ligong Lu
- Zhuhai Precision Medical Center, Zhuhai People's Hospital, Jinan University, Zhuhai, Guangdong, China
| | - Zhou Zhou
- State Key Laboratory of Cardiovascular Disease, Beijing Key Laboratory for Molecular Diagnostics of Cardiovascular Diseases, Diagnostic Laboratory Service, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Guokai Chen
- Centre of Reproduction, Development and Aging, Faculty of Health Sciences, University of Macau, Macau SAR, China. .,Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau SAR, China. .,MoE Frontiers Science Center for Precision Oncology, University of Macau, Macau SAR, China.
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12
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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: 25] [Impact Index Per Article: 6.3] [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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13
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Elsayed AK, Younis I, Ali G, Hussain K, Abdelalim EM. Aberrant development of pancreatic beta cells derived from human iPSCs with FOXA2 deficiency. Cell Death Dis 2021; 12:103. [PMID: 33473118 PMCID: PMC7817686 DOI: 10.1038/s41419-021-03390-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 12/27/2020] [Accepted: 12/29/2020] [Indexed: 01/30/2023]
Abstract
FOXA2 has been identified as an essential factor for pancreas development and emerging evidence supports an association between FOXA2 and diabetes. Although the role of FOXA2 during pancreatic development is well-studied in animal models, its role during human islet cell development remains unclear. Here, we generated induced pluripotent stem cells (iPSCs) from a patient with FOXA2 haploinsufficiency (FOXA2+/- iPSCs) followed by beta-cell differentiation to understand the role of FOXA2 during pancreatic beta-cell development. Our results showed that FOXA2 haploinsufficiency resulted in aberrant expression of genes essential for the differentiation and proper functioning of beta cells. At pancreatic progenitor (PP2) and endocrine progenitor (EPs) stages, transcriptome analysis showed downregulation in genes associated with pancreatic development and diabetes and upregulation in genes associated with nervous system development and WNT signaling pathway. Knockout of FOXA2 in control iPSCs (FOXA2-/- iPSCs) led to severe phenotypes in EPs and beta-cell stages. The expression of NGN3 and its downstream targets at EPs as well as INSUILIN and GLUCAGON at the beta-cell stage, were almost absent in the cells derived from FOXA2-/- iPSCs. These findings indicate that FOXA2 is crucial for human pancreatic endocrine development and its defect may lead to diabetes based on FOXA2 dosage.
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Affiliation(s)
- Ahmed K. Elsayed
- grid.452146.00000 0004 1789 3191Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar
| | - Ihab Younis
- grid.418818.c0000 0001 0516 2170Biological Sciences Program, Carnegie Mellon University, Qatar Foundation, Education City, Doha, Qatar
| | - Gowher Ali
- grid.452146.00000 0004 1789 3191Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar
| | - Khalid Hussain
- Division of Endocrinology, Department of Pediatric Medicine, Sidra Medicine, Doha, Qatar
| | - Essam M. Abdelalim
- grid.452146.00000 0004 1789 3191Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar ,grid.418818.c0000 0001 0516 2170College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Education City, Doha, Qatar
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14
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Yabe SG, Fukuda S, Nishida J, Takeda F, Nashiro K, Okochi H. Efficient induction of pancreatic alpha cells from human induced pluripotent stem cells by controlling the timing for BMP antagonism and activation of retinoic acid signaling. PLoS One 2021; 16:e0245204. [PMID: 33428669 PMCID: PMC7799802 DOI: 10.1371/journal.pone.0245204] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Accepted: 12/23/2020] [Indexed: 01/15/2023] Open
Abstract
Diabetes mellitus is caused by breakdown of blood glucose homeostasis, which is maintained by an exquisite balance between insulin and glucagon produced respectively by pancreatic beta cells and alpha cells. However, little is known about the mechanism of inducing glucagon secretion from human alpha cells. Many methods for generating pancreatic beta cells from human pluripotent stem cells (hPSCs) have been reported, but only two papers have reported generation of pancreatic alpha cells from hPSCs. Because NKX6.1 has been suggested as a very important gene for determining cell fate between pancreatic beta and alpha cells, we searched for the factors affecting expression of NKX6.1 in our beta cell differentiation protocols. We found that BMP antagonism and activation of retinoic acid signaling at stage 2 (from definitive endoderm to primitive gut tube) effectively suppressed NKX6.1 expression at later stages. Using two different hPSCs lines, treatment with BMP signaling inhibitor (LDN193189) and retinoic acid agonist (EC23) at Stage 2 reduced NKX6.1 expression and allowed differentiation of almost all cells into pancreatic alpha cells in vivo after transplantation under a kidney capsule. Our study demonstrated that the cell fate of pancreatic cells can be controlled by adjusting the expression level of NKX6.1 with proper timing of BMP antagonism and activation of retinoic acid signaling during the pancreatic differentiation process. Our method is useful for efficient induction of pancreatic alpha cells from hPSCs.
