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Song H, Li J, Yang H, Kong B, Xu Y, Li X, Li H. Enhancement of functional insulin-producing cell differentiation from embryonic stem cells through MST1-silencing. Diabetol Metab Syndr 2025; 17:93. [PMID: 40108649 PMCID: PMC11924671 DOI: 10.1186/s13098-025-01666-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 03/09/2025] [Indexed: 03/22/2025] Open
Abstract
BACKGROUND Islet β-cell transplantation offers a promising treatment for repairing pancreatic damage in diabetes, with the transcription factor pancreatic duodenal homeobox-1 (PDX1) being crucial for β-cell function and insulin secretion. Mammalian threonine protein kinase (MST1) is recognized for its role in regulating PDX1 during cell apoptosis, yet its function in embryonic stem cell (ESC) differentiation into insulin-producing cells (IPCs) remain underexplored. This study investigated the effect of MST1-silencing on the differentiation of ESC into IPCs. METHODS ESCs were transfected utilizing a recombinant MST1-silencing lentiviral vector (shMST1). qRT-PCR, immunofluorescence, flow cytometry, western blot and ELISA assays were performed to examine function of IPCs in vitro. Furthermore, these IPCs were transplanted into type 1 diabetic mellitus (T1DM) rats. Measuring the changes in blood glucose concentration of animals before and after IPCs transplantation. Intraperitoneal glucose tolerance test (IPGT) was used to determine the regulatory effect of IPCs transplantation on blood glucose stimulation and immunohistochemistry was used to detect the expression of pancreatic Insulin protein in T1DM rats. RESULTS It was observed that IPCs from the shMST1 group exhibited notably improvement in insulin secretion and glucose responsiveness, suggesting MST1 suppression may enhance IPC maturity. The rats demonstrated significant normalization of blood sugar levels and increased insulin levels, akin to non-diabetic controls. This implies that MST1-silencing not only augments IPC function in vitro but also their therapeutic efficacy in vivo. CONCLUSIONS The findings indicate that targeting MST1 offers a novel approach for deriving functionally mature IPCs from ESCs, potentially advancing cell replacement therapies for diabetes. This research underscores the importance of developing IPCs with competent insulin secretion for diabetes treatment in vitro.
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Affiliation(s)
- Hui Song
- Basic Medical School of Ningxia Medical University, Yinchuan, 750004, China
- Institute of Endocrinology, Ningxia Medical University, Yinchuan, 750004, China
- Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Ningxia Medical University, Yinchuan, 750004, China
| | - Jiarui Li
- Basic Medical School of Ningxia Medical University, Yinchuan, 750004, China
- Institute of Endocrinology, Ningxia Medical University, Yinchuan, 750004, China
| | - Haohao Yang
- Basic Medical School of Ningxia Medical University, Yinchuan, 750004, China
- Institute of Endocrinology, Ningxia Medical University, Yinchuan, 750004, China
| | - Bin Kong
- Basic Medical School of Ningxia Medical University, Yinchuan, 750004, China
| | - Yu Xu
- Basic Medical School of Ningxia Medical University, Yinchuan, 750004, China
- Institute of Endocrinology, Ningxia Medical University, Yinchuan, 750004, China
| | - Xiong Li
- People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, 750004, China.
| | - Hui Li
- Basic Medical School of Ningxia Medical University, Yinchuan, 750004, China.
- Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Ningxia Medical University, Yinchuan, 750004, China.
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Madkor HR, Abd El-Aziz MK, Abd El-Maksoud MS, Ibrahim IM, Ali FEM. Stem Cells Reprogramming in Diabetes Mellitus and Diabetic Complications: Recent Advances. Curr Diabetes Rev 2025; 21:21-37. [PMID: 38173073 DOI: 10.2174/0115733998275428231210055650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 11/09/2023] [Accepted: 11/21/2023] [Indexed: 01/05/2024]
Abstract
BACKGROUND The incidence of diabetes mellitus (DM) is dramatically increasing worldwide, and it is expected to affect 700 million cases by 2045. Diabetes influences health care economics, human quality of life, morbidity, and mortality, which were primarily seen extensively in developing countries. Uncontrolled DM, which results in consistent hyperglycemia, may lead to severe life-threatening complications such as nephropathy, retinopathy, neuropathy, and cardiovascular complications. METHODOLOGY In addition to traditional therapies with insulin and oral anti-diabetics, researchers have developed new approaches for treatment, including stem cell (SC) therapy, which exhibits promising outcomes. Besides its significant role in treating type one DM (T1DM) and type two DM (T2DM), it can also attenuate diabetic complications. Furthermore, the development of insulin- producing cells can be achieved by using the different types of SCs, such as embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and multiple types of adult stem cells, such as pancreatic, hepatic, and mesenchymal stem cells (MSC). All these types have been extensively studied and proved their ability to develop insulin-producing cells, but every type has limitations. CONCLUSION This review aims to enlighten researchers about recent advances in stem cell research and their potential benefits in DM and diabetic complications.
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Affiliation(s)
- Hafez R Madkor
- Department of Biochemistry, Faculty of Pharmacy, Al-Azhar University, Assiut, 71524, Egypt
| | | | | | - Islam M Ibrahim
- Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, 71524, Egypt
| | - Fares E M Ali
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, 71524, Egypt
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Rohban R, Martins CP, Esni F. Advanced therapy to cure diabetes: mission impossible is now possible? Front Cell Dev Biol 2024; 12:1484859. [PMID: 39629270 PMCID: PMC11611888 DOI: 10.3389/fcell.2024.1484859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Accepted: 11/04/2024] [Indexed: 12/07/2024] Open
Abstract
Cell and Gene therapy are referred to as advanced therapies that represent overlapping fields of regenerative medicine. They have similar therapeutic goals such as to modify cellular identity, improve cell function, or fight a disease. These two therapeutic avenues, however, possess major differences. While cell therapy involves introduction of new cells, gene therapy entails introduction or modification of genes. Furthermore, the aim of cell therapy is often to replace, or repair damaged tissue, whereas gene therapy is used typically as a preventive approach. Diabetes mellitus severely affects the quality of life of afflicted individuals and has various side effects including cardiovascular, ophthalmic disorders, and neuropathy while putting enormous economic pressure on both the healthcare system and the patient. In recent years, great effort has been made to develop cutting-edge therapeutic interventions for diabetes treatment, among which cell and gene therapies stand out. This review aims to highlight various cell- and gene-based therapeutic approaches leading to the generation of new insulin-producing cells as a topmost "panacea" for treating diabetes, while deliberately avoiding a detailed molecular description of these approaches. By doing so, we aim to target readers who are new to the field and wish to get a broad helicopter overview of the historical and current trends of cell- and gene-based approaches in β-cell regeneration.
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Affiliation(s)
- Rokhsareh Rohban
- Department of Internal Medicine, Division of Hematology, Medical University of Graz, Graz, Austria
| | - Christina P. Martins
- Department of Surgery, Division of Pediatric General and Thoracic Surgery, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
| | - Farzad Esni
- Department of Surgery, Division of Pediatric General and Thoracic Surgery, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
- Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA, United States
- UPMC Hillman Cancer Center, Pittsburgh, PA, United States
- McGowan Institute for regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States
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Crist SB, Azzag K, Kiley J, Coleman I, Magli A, Perlingeiro RCR. The adult environment promotes the transcriptional maturation of human iPSC-derived muscle grafts. NPJ Regen Med 2024; 9:16. [PMID: 38575647 PMCID: PMC10994941 DOI: 10.1038/s41536-024-00360-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 03/26/2024] [Indexed: 04/06/2024] Open
Abstract
Pluripotent stem cell (PSC)-based cell therapy is an attractive option for the treatment of multiple human disorders, including muscular dystrophies. While in vitro differentiating PSCs can generate large numbers of human lineage-specific tissue, multiple studies evidenced that these cell populations mostly display embryonic/fetal features. We previously demonstrated that transplantation of PSC-derived myogenic progenitors provides long-term engraftment and functional improvement in several dystrophic mouse models, but it remained unknown whether donor-derived myofibers mature to match adult tissue. Here, we transplanted iPAX7 myogenic progenitors into muscles of non-dystrophic and dystrophic mice and compared the transcriptional landscape of human grafts with respective in vitro-differentiated iPAX7 myotubes as well as human skeletal muscle biospecimens. Pairing bulk RNA sequencing with computational deconvolution of human reads, we were able to pinpoint key myogenic changes that occur during the in vitro-to-in vivo transition, confirm developmental maturity, and consequently evaluate their applicability for cell-based therapies.
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Affiliation(s)
- Sarah B Crist
- Lillehei Heart Institute, University of Minnesota, Minneapolis, MN, USA
- Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA
| | - Karim Azzag
- Lillehei Heart Institute, University of Minnesota, Minneapolis, MN, USA
- Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA
| | - James Kiley
- Lillehei Heart Institute, University of Minnesota, Minneapolis, MN, USA
- Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA
| | - Ilsa Coleman
- Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Alessandro Magli
- Lillehei Heart Institute, University of Minnesota, Minneapolis, MN, USA.
- Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA.
- Sanofi, Genomic Medicine Unit, 225 2nd Ave, Waltham, MA, 02451, USA.
| | - Rita C R Perlingeiro
- Lillehei Heart Institute, University of Minnesota, Minneapolis, MN, USA.
- Stem Cell Institute, University of Minnesota, Minneapolis, MN, USA.
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Aglan HA, Kotob SE, Mahmoud NS, Kishta MS, Ahmed HH. Bone marrow stem cell-derived β-cells: New issue for diabetes cell therapy. Tissue Cell 2024; 86:102280. [PMID: 38029457 DOI: 10.1016/j.tice.2023.102280] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 11/19/2023] [Accepted: 11/20/2023] [Indexed: 12/01/2023]
Abstract
This investigation aimed to establish the promising role of insulin-producing cells (IPCs) growing from bone marrow-mesenchymal stem cells (BM-MSCs) in relieving hyperglycemia induced in rats. BM-MSCs were differentiated into IPCs using three different protocols. The efficiency of BM-MSCs differentiation into IPCs in vitro was confirmed by detecting IPCs specific gene expression (Foxa-2, PDX-1 and Ngn-3) and insulin release assay. The in vivo study design included 3 groups of male Wistar rats; negative control group, diabetic group and IPCs-transfused group (5 ×106 cells of the most functional IPCs/rat). One month after IPCs infusion, serum glucose, insulin, c-peptide and visfatin levels as well as pancreatic glucagon level were quantified. Gene expression analysis of pancreatic Foxa-2 and Sox-17, IGF-1 and FGF-10 was done. Additionally, histological investigation of pancreatic tissue sections was performed. Our data clarified that, the most functional IPCs are those generated from BM-MSCs using differentiation protocol 3 as indicated by the significant up-regulation of Foxa-2, PDX-1 and Ngn-3 gene expression levels. These findings were further emphasized by releasing of a significant amount of insulin in response to glucose load. The transplantation of the IPCs in diabetic rats elicited significant decline in serum glucose, visfatin and pancreatic glucagon levels along with significant rise in serum insulin and c-peptide levels. Moreover, it triggered significant up-regulation in the expression levels of pancreatic Foxa-2, Sox-17, IGF-1 and FGF-10 genes versus the untreated diabetic counterpart. The histopathological examination of pancreatic tissue almost assisted the biochemical and molecular genetic analyses. These results disclose that the cell therapy holds potential to develop a new cure for DM based on the capability of BM-MSCs to generate β-cell phenotype using specific protocol.
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Affiliation(s)
- Hadeer A Aglan
- Hormones Department, Medical Research and Clinical Studies Institute, National Research Centre, Dokki, Giza, Egypt; Stem Cell Lab., Center of Excellence for Advanced Sciences, National Research Centre, Dokki, Giza, Egypt.
| | - Soheir E Kotob
- Hormones Department, Medical Research and Clinical Studies Institute, National Research Centre, Dokki, Giza, Egypt
| | - Nadia S Mahmoud
- Hormones Department, Medical Research and Clinical Studies Institute, National Research Centre, Dokki, Giza, Egypt; Stem Cell Lab., Center of Excellence for Advanced Sciences, National Research Centre, Dokki, Giza, Egypt
| | - Mohamed S Kishta
- Hormones Department, Medical Research and Clinical Studies Institute, National Research Centre, Dokki, Giza, Egypt; Stem Cell Lab., Center of Excellence for Advanced Sciences, National Research Centre, Dokki, Giza, Egypt
| | - Hanaa H Ahmed
- Hormones Department, Medical Research and Clinical Studies Institute, National Research Centre, Dokki, Giza, Egypt; Stem Cell Lab., Center of Excellence for Advanced Sciences, National Research Centre, Dokki, Giza, Egypt
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Wang Y, Ding H, Guo C, Bao Q, Li D, Xiong Y. LncRNA Malat1 regulates iPSC-derived β-cell differentiation by targeting the miR-15b-5p/Ihh axis. Cell Signal 2024; 113:110975. [PMID: 37972802 DOI: 10.1016/j.cellsig.2023.110975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 10/18/2023] [Accepted: 11/13/2023] [Indexed: 11/19/2023]
Abstract
BACKGROUND Differentiation of induced pluripotent stem cells (iPSCs)-derived β-like cells is a novel strategy for treatment of type 1 diabetes. Elucidation of the regulatory mechanisms of long noncoding RNAs (lncRNAs) in β-like cells derived from iPSCs is important for understanding the development of the pancreas and pancreatic β-cells and may improve the quality of β-like cells for stem cell therapy. METHODS β-like cells were derived from iPSCs in a three-step protocol. RNA sequencing and bioinformatics analysis were carried out to screen the differentially expressed lncRNAs and identify the putative target genes separately. LncRNA Malat1 was chosen for further research. Series of loss and gain of functions experiments were performed to study the biological function of LncRNA Malat1. Quantitative real-time PCR (qRT-PCR), Western blot (WB) analysis and immunofluorescence (IF) staining were carried out to separately detect the functions of pancreatic β-cells at the mRNA and protein levels. Cytoplasmic and nuclear RNA fractionation and fluorescence in situ hybridization (FISH) were used to determine the subcellar location of lncRNA Malat1 in β-like cells. Enzyme-linked immunosorbent assays (ELISAs) were performed to examine the differentiation and insulin secretion of β-like cells after stimulation with different glucose concentrations. Structural interactions between lncRNA Malat1 and miR-15b-5p and between miR-15b-5p/Ihh were detected by dual luciferase reporter assays (LRAs). RESULTS We found that the expression of lncRNA Malat1 declined during differentiation, and overexpression (OE) of lncRNA Malat1 notably impaired the differentiation and maturation of β-like cells derived from iPSCs in vitro and in vivo. Most importantly, lncRNA Malat1 could function as a competing endogenous RNA (ceRNA) of miR-15b-5p to regulate the expression of Ihh according to bioinformatics prediction, mechanistic analysis and downstream experiments. CONCLUSION This study established an unreported regulatory network of lncRNA Malat1 and the miR-15b-5p/Ihh axis during the differentiation of iPSCs into β-like cells. In addition to acting as an oncogene promoting tumorigenesis, lncRNA Malat1 may be an effective and novel target for treatment of diabetes in the future.
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Affiliation(s)
- Yao Wang
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University, Nantong 226001, China; Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, China
| | - Haoxiang Ding
- Nantong University Medical School, Nantong 226001, China
| | - Chengfeng Guo
- Nantong University Medical School, Nantong 226001, China
| | - Qian Bao
- Nantong University Medical School, Nantong 226001, China
| | - Dongqian Li
- Nantong University Medical School, Nantong 226001, China
| | - Yicheng Xiong
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University, Nantong 226001, China.
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Akinmoladun AC, Bello M, Ibukun EO. Upregulation of PCSK9, rho kinase and cardiac troponin by Eucalyptus globulus leaf extract improves fructose-streptozotocin-induced diabetic cardiac dysfunction in rats. Arch Physiol Biochem 2023; 129:1219-1228. [PMID: 34270371 DOI: 10.1080/13813455.2021.1931340] [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: 10/10/2020] [Accepted: 05/12/2021] [Indexed: 10/20/2022]
Abstract
CONTEXT The effect of Eucalyptus globulus in diabetic cardiac dysfunction and the possible mechanisms involved have not been explored. OBJECTIVE To evaluate the effect of ethanol leaf extract of E. globulus (NEE) on the cardiac function of fructose/streptozotocin-induced diabetic rats. MATERIALS AND METHODS Type-2 diabetes was induced in rats with 10% fructose feeding for 14 days and an intraperitoneal administration of 40 mg/kg streptozotocin. Diabetic animals were treated with NEE (100-400 mg/kg) or 5 mg/kg glibenclamide orally for 21 days. Biochemical assays, histopathological examination and analyses of PCSK9, Rho kinase and Cardiac troponin expression were performed. RESULTS The untreated diabetic group showed decreased expression of the genes, oxidative stress, dyslipidemia, increased activities of creatine kinase MB and lactate dehydrogenase, reduced nitric oxide level, and depletion of cardiomyocytes, which were reversed in NEE treated groups. CONCLUSIONS Eucalyptus globulus ameliorated diabetic cardiac dysfunction through increased PCSK9, Rho kinase and Cardiac troponin expression.
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Affiliation(s)
- Afolabi C Akinmoladun
- Phytomedicine, Biochemical Pharmacology and Toxicology Research Laboratories, Department of Biochemistry, School of Sciences, The Federal University of Technology, Akure, Nigeria
| | - Morenikejimi Bello
- Phytomedicine, Biochemical Pharmacology and Toxicology Research Laboratories, Department of Biochemistry, School of Sciences, The Federal University of Technology, Akure, Nigeria
| | - Emmanuel Oluwafemi Ibukun
- Phytomedicine, Biochemical Pharmacology and Toxicology Research Laboratories, Department of Biochemistry, School of Sciences, The Federal University of Technology, Akure, Nigeria
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Verhoeff K, Cuesta-Gomez N, Jasra I, Marfil-Garza B, Dadheech N, Shapiro AMJ. Optimizing Generation of Stem Cell-Derived Islet Cells. Stem Cell Rev Rep 2022; 18:2683-2698. [PMID: 35639237 DOI: 10.1007/s12015-022-10391-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/13/2022] [Indexed: 02/06/2023]
Abstract
Islet transplantation is a highly effective treatment for select patients with type 1 diabetes. Unfortunately, current use is limited to those with brittle disease due to donor limitations and immunosuppression requirements. Discovery of factors for induction of pluripotent stem cells from adult somatic cells into a malleable state has reinvigorated the possibility of autologous-based regenerative cell therapies. Similarly, recent progress in allogeneic human embryonic stem cell islet products is showing early success in clinical trials. Describing safe and standardized differentiation protocols with clear pathways to optimize yield and minimize off-target growth is needed to efficiently move the field forward. This review discusses current islet differentiation protocols with a detailed break-down of differentiation stages to guide step-wise controlled generation of functional islet products.
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Affiliation(s)
- Kevin Verhoeff
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
- Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Nerea Cuesta-Gomez
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
- Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Ila Jasra
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
- Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Braulio Marfil-Garza
- National Institute of Medical Sciences and Nutrition Salvador Zubiran, Mexico City, and CHRISTUS-LatAm Hub - Excellence and Innovation Center, Monterrey, Mexico
| | - Nidheesh Dadheech
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
- Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
| | - A M James Shapiro
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
- Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
- 1-002 Li Ka Shing Centre for Health Research Innovation, 112 St. NW & 87 Ave NW, Edmonton, Alberta, T6G 2E1, Canada.
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9
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Cho YD, Kim KH, Lee YM, Ku Y, Seol YJ. Dental-derived cells for regenerative medicine: stem cells, cell reprogramming, and transdifferentiation. J Periodontal Implant Sci 2022; 52:437-454. [PMID: 36468465 PMCID: PMC9807848 DOI: 10.5051/jpis.2103760188] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 12/08/2021] [Accepted: 01/24/2022] [Indexed: 01/07/2023] Open
Abstract
Embryonic stem cells have been a popular research topic in regenerative medicine owing to their pluripotency and applicability. However, due to the difficulty in harvesting them and their low yield efficiency, advanced cell reprogramming technology has been introduced as an alternative. Dental stem cells have entered the spotlight due to their regenerative potential and their ability to be obtained from biological waste generated after dental treatment. Cell reprogramming, a process of reverting mature somatic cells into stem cells, and transdifferentiation, a direct conversion between different cell types without induction of a pluripotent state, have helped overcome the shortcomings of stem cells and raised interest in their regenerative potential. Furthermore, the potential of these cells to return to their original cell types due to their epigenetic memory has reinforced the need to control the epigenetic background for successful management of cellular differentiation. Herein, we discuss all available sources of dental stem cells, the procedures used to obtain these cells, and their ability to differentiate into the desired cells. We also introduce the concepts of cell reprogramming and transdifferentiation in terms of genetics and epigenetics, including DNA methylation, histone modification, and non-coding RNA. Finally, we discuss a novel therapeutic avenue for using dental-derived cells as stem cells, and explain cell reprogramming and transdifferentiation, which are used in regenerative medicine and tissue engineering.