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Affiliation(s)
- Shigeharu G Yabe
- Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Satsuki Fukuda
- Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Junko Nishida
- Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Fujie Takeda
- Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Kiyoko Nashiro
- Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Hitoshi Okochi
- Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
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15
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Insulin/Glucose-Responsive Cells Derived from Induced Pluripotent Stem Cells: Disease Modeling and Treatment of Diabetes. Cells 2020; 9:cells9112465. [PMID: 33198288 PMCID: PMC7696367 DOI: 10.3390/cells9112465] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 11/03/2020] [Accepted: 11/09/2020] [Indexed: 12/21/2022] Open
Abstract
Type 2 diabetes, characterized by dysfunction of pancreatic β-cells and insulin resistance in peripheral organs, accounts for more than 90% of all diabetes. Despite current developments of new drugs and strategies to prevent/treat diabetes, there is no ideal therapy targeting all aspects of the disease. Restoration, however, of insulin-producing β-cells, as well as insulin-responsive cells, would be a logical strategy for the treatment of diabetes. In recent years, generation of transplantable cells derived from stem cells in vitro has emerged as an important research area. Pluripotent stem cells, either embryonic or induced, are alternative and feasible sources of insulin-secreting and glucose-responsive cells. This notwithstanding, consistent generation of robust glucose/insulin-responsive cells remains challenging. In this review, we describe basic concepts of the generation of induced pluripotent stem cells and subsequent differentiation of these into pancreatic β-like cells, myotubes, as well as adipocyte- and hepatocyte-like cells. Use of these for modeling of human disease is now feasible, while development of replacement therapies requires continued efforts.
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16
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Aigha II, Abdelalim EM. NKX6.1 transcription factor: a crucial regulator of pancreatic β cell development, identity, and proliferation. Stem Cell Res Ther 2020; 11:459. [PMID: 33121533 PMCID: PMC7597038 DOI: 10.1186/s13287-020-01977-0] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 10/15/2020] [Indexed: 12/11/2022] Open
Abstract
Understanding the biology underlying the mechanisms and pathways regulating pancreatic β cell development is necessary to understand the pathology of diabetes mellitus (DM), which is characterized by the progressive reduction in insulin-producing β cell mass. Pluripotent stem cells (PSCs) can potentially offer an unlimited supply of functional β cells for cellular therapy and disease modeling of DM. Homeobox protein NKX6.1 is a transcription factor (TF) that plays a critical role in pancreatic β cell function and proliferation. In human pancreatic islet, NKX6.1 expression is exclusive to β cells and is undetectable in other islet cells. Several reports showed that activation of NKX6.1 in PSC-derived pancreatic progenitors (MPCs), expressing PDX1 (PDX1+/NKX6.1+), warrants their future commitment to monohormonal β cells. However, further differentiation of MPCs lacking NKX6.1 expression (PDX1+/NKX6.1−) results in an undesirable generation of non-functional polyhormonal β cells. The importance of NKX6.1 as a crucial regulator in MPC specification into functional β cells directs attentions to further investigating its mechanism and enhancing NKX6.1 expression as a means to increase β cell function and mass. Here, we shed light on the role of NKX6.1 during pancreatic β cell development and in directing the MPCs to functional monohormonal lineage. Furthermore, we address the transcriptional mechanisms and targets of NKX6.1 as well as its association with diabetes.