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Affiliation(s)
- Young-Dan Cho
- Department of Periodontology, School of Dentistry and Dental Research Institute, Seoul National University and Seoul National University Dental Hospital, Seoul, Korea
| | - Kyoung-Hwa Kim
- Department of Periodontology, School of Dentistry and Dental Research Institute, Seoul National University and Seoul National University Dental Hospital, Seoul, Korea
| | - Yong-Moo Lee
- Department of Periodontology, School of Dentistry and Dental Research Institute, Seoul National University and Seoul National University Dental Hospital, Seoul, Korea
| | - Young Ku
- Department of Periodontology, School of Dentistry and Dental Research Institute, Seoul National University and Seoul National University Dental Hospital, Seoul, Korea
| | - Yang-Jo Seol
- Department of Periodontology, School of Dentistry and Dental Research Institute, Seoul National University and Seoul National University Dental Hospital, Seoul, Korea
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Stem Cell-Derived Islets for Type 2 Diabetes. Int J Mol Sci 2022; 23:ijms23095099. [PMID: 35563490 PMCID: PMC9105352 DOI: 10.3390/ijms23095099] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 04/23/2022] [Accepted: 04/28/2022] [Indexed: 02/04/2023] Open
Abstract
Since the discovery of insulin a century ago, insulin injection has been a primary treatment for both type 1 (T1D) and type 2 diabetes (T2D). T2D is a complicated disea se that is triggered by the dysfunction of insulin-producing β cells and insulin resistance in peripheral tissues. Insulin injection partially compensates for the role of endogenous insulin which promotes glucose uptake, lipid synthesis and organ growth. However, lacking the continuous, rapid, and accurate glucose regulation by endogenous functional β cells, the current insulin injection therapy is unable to treat the root causes of the disease. Thus, new technologies such as human pluripotent stem cell (hPSC)-derived islets are needed for both identifying the key molecular and genetic causes of T2D and for achieving a long-term treatment. This perspective review will provide insight into the efficacy of hPSC-derived human islets for treating and understanding T2D. We discuss the evidence that β cells should be the primary target for T2D treatment, the use of stem cells for the modeling of T2D and the potential use of hPSC-derived islet transplantation for treating T2D.
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Ricci S, Cacialli P. Stem Cell Research Tools in Human Metabolic Disorders: An Overview. Cells 2021; 10:cells10102681. [PMID: 34685661 PMCID: PMC8534517 DOI: 10.3390/cells10102681] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 09/23/2021] [Accepted: 10/04/2021] [Indexed: 12/20/2022] Open
Abstract
Metabolic disorders are very common in the population worldwide and are among the diseases with the highest health utilization and costs per person. Despite the ongoing efforts to develop new treatments, currently, for many of these disorders, there are no approved therapies, resulting in a huge economic hit and tension for society. In this review, we recapitulate the recent advancements in stem cell (gene) therapy as potential tools for the long-term treatment of both inherited (lysosomal storage diseases) and acquired (diabetes mellitus, obesity) metabolic disorders, focusing on the main promising results observed in human patients and discussing the critical hurdles preventing the definitive jump of this approach from the bench to the clinic.
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Affiliation(s)
- Serena Ricci
- Department of Cell Physiology and Metabolism, School of Medicine, University of Geneva, Rue Michel Servet 1, 1206 Geneva, Switzerland;
| | - Pietro Cacialli
- Department of Pathology and Immunology, School of Medicine, University of Geneva, Rue Michel Servet 1, 1206 Geneva, Switzerland
- Correspondence:
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12
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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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13
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Generation of high yield insulin-producing cells (IPCs) from various sources of stem cells. VITAMINS AND HORMONES 2021; 116:235-268. [PMID: 33752820 DOI: 10.1016/bs.vh.2021.02.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Type 1 diabetes mellitus occurs when beta cell mass is reduced to less than 20% of the normal level due to immune system destruction of beta cell resulting in an inability to secrete enough insulin. The prevalence of diabetes is expanding according to the American Diabetes Association and the World Health Organization (WHO), foretold to exceed 350 million by 2030. The current treatment does not cure many of the serious complications associated with the disease such as neuropathy, nephropathy, dyslipidemia, retinopathy and cardiovascular disease. Whole pancreas or isolated pancreatic islet transplantation as an alternative therapy can prevent or reduce some of the complications of diabetes. However, the shortage of matched organ or islets cells donor and alloimmune responses limit this therapeutic strategy. Recently, several reports have raised extremely promising results to use different sources of stem cells to differentiate insulin-producing cells and focus on the expansion of these alternative sources. Stem cells, due to their potential for multiple differentiation and self-renewal can differentiate into all cell types, including insulin-producing cells (IPCs). Generation of new beta cells can be achieved from various stem cell sources, including embryonic stem cells (ESCs), adult stem cells, such as mesenchymal stem cells (MSCs) and induced pluripotent stem cells (iPSCs). Thus, this chapter discusses on the assistance of cellular reprogramming of various stem cells as candidates for the generation of IPCs using transcription factors/miRNA, cytokines/small molecules and tissue engineering.
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14
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Marfil-Garza BA, Shapiro AMJ, Kin T. Clinical islet transplantation: Current progress and new frontiers. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2021; 28:243-254. [PMID: 33417749 DOI: 10.1002/jhbp.891] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 12/12/2020] [Accepted: 12/28/2020] [Indexed: 02/05/2023]
Abstract
Islet transplantation (IT) is now a robust treatment for selected patients with type 1 diabetes suffering from recurrent hypoglycemia and impaired awareness of hypoglycemia. A global soar of clinical islet transplant programs attests to the commitment of many institutions and researchers to advance IT as a potential cure for this devastating disease. However, many challenges limiting the widespread applicability of clinical IT remain. In this review, we will touch on the milestones in the history of IT and its path to clinical success, discuss the current challenges around IT, propose some possible solutions, and elaborate on the frontiers envisioned in the future of clinical IT.
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Affiliation(s)
| | - Andrew Mark James Shapiro
- Department of Surgery, University of Alberta, Edmonton, AB, Canada
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
| | - Tatsuya Kin
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
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15
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Tootee A, Nikbin B, Ghahary A, Esfahani EN, Arjmand B, Aghayan H, Qorbani M, Larijani B. Immunopathology of Type 1 Diabetes and Immunomodulatory Effects of Stem Cells: A Narrative Review of the Literature. Endocr Metab Immune Disord Drug Targets 2021; 22:169-197. [PMID: 33538679 DOI: 10.2174/1871530321666210203212809] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 10/11/2020] [Accepted: 10/27/2020] [Indexed: 11/22/2022]
Abstract
Type 1 Diabetes (T1D) is a complex autoimmune disorder which occurs as a result of an intricate series of pathologic interactions between pancreatic β-cells and a wide range of components of both the innate and the adaptive immune systems. Stem-cell therapy, a recently-emerged potentially therapeutic option for curative treatment of diabetes, is demonstrated to cause significant alternations to both different immune cells such as macrophages, natural killer (NK) cells, dendritic cells, T cells, and B cells and non-cellular elements including serum cytokines and different components of the complement system. Although there exists overwhelming evidence indicating that the documented therapeutic effects of stem cells on patients with T1D is primarily due to their potential for immune regulation rather than pancreatic tissue regeneration, to date, the precise underlying mechanisms remain obscure. On the other hand, immune-mediated rejection of stem cells remains one of the main obstacles to regenerative medicine. Moreover, the consequences of efferocytosis of stem-cells by the recipients' lung-resident macrophages have recently emerged as a responsible mechanism for some immune-mediated therapeutic effects of stem-cells. This review focuses on the nature of the interactions amongst different compartments of the immune systems which are involved in the pathogenesis of T1D and provides explanation as to how stem cell-based interventions can influence immune system and maintain the physiologic equilibrium.
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Affiliation(s)
- Ali Tootee
- Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, . Iran
| | - Behrouz Nikbin
- Research Center of Molecular Immunology, Tehran University of Medical Sciences, Tehran, . Iran
| | - Aziz Ghahary
- British Columbia Professional Firefighters' Burn and Wound Healing Research Laboratory, Department of Surgery, Plastic Surgery, University of British Columbia, Vancouver, . Canada
| | - Ensieh Nasli Esfahani
- Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, . Iran
| | - Babak Arjmand
- Cell therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, . Iran
| | - Hamidreza Aghayan
- Cell therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, . Iran
| | - Mostafa Qorbani
- Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, . Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, . Iran
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16
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Kh S, Haider KH. Stem Cells: A Renewable Source of Pancreatic β-Cells and Future for Diabetes Treatment. Stem Cells 2021. [DOI: 10.1007/978-3-030-77052-5_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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17
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Elnashar M, Vaccarezza M, Al-Salami H. Cutting-edge biotechnological advancement in islet delivery using pancreatic and cellular approaches. Future Sci OA 2020; 7:FSO660. [PMID: 33552541 PMCID: PMC7849926 DOI: 10.2144/fsoa-2020-0105] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
There are approximately 1 billion prediabetic people worldwide, and the global cost for diabetes mellitus (DM) is estimated to be $825 billion. In regard to Type 1 DM, transplanting a whole pancreas or its islets has gained the attention of researchers in the last few decades. Recent studies showed that islet transplantation (ILT) containing insulin-producing β cells is the most notable advancement cure for Type 1 DM. However, this procedure has been hindered by shortage and lack of sufficient islet donors and the need for long-term immunosuppression of any potential graft rejection. The strategy of encapsulation may avoid the rejection of stem-cell-derived allogeneic islets or xenogeneic islets. This review article describes various biotechnology features in encapsulation-of-islet-cell therapy for humans, including the use of bile acids.
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Affiliation(s)
- Magdy Elnashar
- Biotechnology & Drug Development Research Laboratory, School of Pharmacy & Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia.,Centre of Excellence, Department of Polymers, National Research Centre, Cairo, Egypt
| | - Mauro Vaccarezza
- School of Pharmacy & Biomedical Science, Faculty of Health Sciences, Curtin University, Bentley, Perth, WA 6102, Australia
| | - Hani Al-Salami
- Biotechnology & Drug Development Research Laboratory, School of Pharmacy & Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia, Australia
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18
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Mota C, Camarero-Espinosa S, Baker MB, Wieringa P, Moroni L. Bioprinting: From Tissue and Organ Development to in Vitro Models. Chem Rev 2020; 120:10547-10607. [PMID: 32407108 PMCID: PMC7564098 DOI: 10.1021/acs.chemrev.9b00789] [Citation(s) in RCA: 178] [Impact Index Per Article: 35.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2019] [Indexed: 02/08/2023]
Abstract
Bioprinting techniques have been flourishing in the field of biofabrication with pronounced and exponential developments in the past years. Novel biomaterial inks used for the formation of bioinks have been developed, allowing the manufacturing of in vitro models and implants tested preclinically with a certain degree of success. Furthermore, incredible advances in cell biology, namely, in pluripotent stem cells, have also contributed to the latest milestones where more relevant tissues or organ-like constructs with a certain degree of functionality can already be obtained. These incredible strides have been possible with a multitude of multidisciplinary teams around the world, working to make bioprinted tissues and organs more relevant and functional. Yet, there is still a long way to go until these biofabricated constructs will be able to reach the clinics. In this review, we summarize the main bioprinting activities linking them to tissue and organ development and physiology. Most bioprinting approaches focus on mimicking fully matured tissues. Future bioprinting strategies might pursue earlier developmental stages of tissues and organs. The continuous convergence of the experts in the fields of material sciences, cell biology, engineering, and many other disciplines will gradually allow us to overcome the barriers identified on the demanding path toward manufacturing and adoption of tissue and organ replacements.
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Affiliation(s)
- Carlos Mota
- Department of Complex Tissue Regeneration,
MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, 6211 LK Maastricht, The Netherlands
| | - Sandra Camarero-Espinosa
- Department of Complex Tissue Regeneration,
MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, 6211 LK Maastricht, The Netherlands
| | - Matthew B. Baker
- Department of Complex Tissue Regeneration,
MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, 6211 LK Maastricht, The Netherlands
| | - Paul Wieringa
- Department of Complex Tissue Regeneration,
MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, 6211 LK Maastricht, The Netherlands
| | - Lorenzo Moroni
- Department of Complex Tissue Regeneration,
MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, 6211 LK Maastricht, The Netherlands
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19
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Kumar V, Sachan R, Rahman M, Sharma K, Al-Abbasi FA, Anwar F. Prunus amygdalus extract exert antidiabetic effect via inhibition of DPP-IV: in-silico and in-vivo approaches. J Biomol Struct Dyn 2020; 39:4160-4174. [PMID: 32602806 DOI: 10.1080/07391102.2020.1775124] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Prunus amygdalus (PA) is a popular invasive seed utilized in the management of diabetes in Jammu and Kashmir, India. The objective of the current study was to scrutinize the antidiabetic effect of Prunus amygdalus (PA) against Streptozotocin (STZ) induced diabetic rats and explore the possible mechanism of action at cellular and sub-cellular levels. Box Benkan Design (BBD) was performed to determine the effect of PA powder to methanol, extraction time and extraction temperature on DPPH and ABTS free radical scavenging activity of decoction. In-silico study was performed on GLUT1 (5EQG) and dipeptidyl peptidase IV (DPPIV) (2G63) protein. Type II diabetes mellitus was initiated by single intra-peritoneal injection of STZ. The Blood Glucose Level (BGL) and body weight were estimated at regular interval of time. The different biochemical parameters such as hepatic, antioxidant, and lipid parameters were estimated. At end of the study, pancreas was used for histopathological observation. The variation in DPPH antiradical scavenging activity 40.0-90.0% and ABTS antiradical scavenging activity 34-82%, were estimated respectively. STZ induced DM rats showed increased BGL at end of the experimental study. PA treatment significantly (p < 0.001) down-regulated the BGL level. PA significantly (p < 0.001) altered the biochemical, hepatic and antioxidant parameters in a dose-dependent manner. Histopathological examination demonstrated the constructive mass of β-cells in pancreas. Overall, the current study indicates that the PA treatment down-regulated the hyperglycemic, oxidative stress and hyperlipidaemia in diabetic rats, due to inhibition of enzymes or amelioration of oxidative stress. [Formula: see text] Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Vikas Kumar
- Natural Product Drug Discovery Laboratory, Department of Pharmaceutical Sciences, Faculty of Health Sciences, Sam Higginbottom Institute of Agriculture, Technology & Sciences, Allahabad, Uttar Pradesh, India
| | - Richa Sachan
- School of Pharmacy, Sungkyunkwan University, Seobu-ro, Jangan-gu, Suwon, Korea
| | - Mahfoozur Rahman
- Faculty of Health Sciences, Department of Pharmaceutical Sciences, Sam Higginbottom Institute of Agriculture, Technology & Sciences, Allahabad, Uttar Pradesh, India
| | - Kalicharan Sharma
- Faculty of Pharmacy, Department of Pharmaceutical Chemistry, SPER, Jamia Hamdard, New Delhi, India
| | - Fahad A Al-Abbasi
- Faculty of Science, Department of Biochemistry, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Firoz Anwar
- Faculty of Science, Department of Biochemistry, King Abdulaziz University, Jeddah, Saudi Arabia
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20
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Vishwakarma SK, Jaiswal J, Park K, Lakkireddy C, Raju N, Bardia A, Habeeb MA, Paspala SAB, Khan AA, Dhayal M. TiO
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Nanoflowers on Conducting Substrates Ameliorate Effective Transdifferentiation of Human Hepatic Progenitor Cells for Long‐Term Hyperglycemia Reversal in Diabetic Mice. ADVANCED THERAPEUTICS 2020. [DOI: 10.1002/adtp.201900205] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Sandeep Kumar Vishwakarma
- Clinical Research FacilityCSIR‐Centre for Cellular and Molecular Biology Hyderabad Telangana 500007 India
- Central Laboratory for Stem Cell Research and Translational MedicineCentre for Liver Research and Diagnostics, Deccan College of Medical Sciences Kanchanbagh Hyderabad Telangana 500058 India
- Dr. Habeebullah Life Sciences Limited Attapur Hyderabad Telangana 500048 India
| | - Juhi Jaiswal
- Nano‐Cellular Medicine and Biophysics Laboratory, School of Biomedical EngineeringIndian Institute of Technology (Banaras Hindu University) Varanasi Uttar Pradesh 221005 India
| | - Kyung‐Hee Park
- Department of Dental Materials and Hard‐tissue Biointerface Research Center, School of DentistryChonnam National University Gwangju 61186 Republic of Korea
| | - Chandrakala Lakkireddy
- Central Laboratory for Stem Cell Research and Translational MedicineCentre for Liver Research and Diagnostics, Deccan College of Medical Sciences Kanchanbagh Hyderabad Telangana 500058 India
| | - Nagarapu Raju
- Central Laboratory for Stem Cell Research and Translational MedicineCentre for Liver Research and Diagnostics, Deccan College of Medical Sciences Kanchanbagh Hyderabad Telangana 500058 India
- Dr. Habeebullah Life Sciences Limited Attapur Hyderabad Telangana 500048 India
| | - Avinash Bardia
- Central Laboratory for Stem Cell Research and Translational MedicineCentre for Liver Research and Diagnostics, Deccan College of Medical Sciences Kanchanbagh Hyderabad Telangana 500058 India
- Dr. Habeebullah Life Sciences Limited Attapur Hyderabad Telangana 500048 India
| | - Md. Aejaz Habeeb
- Central Laboratory for Stem Cell Research and Translational MedicineCentre for Liver Research and Diagnostics, Deccan College of Medical Sciences Kanchanbagh Hyderabad Telangana 500058 India
- Dr. Habeebullah Life Sciences Limited Attapur Hyderabad Telangana 500048 India
| | - Syed Ameer Basha Paspala
- Central Laboratory for Stem Cell Research and Translational MedicineCentre for Liver Research and Diagnostics, Deccan College of Medical Sciences Kanchanbagh Hyderabad Telangana 500058 India
- Dr. Habeebullah Life Sciences Limited Attapur Hyderabad Telangana 500048 India
| | - Aleem Ahmed Khan
- Central Laboratory for Stem Cell Research and Translational MedicineCentre for Liver Research and Diagnostics, Deccan College of Medical Sciences Kanchanbagh Hyderabad Telangana 500058 India
- Dr. Habeebullah Life Sciences Limited Attapur Hyderabad Telangana 500048 India
| | - Marshal Dhayal
- Clinical Research FacilityCSIR‐Centre for Cellular and Molecular Biology Hyderabad Telangana 500007 India
- Nano‐Cellular Medicine and Biophysics Laboratory, School of Biomedical EngineeringIndian Institute of Technology (Banaras Hindu University) Varanasi Uttar Pradesh 221005 India
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21
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Cari L, Montanucci P, Basta G, Petrillo MG, Ricci E, Pescara T, Greco A, Cipriani S, Shimizu J, Migliorati G, Nocentini G, Calafiore R, Riccardi C. Microencapsulated G3C Hybridoma Cell Graft Delays the Onset of Spontaneous Diabetes in NOD Mice by an Expansion of Gitr + Treg Cells. Diabetes 2020; 69:965-980. [PMID: 32169893 DOI: 10.2337/db19-0087] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 02/25/2020] [Indexed: 11/13/2022]
Abstract
As an alternative to lifelong insulin supplementation, potentiation of immune tolerance in patients with type 1 diabetes could prevent the autoimmune destruction of pancreatic islet β-cells. This study was aimed to assess whether the G3c monoclonal antibody (mAb), which triggers the glucocorticoid-induced TNFR-related (Gitr) costimulatory receptor, promotes the expansion of regulatory T cells (Tregs) in SV129 (wild-type) and diabetic-prone NOD mice. The delivery of the G3c mAb via G3C hybridoma cells enveloped in alginate-based microcapsules (G3C/cps) for 3 weeks induced Foxp3+ Treg-cell expansion in the spleen of wild-type mice but not in Gitr-/- mice. G3C/cps also induced the expansion of nonconventional Cd4+Cd25-/lowFoxp3lowGitrint/high (GITR single-positive [sp]) Tregs. Both Cd4+Cd25+GitrhighFoxp3+ and GITRsp Tregs (including also antigen-specific cells) were expanded in the spleen and pancreas of G3C/cps-treated NOD mice, and the number of intact islets was higher in G3C/cps-treated than in empty cps-treated and untreated animals. Consequently, all but two G3C/cps-treated mice did not develop diabetes and all but one survived until the end of the 24-week study. In conclusion, long-term Gitr triggering induces Treg expansion, thereby delaying/preventing diabetes development in NOD mice. This therapeutic approach may have promising clinical potential for the treatment of inflammatory and autoimmune diseases.