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Affiliation(s)
- Idil I Aigha
- College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar.,Diabetes Research Center (DRC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar
| | - Essam M Abdelalim
- College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar. .,Diabetes Research Center (DRC), Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar.
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17
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Chen S, Du K, Zou C. Current progress in stem cell therapy for type 1 diabetes mellitus. Stem Cell Res Ther 2020; 11:275. [PMID: 32641151 PMCID: PMC7346484 DOI: 10.1186/s13287-020-01793-6] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 06/19/2020] [Accepted: 06/29/2020] [Indexed: 02/06/2023] Open
Abstract
Type 1 diabetes mellitus (T1DM) is the most common chronic autoimmune disease in young patients and is characterized by the loss of pancreatic β cells; as a result, the body becomes insulin deficient and hyperglycemic. Administration or injection of exogenous insulin cannot mimic the endogenous insulin secreted by a healthy pancreas. Pancreas and islet transplantation have emerged as promising treatments for reconstructing the normal regulation of blood glucose in T1DM patients. However, a critical shortage of pancreases and islets derived from human organ donors, complications associated with transplantations, high cost, and limited procedural availability remain bottlenecks in the widespread application of these strategies. Attempts have been directed to accommodate the increasing population of patients with T1DM. Stem cell therapy holds great potential for curing patients with T1DM. With the advent of research on stem cell therapy for various diseases, breakthroughs in stem cell-based therapy for T1DM have been reported. However, many unsolved issues need to be addressed before stem cell therapy will be clinically feasible for diabetic patients. In this review, we discuss the current research advances in strategies to obtain insulin-producing cells (IPCs) from different precursor cells and in stem cell-based therapies for diabetes.
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Affiliation(s)
- Shuai Chen
- Key Laboratory of Longevity and Ageing-Related Disease of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Kechen Du
- Key Laboratory of Longevity and Ageing-Related Disease of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Chunlin Zou
- Key Laboratory of Longevity and Ageing-Related Disease of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, 530021, Guangxi, China.
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Arutyunyan IV, Fatkhudinov TK, Makarov AV, Elchaninov AV, Sukhikh GT. Regenerative medicine of pancreatic islets. World J Gastroenterol 2020; 26:2948-2966. [PMID: 32587441 PMCID: PMC7304103 DOI: 10.3748/wjg.v26.i22.2948] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 05/13/2020] [Accepted: 05/26/2020] [Indexed: 02/06/2023] Open
Abstract
The pancreas became one of the first objects of regenerative medicine, since other possibilities of dealing with the pancreatic endocrine insufficiency were clearly exhausted. The number of people living with diabetes mellitus is currently approaching half a billion, hence the crucial relevance of new methods to stimulate regeneration of the insulin-secreting β-cells of the islets of Langerhans. Natural restrictions on the islet regeneration are very tight; nevertheless, the islets are capable of physiological regeneration via β-cell self-replication, direct differentiation of multipotent progenitor cells and spontaneous α- to β- or δ- to β-cell conversion (trans-differentiation). The existing preclinical models of β-cell dysfunction or ablation (induced surgically, chemically or genetically) have significantly expanded our understanding of reparative regeneration of the islets and possible ways of its stimulation. The ultimate goal, sufficient level of functional activity of β-cells or their substitutes can be achieved by two prospective broad strategies: β-cell replacement and β-cell regeneration. The "regeneration" strategy aims to maintain a preserved population of β-cells through in situ exposure to biologically active substances that improve β-cell survival, replication and insulin secretion, or to evoke the intrinsic adaptive mechanisms triggering the spontaneous non-β- to β-cell conversion. The "replacement" strategy implies transplantation of β-cells (as non-disintegrated pancreatic material or isolated donor islets) or β-like cells obtained ex vivo from progenitors or mature somatic cells (for example, hepatocytes or α-cells) under the action of small-molecule inducers or by genetic modification. We believe that the huge volume of experimental and clinical studies will finally allow a safe and effective solution to a seemingly simple goal-restoration of the functionally active β-cells, the innermost hope of millions of people globally.
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Affiliation(s)
- Irina V Arutyunyan
- National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V. I. Kulakov of Ministry of Healthcare of Russian Federation, Moscow 117997, Russia
| | - Timur Kh Fatkhudinov
- Research Institute of Human Morphology, Moscow 117418, Russia
- Peoples Friendship University of Russia, Moscow 117198, Russia
| | - Andrey V Makarov
- National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V. I. Kulakov of Ministry of Healthcare of Russian Federation, Moscow 117997, Russia
- Pirogov Russian National Research Medical University, Ministry of Healthcare of the Russian Federation, Moscow 117997, Russia
| | - Andrey V Elchaninov
- National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V. I. Kulakov of Ministry of Healthcare of Russian Federation, Moscow 117997, Russia
| | - Gennady T Sukhikh
- National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V. I. Kulakov of Ministry of Healthcare of Russian Federation, Moscow 117997, Russia
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19
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He F, Li N, Huang HB, Wang JB, Yang XF, Wang HD, Huang W, Li FR. LSD1 inhibition yields functional insulin-producing cells from human embryonic stem cells. Stem Cell Res Ther 2020; 11:163. [PMID: 32345350 PMCID: PMC7189473 DOI: 10.1186/s13287-020-01674-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Revised: 03/15/2020] [Accepted: 04/08/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Human embryonic stem cells represent a potentially unlimited source of insulin-producing cells for diabetes therapy. While tremendous progress has been made in directed differentiation of human embryonic stem cells into IPCs in vitro, the mechanisms controlling its differentiation and function are not fully understood. Previous studies revealed that lysine-specific demethylase 1(LSD1) balanced the self-renewal and differentiation in human induced pluripotent stem cells and human embryonic stem cells. This study aims to explore the role of LSD1 in directed differentiation of human embryonic stem cells into insulin-producing cells. METHODS Human embryonic stem cell line H9 was induced into insulin-producing cells by a four-step differentiation protocol. Lentivirus transfection was applied to knockdown LSD1 expression. Immunofluorescence assay and flow cytometry were utilized to check differentiation efficiency. Western blot was used to examine signaling pathway proteins and differentiation-associated proteins. Insulin/C-peptide release was assayed by ELISA. Statistical analysis between groups was carried out with one-way ANOVA tests or a student's t test when appropriate. RESULTS Inhibition or silencing LSD1 promotes the specification of pancreatic progenitors and finally the commitment of functional insulin-producing β cells; Moreover, inhibition or silencing LSD1 activated ERK signaling and upregulated pancreatic progenitor associated genes, accelerating pre-maturation of pancreatic progenitors, and conferred the NKX6.1+ population with better proliferation ability. IPCs with LSD1 inhibitor tranylcypromine treatment displayed enhanced insulin secretion in response to glucose stimulation. CONCLUSIONS We identify a novel role of LSD1 inhibition in promoting IPCs differentiation from hESCs, which would be emerged as potential intervention for generation of functional pancreatic β cells to cure diabetes.
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Affiliation(s)
- Fei He
- Translational Medicine Collaborative Innovation Center, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, 1017 Dongmen North Road, Shenzhen, 518020, China
- Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou, 510632, China
| | - Ning Li
- Translational Medicine Collaborative Innovation Center, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, 1017 Dongmen North Road, Shenzhen, 518020, China
- Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou, 510632, China
| | - Hai-Bo Huang
- Translational Medicine Collaborative Innovation Center, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, 1017 Dongmen North Road, Shenzhen, 518020, China
- Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou, 510632, China
| | - Jing-Bo Wang
- Translational Medicine Collaborative Innovation Center, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, 1017 Dongmen North Road, Shenzhen, 518020, China
- Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou, 510632, China
| | - Xiao-Fei Yang
- Translational Medicine Collaborative Innovation Center, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, 1017 Dongmen North Road, Shenzhen, 518020, China
- Guangdong Engineering Technology Research Center of Stem Cell and Cell therapy, Shenzhen, 518020, China
- Shenzhen Key Laboratory of Stem Cell Research and Clinical Transformation, Shenzhen, 518020, China
| | - Hua-Dong Wang
- Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Wei Huang
- Department of Biology, Southern University of Science and Technology, Shenzhen, 518055, China
| | - Fu-Rong Li
- Translational Medicine Collaborative Innovation Center, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, 1017 Dongmen North Road, Shenzhen, 518020, China.