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Affiliation(s)
- Luigi Cari
- Section of Pharmacology, Department of Medicine, University of Perugia, Perugia, Italy
| | - Pia Montanucci
- Section of Internal Medicine and Endocrine and Metabolic Sciences, Department of Medicine, and Laboratory for Endocrine Cell Transplants and Biohybrid Organs, University of Perugia, Perugia, Italy
| | - Giuseppe Basta
- Section of Internal Medicine and Endocrine and Metabolic Sciences, Department of Medicine, and Laboratory for Endocrine Cell Transplants and Biohybrid Organs, University of Perugia, Perugia, Italy
| | - Maria G Petrillo
- Section of Pharmacology, Department of Medicine, University of Perugia, Perugia, Italy
| | - Erika Ricci
- Section of Pharmacology, Department of Medicine, University of Perugia, Perugia, Italy
| | - Teresa Pescara
- Section of Internal Medicine and Endocrine and Metabolic Sciences, Department of Medicine, and Laboratory for Endocrine Cell Transplants and Biohybrid Organs, University of Perugia, Perugia, Italy
| | - Alessia Greco
- Section of Internal Medicine and Endocrine and Metabolic Sciences, Department of Medicine, and Laboratory for Endocrine Cell Transplants and Biohybrid Organs, University of Perugia, Perugia, Italy
| | - Sabrina Cipriani
- Rheumatology Unit, Department of Medicine, School of Medicine, University of Perugia, Perugia, Italy
| | - Jun Shimizu
- Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Graziella Migliorati
- Section of Pharmacology, Department of Medicine, University of Perugia, Perugia, Italy
| | - Giuseppe Nocentini
- Section of Pharmacology, Department of Medicine, University of Perugia, Perugia, Italy
| | - Riccardo Calafiore
- Section of Internal Medicine and Endocrine and Metabolic Sciences, Department of Medicine, and Laboratory for Endocrine Cell Transplants and Biohybrid Organs, University of Perugia, Perugia, Italy
| | - Carlo Riccardi
- Section of Pharmacology, Department of Medicine, University of Perugia, Perugia, Italy
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22
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Lu Z, Li Y, Syn WK, Wang Z, Lopes-Virella MF, Lyons TJ, Huang Y. Amitriptyline inhibits nonalcoholic steatohepatitis and atherosclerosis induced by high-fat diet and LPS through modulation of sphingolipid metabolism. Am J Physiol Endocrinol Metab 2020; 318:E131-E144. [PMID: 31821039 PMCID: PMC7052581 DOI: 10.1152/ajpendo.00181.2019] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
We reported previously that increased acid sphingomyelinase (ASMase)-catalyzed hydrolysis of sphingomyelin, which leads to increases in ceramide and sphingosine 1 phosphate (S1P), played a key role in the synergistic upregulation of proinflammatory cytokines by palmitic acid (PA), a major saturated fatty acid, and lipopolysaccharide (LPS) in macrophages. Since macrophages are vital players in nonalcoholic steatohepatitis (NASH) and atherosclerosis, we assessed the effect of ASMase inhibition on NASH and atherosclerosis cooperatively induced by high-PA-containing high-fat diet (HP-HFD) and LPS in LDL receptor-deficient (LDLR-/-) mice. LDLR-/- mice were fed HP-HFD, injected with low dose of LPS and treated with or without the ASMase inhibitor amitriptyline. The neutral sphingomyelinase inhibitor GW4869 was used as control. Metabolic study showed that both amitriptyline and GW4869 reduced glucose, lipids, and insulin resistance. Histological analysis and Oil Red O staining showed that amitriptyline robustly reduced hepatic steatosis while GW4869 had modest effects. Interestingly, immunohistochemical study showed that amitriptyline, but not GW4869, strongly reduced hepatic inflammation. Furthermore, results showed that both amitriptyline and GW4869 attenuated atherosclerosis. To elucidate the underlying mechanisms whereby amitriptyline inhibited both NASH and atherosclerosis, but GW4869 only inhibited atherosclerosis, we found that amitriptyline, but not GW4869, downregulated proinflammatory cytokines in macrophages. Finally, we found that inhibition of sphingosine 1 phosphate production is a potential mechanism whereby amitriptyline inhibited proinflammatory cytokines. Collectively, this study showed that amitriptyline inhibited NASH and atherosclerosis through modulation of sphingolipid metabolism in LDLR-/- mice, indicating that sphingolipid metabolism in macrophages plays a crucial role in the linkage of NASH and atherosclerosis.
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Affiliation(s)
- Zhongyang Lu
- Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina
| | - Yanchun Li
- Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
| | - Wing-Kin Syn
- Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina
- Division of Gastroenterology and Hepatology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
- Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country, Euskal Herriko Unibertsitatea/Universidad del País Vasco, Leioa, Spain
| | - Zhewu Wang
- Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina
- Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, South Carolina
| | - Maria F Lopes-Virella
- Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina
- Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
| | - Timothy J Lyons
- Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
| | - Yan Huang
- Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina
- Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
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23
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Hoveizi E, Tavakol S, Shirian S, Sanamiri K. Electrospun Nanofibers for Diabetes: Tissue Engineering and Cell-Based Therapies. Curr Stem Cell Res Ther 2019; 14:152-168. [PMID: 30338744 DOI: 10.2174/1574888x13666181018150107] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Revised: 03/11/2018] [Accepted: 09/05/2018] [Indexed: 02/08/2023]
Abstract
Diabetes mellitus is an autoimmune disease which causes loss of insulin secretion producing hyperglycemia by promoting progressive destruction of pancreatic β cells. An ideal therapeutic approach to manage diabetes mellitus is pancreatic β cells replacement. The aim of this review article was to evaluate the role of nanofibrous scaffolds and stem cells in the treatment of diabetes mellitus. Various studies have pointed out that application of electrospun biomaterials has considerably attracted researchers in the field of tissue engineering. The principles of cell therapy for diabetes have been reviewed in the first part of this article, while the usability of tissue engineering as a new therapeutic approach is discussed in the second part.
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Affiliation(s)
- Elham Hoveizi
- Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran.,Stem Cells and Transgenic Technology Research Center (STTRC), Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Shima Tavakol
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Sadegh Shirian
- Department of Pathology, School of Veterinary Medicine, Shahrekord University, Shahrekord, Iran.,Shiraz Molecular Research Center, Dr. Daneshbod Pathology Lab, Shiraz, Iran
| | - Khadije Sanamiri
- Department of Animal Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
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24
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Huang Y, Xu Y, Lu Y, Zhu S, Guo Y, Sun C, Xu L, Chen X, Zhao Y, Yu B, Yang Y, Wang Z. lncRNA Gm10451 regulates PTIP to facilitate iPSCs-derived β-like cell differentiation by targeting miR-338-3p as a ceRNA. Biomaterials 2019; 216:119266. [PMID: 31220795 DOI: 10.1016/j.biomaterials.2019.119266] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 06/03/2019] [Accepted: 06/08/2019] [Indexed: 02/08/2023]
Abstract
iPSCs-derived insulin-producing cell transplantation is a promising strategy for diabetes therapy. Although there have been many protocols of mature, glucose-responsive β cells induced in vitro over the past few years, many underlying problems remain to be resolved. As a crucial regulator, long noncoding RNAs (lncRNAs) participate in numerous biological processes, including the maintenance of pluripotency, and stem cell differentiation. In this study, we identified a novel lncRNA Gm10451 as a functional regulator for β-like cell differentiation. Localized to the cytoplasm, Gm10451 regulates histone H3K4 methyltransferase complex PTIP to facilitate Insulin+/Nkx6.1+ β-like cell differentiation by targeting miR-338-3p as a competing endogenous RNA (ceRNA). miR-338-3p has also been shown to suppress Nkx6.1+ early-stage β-like cell differentiation by targeting PTIP. Following transplantation into streptozotocin (STZ)-mice, Gm10451 loss in β-like cells prevented the expression of mature β-cell makers, such as Insulin, Nkx6.1, and Mafa. Accordingly, hyperglycemia in the mice was not resolved. Taken together, this study provides an efficient epigenetic target for generating more mature and functional iPSCs-derived β-like cells. We anticipate that pancreatic organoids, which are generated from human stem cells, biological materials, and epigenetic modifications, can be used in the future as a novel diabetes treatment option.
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Affiliation(s)
- Yan Huang
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University, Nantong, 226001, China; Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, 226001, China
| | - Yang Xu
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, 226001, China
| | - Yuhua Lu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University, Nantong, 226001, China; Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, 226001, China.
| | - Shajun Zhu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University, Nantong, 226001, China
| | - Yibing Guo
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, 226001, China
| | - Cheng Sun
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China
| | - Lianchen Xu
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, 226001, China
| | - Xiaolan Chen
- Department of Nephrology, Affiliated Hospital of Nantong University, Nantong, 226001, China
| | - Yahong Zhao
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China
| | - Bin Yu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China; Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Affiliated Hospital of Nantong University, Nantong 226001, China
| | - Yumin Yang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China.
| | - Zhiwei Wang
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Nantong University, Nantong, 226001, 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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Kumar SA, Delgado M, Mendez VE, Joddar B. Applications of stem cells and bioprinting for potential treatment of diabetes. World J Stem Cells 2019; 11:13-32. [PMID: 30705712 PMCID: PMC6354103 DOI: 10.4252/wjsc.v11.i1.13] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 12/26/2018] [Accepted: 01/05/2019] [Indexed: 02/06/2023] Open
Abstract
Currently, there does not exist a strategy that can reduce diabetes and scientists are working towards a cure and innovative approaches by employing stem cell-based therapies. On the other hand, bioprinting technology is a novel therapeutic approach that aims to replace the diseased or lost β-cells, insulin-secreting cells in the pancreas, which can potentially regenerate damaged organs such as the pancreas. Stem cells have the ability to differentiate into various cell lines including insulin-producing cells. However, there are still barriers that hamper the successful differentiation of stem cells into β-cells. In this review, we focus on the potential applications of stem cell research and bioprinting that may be targeted towards replacing the β-cells in the pancreas and may offer approaches towards treatment of diabetes. This review emphasizes on the applicability of employing both stem cells and other cells in 3D bioprinting to generate substitutes for diseased β-cells and recover lost pancreatic functions. The article then proceeds to discuss the overall research done in the field of stem cell-based bioprinting and provides future directions for improving the same for potential applications in diabetic research.
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Affiliation(s)
- Shweta Anil Kumar
- Inspired Materials and Stem-Cell Based Tissue Engineering Laboratory, Department of Metallurgical, Materials and Biomedical Engineering, University of Texas at El Paso, 500 W University Avenue, El Paso, TX 79968, United States
| | - Monica Delgado
- Inspired Materials and Stem-Cell Based Tissue Engineering Laboratory, Department of Metallurgical, Materials and Biomedical Engineering, University of Texas at El Paso, 500 W University Avenue, El Paso, TX 79968, United States
| | - Victor E Mendez
- Inspired Materials and Stem-Cell Based Tissue Engineering Laboratory, Department of Metallurgical, Materials and Biomedical Engineering, University of Texas at El Paso, 500 W University Avenue, El Paso, TX 79968, United States
| | - Binata Joddar
- Inspired Materials and Stem-Cell Based Tissue Engineering Laboratory, Department of Metallurgical, Materials and Biomedical Engineering, University of Texas at El Paso, 500 W University Avenue, El Paso, TX 79968, United States
- Border Biomedical Research Center, University of Texas at El Paso, 500 W University Avenue, El Paso, TX 79968, United States.
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27
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Abstract
PURPOSE OF REVIEW Engineering endocrine pancreatic tissue is an emerging topic in type 1 diabetes with the intent to overcome the current limitation of β cell transplantation. During islet isolation, the vascularized structure and surrounding extracellular matrix (ECM) are completely disrupted. Once implanted, islets slowly engraft and mostly are lost for the initial avascular phase. This review discusses the main building blocks required to engineer the endocrine pancreas: (i) islet niche ECM, (ii) islet niche vascular network, and (iii) new available sources of endocrine cells. RECENT FINDINGS Current approaches include the following: tissue engineering of endocrine grafts by seeding of native or synthetic ECM scaffolds with human islets, vascularization of native or synthetic ECM prior to implantation, vascular functionalization of ECM structures to enhance angiogenesis after implantation, generation of engineered animals as human organ donors, and embryonic and pluripotent stem cell-derived endocrine cells that may be encapsulated or genetically engineered to be immunotolerated. Substantial technological improvements have been made to regenerate or engineer endocrine pancreatic tissue; however, significant hurdles remain, and more research is needed to develop a technology to integrate all components of viable endocrine tissue for clinical application.
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Affiliation(s)
- Antonio Citro
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy
| | - Harald C Ott
- Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, CPZN 4700, Boston, MA, 02114, USA.
- Harvard Medical School, Boston, MA, USA.
- Division of Thoracic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA.