- Guangdong Engineering Technology Research Center of Stem Cell and Cell therapy, Shenzhen, 518020, China.
- Shenzhen Key Laboratory of Stem Cell Research and Clinical Transformation, Shenzhen, 518020, China.
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20
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Ali G, Elsayed AK, Nandakumar M, Bashir M, Younis I, Abu Aqel Y, Memon B, Temanni R, Abubaker F, Taheri S, Abdelalim EM. Keratinocytes Derived from Patient-Specific Induced Pluripotent Stem Cells Recapitulate the Genetic Signature of Psoriasis Disease. Stem Cells Dev 2020; 29:383-400. [PMID: 31996098 PMCID: PMC7153648 DOI: 10.1089/scd.2019.0150] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Psoriasis is characterized by hyperproliferation and defective differentiation of keratinocytes (KCs). Patients with psoriasis are at a high risk of developing diabetes and cardiovascular diseases. The debate on the genetic origin of psoriasis pathogenesis remains unresolved due to lack of suitable in vitro human models mimicking the disease phenotypes. In this study, we provide the first human induced pluripotent stem cell (iPSC) model for psoriasis carrying the genetic signature of the patients. iPSCs were generated from patients with psoriasis (PsO-iPSCs) and healthy donors (Ctr-iPSCs) and were efficiently differentiated into mature KCs. RNA sequencing of KCs derived from Ctr-iPSCs and PsO-iPSCs identified 361 commonly upregulated and 412 commonly downregulated genes. KCs derived from PsO-iPSCs showed dysregulated transcripts associated with psoriasis and KC differentiation, such as HLA-C, KLF4, chemokines, type I interferon-inducible genes, solute carrier family, IVL, DSG1, and HLA-DQA1, as well as transcripts associated with insulin resistance, such as IRS2, GDF15, GLUT10, and GLUT14. Our data suggest that the KC abnormalities are the main driver triggering psoriasis pathology and highlights the substantial contribution of genetic predisposition in the development of psoriasis and insulin resistance.
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Affiliation(s)
- Gowher Ali
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
| | - Ahmed K Elsayed
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
| | - Manjula Nandakumar
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
| | - Mohammed Bashir
- Department of Endocrinology, Qatar Metabolic Institute, Hamad Medical Corporation, Doha, Qatar
| | - Ihab Younis
- Biological Sciences Program, Carnegie Mellon University in Qatar, Qatar Foundation, Education City, Doha, Qatar
| | - Yasmin Abu Aqel
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar.,College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Education City, Doha, Qatar
| | - Bushra Memon
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar.,College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Education City, Doha, Qatar
| | - Ramzi Temanni
- Biomedical Informatics Division, Sidra Medicine, Doha, Qatar
| | - Fadhil Abubaker
- Computer Sciences Program, Carnegie Mellon University in Qatar, Qatar Foundation, Education City, Doha, Qatar
| | - Shahrad Taheri
- Department of Medicine and Clinical Research Core, Weill Cornell Medicine-Qatar, Qatar Foundation, Education City, Doha, Qatar
| | - Essam M Abdelalim
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar.,College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Education City, Doha, Qatar
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21
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Memon B, Abdelalim EM. Stem Cell Therapy for Diabetes: Beta Cells versus Pancreatic Progenitors. Cells 2020; 9:cells9020283. [PMID: 31979403 PMCID: PMC7072676 DOI: 10.3390/cells9020283] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 01/16/2020] [Accepted: 01/17/2020] [Indexed: 12/16/2022] Open
Abstract
Diabetes mellitus (DM) is one of the most prevalent metabolic disorders. In order to replace the function of the destroyed pancreatic beta cells in diabetes, islet transplantation is the most widely practiced treatment. However, it has several limitations. As an alternative approach, human pluripotent stem cells (hPSCs) can provide an unlimited source of pancreatic cells that have the ability to secrete insulin in response to a high blood glucose level. However, the determination of the appropriate pancreatic lineage candidate for the purpose of cell therapy for the treatment of diabetes is still debated. While hPSC-derived beta cells are perceived as the ultimate candidate, their efficiency needs further improvement in order to obtain a sufficient number of glucose responsive beta cells for transplantation therapy. On the other hand, hPSC-derived pancreatic progenitors can be efficiently generated in vitro and can further mature into glucose responsive beta cells in vivo after transplantation. Herein, we discuss the advantages and predicted challenges associated with the use of each of the two pancreatic lineage products for diabetes cell therapy. Furthermore, we address the co-generation of functionally relevant islet cell subpopulations and structural properties contributing to the glucose responsiveness of beta cells, as well as the available encapsulation technology for these cells.
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Affiliation(s)
- Bushra Memon
- College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Education City, P.O。 Box 34110 Doha, Qatar;
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), P.O. Box 34110 Doha, Qatar
| | - Essam M. Abdelalim
- College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Education City, P.O。 Box 34110 Doha, Qatar;
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), P.O. Box 34110 Doha, Qatar
- Correspondence: ; Tel.: +97-44-4546-432; Fax: +97-44-4541-770
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22
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In Vivo and In Vitro Models of Diabetes: A Focus on Pregnancy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1307:553-576. [PMID: 32504388 DOI: 10.1007/5584_2020_536] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Diabetes in pregnancy is associated with an increased risk of poor outcomes, both for the mother and her offspring. Although clinical and epidemiological studies are invaluable to assess these outcomes and the effectiveness of potential treatments, there are certain ethical and practical limitations to what can be assessed in human studies.Thus, both in vivo and in vitro models can aid us in the understanding of the mechanisms behind these complications and, in the long run, towards their prevention and treatment. This review summarizes the existing animal and cell models used to mimic diabetes, with a specific focus on the intrauterine environment. Summary of this review.
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23
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Ma Y, Ma M, Sun J, Li W, Li Y, Guo X, Zhang H. CHIR-99021 regulates mitochondrial remodelling via β-catenin signalling and miRNA expression during endodermal differentiation. J Cell Sci 2019; 132:jcs.229948. [PMID: 31289194 DOI: 10.1242/jcs.229948] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Accepted: 06/17/2019] [Indexed: 12/19/2022] Open
Abstract
Mitochondrial remodelling is a central feature of stem cell differentiation. However, little is known about the regulatory mechanisms during these processes. Previously, we found that a pharmacological inhibitor of glycogen synthase kinase-3α and -3β, CHIR-99021, initiates human adipose stem cell differentiation into human definitive endodermal progenitor cells (hEPCs), which were directed to differentiate synchronously into hepatocyte-like cells after further treatment with combinations of soluble factors. In this study, we show that CHIR-99021 promotes mitochondrial biogenesis, the expression of PGC-1α (also known as PPARGC1A), TFAM and NRF1 (also known as NFE2L1), oxidative phosphorylation capacities, and the production of reactive oxygen species in hEPCs. Blocking mitochondrial dynamics using siRNA targeting DRP1 (also known as DNM1L) impaired definitive endodermal differentiation. Downregulation of β-catenin (CTNNB1) expression weakened the effect of CHIR-99021 on the induction of mitochondrial remodelling and the expression of transcription factors for mitochondrial biogenesis. Moreover, CHIR-99021 decreased the expression of miR-19b-2-5p, miR-23a-3p, miR-23c, miR-130a-3p and miR-130a-5p in hEPCs, which target transcription factors for mitochondrial biogenesis. These data demonstrate that CHIR-99021 plays a role in mitochondrial structure and function remodelling via activation of the β-catenin signalling pathway and inhibits the expression of miRNAs during definitive endodermal differentiation.This article has an associated First Person interview with the first author of the paper.