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28
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Pesaresi M, Sebastian-Perez R, Cosma MP. Dedifferentiation, transdifferentiation and cell fusion: in vivo reprogramming strategies for regenerative medicine. FEBS J 2018; 286:1074-1093. [PMID: 30103260 DOI: 10.1111/febs.14633] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Revised: 07/01/2018] [Accepted: 08/10/2018] [Indexed: 12/23/2022]
Abstract
Regenerative capacities vary enormously across the animal kingdom. In contrast to most cold-blooded vertebrates, mammals, including humans, have very limited regenerative capacity when it comes to repairing damaged or degenerating tissues. Here, we review the main mechanisms of tissue regeneration, underlying the importance of cell dedifferentiation and reprogramming. We discuss the significance of cell fate and identity changes in the context of regenerative medicine, with a particular focus on strategies aiming at the promotion of the body's self-repairing mechanisms. We also introduce some of the most recent advances that have resulted in complete reprogramming of cell identity in vivo. Lastly, we discuss the main challenges that need to be addressed in the near future to develop in vivo reprogramming approaches with therapeutic potential.
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Affiliation(s)
- Martina Pesaresi
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Spain
| | - Ruben Sebastian-Perez
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Spain
| | - Maria Pia Cosma
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Spain.,Universitat Pompeu Fabra (UPF), Barcelona, Spain.,Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
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29
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Duffy C, Prugue C, Glew R, Smith T, Howell C, Choi G, Cook AD. Feasibility of Induced Pluripotent Stem Cell Therapies for Treatment of Type 1 Diabetes. TISSUE ENGINEERING PART B-REVIEWS 2018; 24:482-492. [PMID: 29947303 DOI: 10.1089/ten.teb.2018.0124] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
IMPACT STATEMENT This review of iPSCs to treat T1D provides a current assessment of the challenges and potential for this proposed new therapy.
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Affiliation(s)
- Caden Duffy
- Department of Chemical Engineering, Brigham Young University , Provo, Utah
| | - Cesar Prugue
- Department of Chemical Engineering, Brigham Young University , Provo, Utah
| | - Rachel Glew
- Department of Chemical Engineering, Brigham Young University , Provo, Utah
| | - Taryn Smith
- Department of Chemical Engineering, Brigham Young University , Provo, Utah
| | - Calvin Howell
- Department of Chemical Engineering, Brigham Young University , Provo, Utah
| | - Gina Choi
- Department of Chemical Engineering, Brigham Young University , Provo, Utah
| | - Alonzo D Cook
- Department of Chemical Engineering, Brigham Young University , Provo, Utah
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30
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Huang Y, Wan J, Guo Y, Zhu S, Wang Y, Wang L, Guo Q, Lu Y, Wang Z. Transcriptome Analysis of Induced Pluripotent Stem Cell (iPSC)-derived Pancreatic β-like Cell Differentiation. Cell Transplant 2018; 26:1380-1391. [PMID: 28901190 PMCID: PMC5680972 DOI: 10.1177/0963689717720281] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Diabetes affects millions of people worldwide, and β-cell replacement is one of the promising new strategies for treatment. Induced pluripotent stem cells (iPSCs) can differentiate into any cell type, including pancreatic β cells, providing a potential treatment for diabetes. However, the molecular mechanisms underlying the differentiation of iPSC-derived β cells have not yet been fully elucidated. Here, we generated pancreatic β-like cells from mouse iPSCs using a 3-step protocol and performed deep RNA sequencing to get a transcriptional landscape of iPSC-derived pancreatic β-like cells during the selective differentiation period. We then focused on the differentially expressed genes (DEGs) during the time course of the differentiation period, and these genes underwent Gene Ontology annotation and Kyoto Encyclopedia of Genes and Genomes pathway analysis. In addition, gene-act networks were constructed for these DEGs, and the expression of pivotal genes detected by quantitative real-time polymerase chain reaction was well correlated with RNA sequence (RNA-seq). Overall, our study provides valuable information regarding the transcriptome changes in β cells derived from iPSCs during differentiation, elucidates the biological process and pathways underlying β-cell differentiation, and promotes the identification and functional analysis of potential genes that could be used for improving functional β-cell generation from iPSCs.
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Affiliation(s)
- Yan Huang
- 1 Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China
| | - Jian Wan
- 1 Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China
| | - Yibing Guo
- 2 Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China
| | - Shajun Zhu
- 1 Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China
| | - Yao Wang
- 1 Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China
| | - Lei Wang
- 1 Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China
| | - Qingsong Guo
- 1 Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China
| | - Yuhua Lu
- 1 Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China
| | - Zhiwei Wang
- 1 Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China
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31
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Zhu H, Zhang X, He Y, Yu L, Lü Y, Pan K, Wang B, Chen G. [Research progress on the donor cell sources of pancreatic islet transplantation for treatment of diabetes mellitus]. ZHONGGUO XIU FU CHONG JIAN WAI KE ZA ZHI = ZHONGGUO XIUFU CHONGJIAN WAIKE ZAZHI = CHINESE JOURNAL OF REPARATIVE AND RECONSTRUCTIVE SURGERY 2018; 32:104-111. [PMID: 29806374 PMCID: PMC8414200 DOI: 10.7507/1002-1892.201707049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Revised: 12/13/2017] [Indexed: 11/03/2022]
Abstract
Objective To summarize the research progress on the source and selection of donor cells in the field of islet replacement therapy for diabetes mellitus. Methods Domestic and abroad literature concerning islet replacement therapy for diabetes mellitus, as well as donor source and donor selection was reviewed and analyzed thoroughly. Results The shortage of donor supply is still a major obstacle for the widely clinical application of pancreatic islet transplantation (PIT). Currently, in addition to the progress on the allogeneic/autologous donor islet supply, some remarkable achievements have been also attained in the application of xenogeneic islet (from pig donor), as well as islet like cells derived from stem cells and islet cell line, potentially enlarging the source of implantable cells. Conclusion Adequate and suitable donor cell supply is an essential prerequisite for widely clinical application of PIT therapy for type 1 diabetes mellitus (T1DM). Further perfection of organ donation system, together with development of immune-tolerance induction, gene and bioengineering technology etc. will possibly solve the problem of donor cell shortage and provide a basis for clinical application of cellular replacement therapy for T1DM.
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Affiliation(s)
- Haitao Zhu
- Department of Pediatrics (No. 3 Ward), Northwest Women's and Children's Hospital, Xi'an Shaanxi, 710061, P.R.China;Department of Hepatobiliary Surgery, the First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an Shaanxi, 710061, P.R.China
| | - Xiaoge Zhang
- Department of Pediatrics (No. 3 Ward), Northwest Women's and Children's Hospital, Xi'an Shaanxi, 710061, P.R.China
| | - Yayi He
- Department of Endocrinology, the First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an Shaanxi, 710061, P.R.China
| | - Liang Yu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an Shaanxi, 710061, P.R.China
| | - Yi Lü
- Department of Hepatobiliary Surgery, the First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an Shaanxi, 710061, P.R.China;Research Institute of Advanced Surgical Technology and Engineering, Xi'an Jiaotong University, Xi'an Shaanxi, 710061, P.R.China
| | - Kaili Pan
- Department of Pediatrics (No. 2 Ward), Northwest Women's and Children's Hospital, Xi'an Shaanxi, 710061, P.R.China
| | - Bo Wang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an Shaanxi, 710061, P.R.China;Department of Endocrinology, the First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an Shaanxi, 710061,
| | - Guoqiang Chen
- Department of Pediatrics (No. 3 Ward), Northwest Women's and Children's Hospital, Xi'an Shaanxi, 710061,
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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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Peng BY, Dubey NK, Mishra VK, Tsai FC, Dubey R, Deng WP, Wei HJ. Addressing Stem Cell Therapeutic Approaches in Pathobiology of Diabetes and Its Complications. J Diabetes Res 2018; 2018:7806435. [PMID: 30046616 PMCID: PMC6036791 DOI: 10.1155/2018/7806435] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2018] [Revised: 04/19/2018] [Accepted: 05/27/2018] [Indexed: 12/14/2022] Open
Abstract
High morbidity and mortality of diabetes mellitus (DM) throughout the human population is a serious threat which needs to be addressed cautiously. Type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) are most prevalent forms. Disruption in insulin regulation and resistance leads to increased formation and accumulation of advanced end products (AGEs), which further enhance oxidative and nitrosative stress leading to microvascular (retinopathy, neuropathy, and nephropathy) and macrovascular complications. These complications affect the normal function of organ and tissues and may cause life-threatening disorders, if hyperglycemia persists and improperly controlled. Current and traditional treatment procedures are only focused on to regulate the insulin level and do not cure the diabetic complications. Pancreatic transplantation seemed a viable alternative; however, it is limited due to lack of donors. Cell-based therapy such as stem cells is considered as a promising therapeutic agent against DM and diabetic complications owing to their multilineage differentiation and regeneration potential. Previous studies have demonstrated the various impacts of both pluripotent and multipotent stem cells on DM and its micro- and macrovascular complications. Therefore, this review summarizes the potential of stem cells to treat DM and its related complications.
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Affiliation(s)
- Bou-Yue Peng
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei City 110, Taiwan
- Department of Dentistry, Taipei Medical University Hospital, Taipei City 110, Taiwan
| | - Navneet Kumar Dubey
- Ceramics and Biomaterials Research Group, Advanced Institute of Materials Science, Ton Duc Thang University, Ho Chi Minh City, Vietnam
- Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, Vietnam
| | - Viraj Krishna Mishra
- Applied Biotech Engineering Centre (ABEC), Department of Biotechnology, Ambala College of Engineering and Applied Research, Ambala, India
| | - Feng-Chou Tsai
- Department of Stem Cell Research, Cosmetic Clinic Group, Taipei City 110, Taiwan
| | - Rajni Dubey
- Graduate Institute of Food Science and Technology, National Taiwan University, Taipei City 106, Taiwan
| | - Win-Ping Deng
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei City 110, Taiwan
- Stem Cell Research Center, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
- Graduate Institute of Basic Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan
| | - Hong-Jian Wei
- Stem Cell Research Center, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
- School of Dental Technology, College of Oral Medicine, Taipei Medical University, Taipei City 110, Taiwan
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34
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Kuo YC, Rajesh R. Guided differentiation and tissue regeneration of induced pluripotent stem cells using biomaterials. J Taiwan Inst Chem Eng 2017. [DOI: 10.1016/j.jtice.2017.04.043] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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35
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Al-Khawaga S, Memon B, Butler AE, Taheri S, Abou-Samra AB, Abdelalim EM. Pathways governing development of stem cell-derived pancreatic β cells: lessons from embryogenesis. Biol Rev Camb Philos Soc 2017. [DOI: 10.1111/brv.12349] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Sara Al-Khawaga
- Diabetes Research Center, Qatar Biomedical Research Institute; Hamad Bin Khalifa University, Qatar Foundation, Education City; Doha Qatar
| | - Bushra Memon
- Diabetes Research Center, Qatar Biomedical Research Institute; Hamad Bin Khalifa University, Qatar Foundation, Education City; Doha Qatar
| | - Alexandra E. Butler
- Larry L. Hillblom Islet Research Center, David Geffen School of Medicine; University of California; Los Angeles CA 90095 U.S.A
| | - Shahrad Taheri
- Department of Medicine; Weill Cornell Medicine in Qatar, Qatar Foundation, Education City, PO BOX 24144; Doha Qatar
- Department of Medicine; Qatar Metabolic Institute, Hamad Medical Corporation; Doha Qatar
| | - Abdul B. Abou-Samra
- Department of Medicine; Weill Cornell Medicine in Qatar, Qatar Foundation, Education City, PO BOX 24144; Doha Qatar
- Department of Medicine; Qatar Metabolic Institute, Hamad Medical Corporation; Doha Qatar
| | - Essam M. Abdelalim
- Diabetes Research Center, Qatar Biomedical Research Institute; Hamad Bin Khalifa University, Qatar Foundation, Education City; Doha Qatar
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36
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Rawat N, Singh MK. Induced pluripotent stem cell: A headway in reprogramming with promising approach in regenerative biology. Vet World 2017; 10:640-649. [PMID: 28717316 PMCID: PMC5499081 DOI: 10.14202/vetworld.2017.640-649] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2017] [Accepted: 04/26/2017] [Indexed: 12/17/2022] Open
Abstract
Since the embryonic stem cells have knocked the doorsteps, they have proved themselves in the field of science, research, and medicines, but the hovered restrictions confine their application in human welfare. Alternate approaches used to reprogram the cells to the pluripotent state were not up to par, but the innovation of induced pluripotent stem cells (iPSCs) paved a new hope for the researchers. Soon after the discovery, iPSCs technology is undergoing renaissance day by day, i.e., from the use of genetic material to recombinant proteins and now only chemicals are employed to convert somatic cells to iPSCs. Thus, this technique is moving straightforward and productive at an astonishing pace. Here, we provide a brief introduction to iPSCs, the mechanism and methods for their generation, their prevailing and prospective applications and the future opportunities that can be expected from them.