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Affiliation(s)
- Yuejiao Ma
- Department of Cell Biology, School of Basic Medical Science, Capital Medical University, Beijing 100069, China
| | - Minghui Ma
- Department of Cell Biology, School of Basic Medical Science, Capital Medical University, Beijing 100069, China
| | - Jie Sun
- Department of Cell Biology, School of Basic Medical Science, Capital Medical University, Beijing 100069, China
| | - Weihong Li
- Department of Cell Biology, School of Basic Medical Science, Capital Medical University, Beijing 100069, China
| | - Yaqiong Li
- Department of Cell Biology, School of Basic Medical Science, Capital Medical University, Beijing 100069, China
| | - Xinyue Guo
- Department of Cell Biology, School of Basic Medical Science, Capital Medical University, Beijing 100069, China
| | - Haiyan Zhang
- Department of Cell Biology, School of Basic Medical Science, Capital Medical University, Beijing 100069, China
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microRNA-690 regulates induced pluripotent stem cells (iPSCs) differentiation into insulin-producing cells by targeting Sox9. Stem Cell Res Ther 2019; 10:59. [PMID: 30767782 PMCID: PMC6376733 DOI: 10.1186/s13287-019-1154-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 01/14/2019] [Accepted: 01/24/2019] [Indexed: 12/31/2022] Open
Abstract
Background The regulatory mechanism of insulin-producing cells (IPCs) differentiation from induced pluripotent stem cells (iPSCs) in vitro is very important in the phylogenetics of pancreatic islets, the molecular pathogenesis of diabetes, and the acquisition of high-quality pancreatic β-cells derived from stem cells for cell therapy. Methods miPSCs were induced for IPCs differentiation. miRNA microarray assays were performed by using total RNA from our iPCs-derived IPCs containing undifferentiated iPSCs and iPSCs-derived IPCSs at day 4, day 14, and day 21 during step 3 to screen the differentially expressed miRNAs (DEmiRNAs) related to IPCs differentiation, and putative target genes of DEmiRNAs were predicted by bioinformatics analysis. miR-690 was selected for further research, and MPCs were transfected by miR-690-agomir to confirm whether it was involved in the regulation of IPCs differentiation in iPSCs. Quantitative Real-Time PCR (qRT-PCR), Western blotting, and immunostaining assays were performed to examine the pancreatic function of IPCs at mRNA and protein level respectively. Flow cytometry and ELISA were performed to detect differentiation efficiency and insulin content and secretion from iPSCs-derived IPCs in response to stimulation at different concentration of glucose. The targeting of the 3′-untranslated region of Sox9 by miR-690 was examined by luciferase assay. Results We found that miR-690 was expressed dynamically during IPCs differentiation according to the miRNA array results and that overexpression of miR-690 significantly impaired the maturation and insulinogenesis of IPCs derived from iPSCs both in vitro and in vivo. Bioinformatic prediction and mechanistic analysis revealed that miR-690 plays a pivotal role during the differentiation of IPCs by directly targeting the transcription factor sex-determining region Y (SRY)-box9. Furthermore, downstream experiments indicated that miR-690 is likely to act as an inactivated regulator of the Wnt signaling pathway in this process. Conclusions We discovered a previously unknown interaction between miR-690 and sox9 but also revealed a new regulatory signaling pathway of the miR-690/Sox9 axis during iPSCs-induced IPCs differentiation. Electronic supplementary material The online version of this article (10.1186/s13287-019-1154-8) contains supplementary material, which is available to authorized users.
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Srivastava A, Dadheech N, Vakani M, Gupta S. Pancreatic resident endocrine progenitors demonstrate high islet neogenic fidelity and committed homing towards diabetic mice pancreas. J Cell Physiol 2018; 234:8975-8987. [PMID: 30341903 DOI: 10.1002/jcp.27568] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Accepted: 09/13/2018] [Indexed: 12/13/2022]
Abstract
Pancreatic progenitors have been explored for their profound characteristics and unique commitment to generate new functional islets in regenerative medicine. Pancreatic resident endocrine progenitors (PREPs) with mesenchymal stem cell (MSC) phenotype were purified from BALB/c mice pancreas and characterized. PREPs were differentiated into mature islet clusters in vitro by activin-A and swertisin and functionally characterized. A temporal gene and protein profiling was performed during differentiation. Furthermore, PREPs were labeled with green fluorescent protein (GFP) and transplanted intravenously into streptozotocin (STZ) diabetic mice while monitoring their homing and differentiation leading to amelioration in the diabetic condition. PREPs were positive for unique progenitor markers and transcription factors essential for endocrine pancreatic homeostasis along with having the multipotent MSC phenotype. These cells demonstrated high fidelity for islet neogenesis in minimum time (4 days) to generate mature functional islet clusters (shortest reported period for any isolated stem/progenitor). Furthermore, GFP-labeled PREPs transplanted in STZ diabetic mice migrated and localized within the injured pancreas without trapping in any other major organ and differentiated rapidly into insulin-producing cells without an external stimulus. A rapid decrease in fasting blood glucose levels toward normoglycemia along with significant increase in fasting serum insulin levels was observed, which ameliorated the diabetic condition. This study highlights the unique potential of PREPs to generate mature islets within the shortest period and their robust homing toward the damaged pancreas, which ameliorated the diabetic condition suggesting PREPs affinity toward their niche, which can be exploited and extended to other stem cell sources in diabetic therapeutics.
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Affiliation(s)
- Abhay Srivastava
- Molecular Endocrinology and Stem Cell Research Lab, Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, India
| | - Nidheesh Dadheech
- Dr. AM James Shapiro Laboratory, Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
| | - Mitul Vakani
- Molecular Endocrinology and Stem Cell Research Lab, Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, India
| | - Sarita Gupta
- Molecular Endocrinology and Stem Cell Research Lab, Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, India
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Deola S, Guerrouahen BS, Sidahmed H, Al-Mohannadi A, Elnaggar M, Elsadig R, Abdelalim EM, Petrovski G, Gadina M, Thrasher A, Wels WS, Hunger SP, Wang E, Marincola FM, Maccalli C, Cugno C. Tailoring cells for clinical needs: Meeting report from the Advanced Therapy in Healthcare symposium (October 28-29 2017, Doha, Qatar). J Transl Med 2018; 16:276. [PMID: 30305089 PMCID: PMC6180452 DOI: 10.1186/s12967-018-1652-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 10/01/2018] [Indexed: 02/07/2023] Open
Abstract
New technologies and therapies designed to facilitate development of personalized treatments are rapidly emerging in the field of biomedicine. Strikingly, the goal of personalized medicine refined the concept of therapy by developing cell-based therapies, the so-called “living drugs”. Breakthrough advancements were achieved in this regard in the fields of gene therapy, cell therapy, tissue-engineered products and advanced therapeutic techniques. The Advanced Therapies in Healthcare symposium, organized by the Clinical Research Center Department of Sidra Medicine, in Doha, Qatar (October 2017), brought together world-renowned experts from the fields of oncology, hematology, immunology, inflammation, autoimmune disorders, and stem cells to offer a comprehensive picture of the status of worldwide advanced therapies in both pre-clinical and clinical development, providing insights to the research phase, clinical data and regulatory aspects of these therapies. Highlights of the meeting are provided in this meeting report.
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Affiliation(s)
- Sara Deola
- Research Department, Clinical Research Center, Sidra Medicine, Doha, Qatar
| | | | - Heba Sidahmed
- Research Department, Clinical Research Center, Sidra Medicine, Doha, Qatar
| | - Anjud Al-Mohannadi
- Research Department, Clinical Research Center, Sidra Medicine, Doha, Qatar
| | - Muhammad Elnaggar
- Research Department, Clinical Research Center, Sidra Medicine, Doha, Qatar
| | - Ramaz Elsadig
- Research Department, Clinical Research Center, Sidra Medicine, Doha, Qatar
| | - Essam M Abdelalim
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Education City, Doha, Qatar
| | | | | | - Adrian Thrasher
- UCL Great Ormond Street Institute of Child Health, London, UK
| | - Winfried S Wels
- Georg Speyer Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt, Germany
| | | | - Ena Wang
- Immune Oncology Discovery and System Biology, AbbVie, Redwood City, CA, USA
| | | | | | - Cristina Maccalli
- Research Department, Clinical Research Center, Sidra Medicine, Doha, Qatar
| | - Chiara Cugno
- Research Department, Clinical Research Center, Sidra Medicine, Doha, Qatar.
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