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Affiliation(s)
- N Rawat
- Embryo Biotechnology Lab, Animal Biotechnology Centre, ICAR - National Dairy Research Institute, Karnal - 132 001, Haryana, India
| | - M K Singh
- Embryo Biotechnology Lab, Animal Biotechnology Centre, ICAR - National Dairy Research Institute, Karnal - 132 001, Haryana, India
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37
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Culture of iPSCs Derived Pancreatic β-Like Cells In Vitro Using Decellularized Pancreatic Scaffolds: A Preliminary Trial. BIOMED RESEARCH INTERNATIONAL 2017; 2017:4276928. [PMID: 28480220 PMCID: PMC5396430 DOI: 10.1155/2017/4276928] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Revised: 12/30/2016] [Accepted: 01/19/2017] [Indexed: 12/11/2022]
Abstract
Diabetes mellitus is a disease which has affected 415 million patients in 2015. In an effort to replace the significant demands on transplantation and morbidity associated with transplantation, the production of β-like cells differentiated from induced pluripotent stem cells (iPSCs) was evaluated. This approach is associated with promising decellularized scaffolds with natural extracellular matrix (ECM) and ideal cubic environment that will promote cell growth in vivo. Our efforts focused on combining decellularized rat pancreatic scaffolds with mouse GFP+-iPSCs-derived pancreatic β-like cells, to evaluate whether decellularized scaffolds could facilitate the growth and function of β-like cells. β-like cells were differentiated from GFP+-iPSCs and evaluated via cultivating in the dynamic circulation perfusion device. Our results demonstrated that decellularized pancreatic scaffolds display favorable biochemical properties. Furthermore, not only could the scaffolds support the survival of β-like cells, but they also accelerated the expression of the insulin as compared to plate-based cell culture. In conclusion, these results suggest that decellularized pancreatic scaffolds could provide a suitable platform for cellular activities of β-like cells including survival and insulin secretion. This study provides preliminary support for regenerating insulin-secreting organs from the decellularized scaffolds combined with iPSCs derived β-like cells as a potential clinical application.
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Sebastiani G, Valentini M, Grieco GE, Ventriglia G, Nigi L, Mancarella F, Pellegrini S, Martino G, Sordi V, Piemonti L, Dotta F. MicroRNA expression profiles of human iPSCs differentiation into insulin-producing cells. Acta Diabetol 2017; 54:265-281. [PMID: 28039581 DOI: 10.1007/s00592-016-0955-9] [Citation(s) in RCA: 30] [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: 09/22/2016] [Accepted: 12/15/2016] [Indexed: 01/10/2023]
Abstract
AIMS MicroRNAs are a class of small noncoding RNAs, which control gene expression by inhibition of mRNA translation. MicroRNAs are involved in the control of biological processes including cell differentiation. Here, we aim at characterizing microRNA expression profiles during differentiation of human induced pluripotent stem cells (hiPSCs) into insulin-producing cells. METHODS We differentiated hiPSCs toward endocrine pancreatic lineage following a 18-day protocol. We analyzed genes and microRNA expression levels using RT real-time PCR and TaqMan microRNA arrays followed by bioinformatic functional analysis. RESULTS MicroRNA expression profiles analysis of undifferentiated hiPSCs during pancreatic differentiation revealed that 347/768 microRNAs were expressed at least in one time point of all samples. We observed 18 microRNAs differentially expressed: 11 were upregulated (miR-9-5p, miR-9-3p, miR-10a, miR-99a-3p, miR-124a, miR-135a, miR-138, miR-149, miR-211, miR-342-3p and miR-375) and 7 downregulated (miR-31, miR-127, miR-143, miR-302c-3p, miR-373, miR-518b and miR-520c-3p) during differentiation into insulin-producing cells. Selected microRNAs were further evaluated during differentiation of Sendai-virus-reprogrammed hiPSCs using an improved endocrine pancreatic beta cell derivation protocol and, moreover, in differentiated NKX6.1+ sorted cells. Following Targetscan7.0 analysis of target genes of differentially expressed microRNAs and gene ontology classification, we found that such target genes belong to categories of major significance in pancreas organogenesis and development or exocytosis. CONCLUSIONS We detected a specific hiPSCs microRNAs signature during differentiation into insulin-producing cells and demonstrated that differentially expressed microRNAs target several genes involved in pancreas organogenesis.
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Affiliation(s)
- Guido Sebastiani
- Diabetes Unit, Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy
- Fondazione Umberto di Mario ONLUS, Toscana Life Sciences, Siena, Italy
| | - Marco Valentini
- Diabetes Unit, Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy
- Fondazione Umberto di Mario ONLUS, Toscana Life Sciences, Siena, Italy
| | - Giuseppina Emanuela Grieco
- Diabetes Unit, Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy
- Fondazione Umberto di Mario ONLUS, Toscana Life Sciences, Siena, Italy
| | - Giuliana Ventriglia
- Diabetes Unit, Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy
- Fondazione Umberto di Mario ONLUS, Toscana Life Sciences, Siena, Italy
| | - Laura Nigi
- Diabetes Unit, Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy
- Fondazione Umberto di Mario ONLUS, Toscana Life Sciences, Siena, Italy
| | - Francesca Mancarella
- Diabetes Unit, Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy
- Fondazione Umberto di Mario ONLUS, Toscana Life Sciences, Siena, Italy
| | - Silvia Pellegrini
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Gianvito Martino
- Division of Neuroscience, Institute of Experimental Neurology (INSpe), IRCCS San Raffaele Hospital, Milan, Italy
| | - Valeria Sordi
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Lorenzo Piemonti
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Francesco Dotta
- Diabetes Unit, Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy.
- Fondazione Umberto di Mario ONLUS, Toscana Life Sciences, Siena, Italy.
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Llano-Diez M, Sinclair J, Yamada T, Zong M, Fauconnier J, Zhang SJ, Katz A, Jardemark K, Westerblad H, Andersson DC, Lanner JT. The Role of Reactive Oxygen Species in β-Adrenergic Signaling in Cardiomyocytes from Mice with the Metabolic Syndrome. PLoS One 2016; 11:e0167090. [PMID: 27907040 PMCID: PMC5131978 DOI: 10.1371/journal.pone.0167090] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Accepted: 11/07/2016] [Indexed: 12/20/2022] Open
Abstract
The metabolic syndrome is associated with prolonged stress and hyperactivity of the sympathetic nervous system and afflicted subjects are prone to develop cardiovascular disease. Under normal conditions, the cardiomyocyte response to acute β-adrenergic stimulation partly depends on increased production of reactive oxygen species (ROS). Here we investigated the interplay between beta-adrenergic signaling, ROS and cardiac contractility using freshly isolated cardiomyocytes and whole hearts from two mouse models with the metabolic syndrome (high-fat diet and ob/ob mice). We hypothesized that cardiomyocytes of mice with the metabolic syndrome would experience excessive ROS levels that trigger cellular dysfunctions. Fluorescent dyes and confocal microscopy were used to assess mitochondrial ROS production, cellular Ca2+ handling and contractile function in freshly isolated adult cardiomyocytes. Immunofluorescence, western blot and enzyme assay were used to study protein biochemistry. Unexpectedly, our results point towards decreased cardiac ROS signaling in a stable, chronic phase of the metabolic syndrome because: β-adrenergic-induced increases in the amplitude of intracellular Ca2+ signals were insensitive to antioxidant treatment; mitochondrial ROS production showed decreased basal rate and smaller response to β-adrenergic stimulation. Moreover, control hearts and hearts with the metabolic syndrome showed similar basal levels of ROS-mediated protein modification, but only control hearts showed increases after β-adrenergic stimulation. In conclusion, in contrast to the situation in control hearts, the cardiomyocyte response to acute β-adrenergic stimulation does not involve increased mitochondrial ROS production in a stable, chronic phase of the metabolic syndrome. This can be seen as a beneficial adaptation to prevent excessive ROS levels.
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Affiliation(s)
- Monica Llano-Diez
- Karolinska Institutet, Department of Physiology & Pharmacology, Stockholm, Sweden
| | - Jon Sinclair
- Karolinska Institutet, Department of Physiology & Pharmacology, Stockholm, Sweden
| | - Takashi Yamada
- Karolinska Institutet, Department of Physiology & Pharmacology, Stockholm, Sweden
| | - Mei Zong
- Karolinska University Hospital, Rheumatology unit, CMM, Stockholm Sweden
| | - Jeremy Fauconnier
- Karolinska Institutet, Department of Physiology & Pharmacology, Stockholm, Sweden
| | - Shi-Jin Zhang
- Karolinska Institutet, Department of Physiology & Pharmacology, Stockholm, Sweden
| | - Abram Katz
- Karolinska Institutet, Department of Physiology & Pharmacology, Stockholm, Sweden
| | - Kent Jardemark
- Karolinska Institutet, Department of Physiology & Pharmacology, Stockholm, Sweden
| | - Håkan Westerblad
- Karolinska Institutet, Department of Physiology & Pharmacology, Stockholm, Sweden
| | | | - Johanna T. Lanner
- Karolinska Institutet, Department of Physiology & Pharmacology, Stockholm, Sweden
- * E-mail:
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40
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Pellegrini S, Cantarelli E, Sordi V, Nano R, Piemonti L. The state of the art of islet transplantation and cell therapy in type 1 diabetes. Acta Diabetol 2016; 53:683-91. [PMID: 26923700 DOI: 10.1007/s00592-016-0847-z] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Accepted: 02/06/2016] [Indexed: 12/17/2022]
Abstract
In patients with type 1 diabetes (T1D), pancreatic β cells are destroyed by a selective autoimmune attack and their replacement with functional insulin-producing cells is the only possible cure for this disease. The field of islet transplantation has evolved significantly from the breakthrough of the Edmonton Protocol in 2000, since significant advances in islet isolation and engraftment, together with improved immunosuppressive strategies, have been reported. The main limitations, however, remain the insufficient supply of human tissue and the need for lifelong immunosuppression therapy. Great effort is then invested in finding innovative sources of insulin-producing β cells. One old alternative with new recent perspectives is the use of non-human donor cells, in particular porcine β cells. Also the field of preexisting β cell expansion has advanced, with the development of new human β cell lines. Yet, large-scale production of human insulin-producing cells from stem cells is the most recent and promising alternative. In particular, the optimization of in vitro strategies to differentiate human embryonic stem cells into mature insulin-secreting β cells has made considerable progress and recently led to the first clinical trial of stem cell treatment for T1D. Finally, the discovery that it is possible to derive human induced pluripotent stem cells from somatic cells has raised the possibility that a sufficient amount of patient-specific β cells can be derived from patients through cell reprogramming and differentiation, suggesting that in the future there might be a cell therapy without immunosuppression.
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Affiliation(s)
- Silvia Pellegrini
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Elisa Cantarelli
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Valeria Sordi
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Rita Nano
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Lorenzo Piemonti
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy.
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41
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Makrantonaki E, Jiang D, Hossini AM, Nikolakis G, Wlaschek M, Scharffetter-Kochanek K, Zouboulis CC. Diabetes mellitus and the skin. Rev Endocr Metab Disord 2016; 17:269-282. [PMID: 27432328 DOI: 10.1007/s11154-016-9373-0] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Diabetes is a debilitating, life-threatening disease accounting in 2015 for the death of 5 million people worldwide. According to new estimations, 415 million adults currently suffer from the disease, and this number is expected to rise to 642 million by 2040. High glucose blood levels also affect the skin among systemic organs, and skin disorders can often predict the onset of this metabolic disorder. In this review, we address the pathomechanistic effects of diabetes on the skin and give an overview on the most common skin diseases associated with diabetes.
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Affiliation(s)
- E Makrantonaki
- Department of Dermatology and Allergic Diseases, Universitätsklinikum Ulm, Life Science Building N27, James-Franck Ring/Meyerhofstrasse 11c, 89081, Ulm, Germany.
- Department of Dermatology, Venereology, Allergology and Immunology, Städtisches Klinikum Dessau, Dessau, Germany.
| | - D Jiang
- Department of Dermatology and Allergic Diseases, Universitätsklinikum Ulm, Life Science Building N27, James-Franck Ring/Meyerhofstrasse 11c, 89081, Ulm, Germany
| | - A M Hossini
- Department of Dermatology, Venereology, Allergology and Immunology, Städtisches Klinikum Dessau, Dessau, Germany
| | - G Nikolakis
- Department of Dermatology, Venereology, Allergology and Immunology, Städtisches Klinikum Dessau, Dessau, Germany
| | - M Wlaschek
- Department of Dermatology and Allergic Diseases, Universitätsklinikum Ulm, Life Science Building N27, James-Franck Ring/Meyerhofstrasse 11c, 89081, Ulm, Germany
| | - K Scharffetter-Kochanek
- Department of Dermatology and Allergic Diseases, Universitätsklinikum Ulm, Life Science Building N27, James-Franck Ring/Meyerhofstrasse 11c, 89081, Ulm, Germany
| | - C C Zouboulis
- Department of Dermatology, Venereology, Allergology and Immunology, Städtisches Klinikum Dessau, Dessau, Germany
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Vieira A, Courtney M, Druelle N, Avolio F, Napolitano T, Hadzic B, Navarro-Sanz S, Ben-Othman N, Collombat P. β-Cell replacement as a treatment for type 1 diabetes: an overview of possible cell sources and current axes of research. Diabetes Obes Metab 2016; 18 Suppl 1:137-43. [PMID: 27615143 DOI: 10.1111/dom.12721] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Accepted: 04/27/2016] [Indexed: 01/09/2023]
Abstract
To efficiently treat type 1 diabetes, exogenous insulin injections currently represent the main approach to counter chronic hyperglycaemia. Unfortunately, such a therapeutic approach does not allow for perfectly maintained glucose homeostasis and, in time, cardiovascular complications may arise. Therefore, seeking alternative/improved treatments has become a major health concern as an increasing proportion of type 2 diabetes patients also require insulin supplementation. Towards this goal, numerous laboratories have focused their research on β-cell replacement therapies. Herein, we will review the current state of this research area and describe the cell sources that could potentially be used to replenish the depleted β-cell mass in diabetic patients.
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Affiliation(s)
- A Vieira
- Université Côte d'Azur, CNRS, Inserm, iBV, France
| | - M Courtney
- Université Côte d'Azur, CNRS, Inserm, iBV, France
| | - N Druelle
- Université Côte d'Azur, CNRS, Inserm, iBV, France
| | - F Avolio
- Université Côte d'Azur, CNRS, Inserm, iBV, France
| | - T Napolitano
- Université Côte d'Azur, CNRS, Inserm, iBV, France
| | - B Hadzic
- Université Côte d'Azur, CNRS, Inserm, iBV, France
| | | | - N Ben-Othman
- Université Côte d'Azur, CNRS, Inserm, iBV, France
| | - P Collombat
- Université Côte d'Azur, CNRS, Inserm, iBV, France.
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Lemaire K, Thorrez L, Schuit F. Disallowed and Allowed Gene Expression: Two Faces of Mature Islet Beta Cells. Annu Rev Nutr 2016; 36:45-71. [DOI: 10.1146/annurev-nutr-071715-050808] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
| | - Lieven Thorrez
- Gene Expression Unit, Department of Cellular and Molecular Medicine, Faculty of Medicine, KU Leuven, Leuven B3000, Belgium; , ,
| | - Frans Schuit
- Gene Expression Unit, Department of Cellular and Molecular Medicine, Faculty of Medicine, KU Leuven, Leuven B3000, Belgium; , ,
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Ichihara Y, Utoh R, Yamada M, Shimizu T, Uchigata Y. Size effect of engineered islets prepared using microfabricated wells on islet cell function and arrangement. Heliyon 2016; 2:e00129. [PMID: 27441299 PMCID: PMC4946309 DOI: 10.1016/j.heliyon.2016.e00129] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2016] [Revised: 05/29/2016] [Accepted: 06/23/2016] [Indexed: 01/02/2023] Open
Abstract
Pancreatic islets are heterogeneous clusters mainly composed of α and β cells, and these clusters range in diameter from 50 to several hundred micrometers. Native small islets are known to have a higher insulin secretion ability in vitro and to provide better transplantation outcomes when compared with large islets. In this study, we prepared microengineered pseudo-islets from dispersed rat islet cells using precisely-fabricated agarose gel-based microwells with different diameters (100, 300, or 500 μm) to investigate the function and survival of islet cell aggregates with well-controlled sizes. We observed that dead cells were rarely present in the small pseudo-islets with an average diameter of ∼60 μm prepared using 100 μm microwells. In contrast, we observed more dead cells in the larger pseudo-islets prepared using 300 and 500 μm microwells. The relative amount of hypoxic cells was significantly low in the small pseudo-islets whereas a hypoxic condition was present in the core region of the larger pseudo-islets. In addition, we found that the small-sized pseudo-islets reconstituted the in vivo-tissue like arrangement of the α and β cells, and restored the high insulin secretory capacity in response to high glucose. These results clearly suggest that precise size control of pseudo-islets is essential for maintaining islet cell function and survival in vitro. The small-sized pseudo-islets may be advantageous for providing a better therapeutic approach for treating type 1 diabetes mellitus via islet reorganization and transplantation.
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Affiliation(s)
- Yumie Ichihara
- Diabetes Center, Tokyo Women's Medical University School of Medicine, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Rie Utoh
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
- Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
- Corresponding author at: Research Fellow of the Japan Society for the Promotion of Science (JSPS). Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, Chiba University, 1–33 Yayoi-cho, Inage-ku, Chiba 263–8522, Japan.Department of Applied Chemistry and BiotechnologyGraduate School of EngineeringChiba University1-33 Yayoi-choInage-kuChiba263-8522Japan
| | - Masumi Yamada
- Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
| | - Tatsuya Shimizu
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Yasuko Uchigata
- Diabetes Center, Tokyo Women's Medical University School of Medicine, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
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Shaer A, Azarpira N, Karimi MH, Soleimani M, Dehghan S. Differentiation of Human-Induced Pluripotent Stem Cells Into Insulin-Producing Clusters by MicroRNA-7. EXP CLIN TRANSPLANT 2016; 14:555-563. [PMID: 26103160 DOI: 10.6002/ect.2014.0144] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES Diabetes results from inadequate insulin production from pancreatic β-cells. Islet cell replacement is an effective approach for diabetes treatment; however, it is not sufficient for all diabetic patients. Thus, finding a new source with effective maturation of β-cells is the major goal of many studies. MicroRNAs are a class of small noncoding ribonucleic acid that regulate gene expression through posttranscriptional mechanisms. MicroRNA-7 has high expression level during pancreatic islet development in humans, thereby playing a critical role in pancreatic β-cell function. We study aimed to develop a protocol to differentiate human-induced pluripotent stem cells efficiently into isletlike cell clusters in vitro by using microRNA-7. MATERIALS AND METHODS Human-induced pluripotent stem cell colonies were transfected with hsa-microRNA-7 by using siPORT NeoFX transfection agent. Total ribonucleic acid was extracted 24 and 48 hours after transfection. The expression of transcription factors which were important during pancreases development was also performed. On the third day, the potency of the clusters was assessed in response to high glucose levels. Diphenylthiocarbazone was used to identify the existence of the β-cells. The presence of insulin and Neurogenin-3 proteins was investigated by immunocytochemistry. RESULTS Morphologic changes were observed on the first day after chemical transfection, and cell clusters were formed on the third day. The expression of pancreatic specific transcription factors was increased on the first day and significantly increased on the second day. The isletlike cell clusters were positive for insulin and Neurogenin-3 proteins in immunocytochemistry. The clusters were stained with Diphenylthiocarbazone and secreted insulin in a glucose challenge test. CONCLUSIONS MicroRNA-7 transcription factor network is important in pancreatic endocrine differentiation. Chemical transfection with microRNA-7 can differentiate human induced pluripotent stem cells into functional isletlike cell clusters in a short time.
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Affiliation(s)
- Anahita Shaer
- From the Department of Genetics, Zarghan Branch, Islamic Azad University, Fars, Iran; and Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Lima MJ, Muir KR, Docherty HM, McGowan NWA, Forbes S, Heremans Y, Heimberg H, Casey J, Docherty K. Generation of Functional Beta-Like Cells from Human Exocrine Pancreas. PLoS One 2016; 11:e0156204. [PMID: 27243814 PMCID: PMC4887015 DOI: 10.1371/journal.pone.0156204] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Accepted: 05/10/2016] [Indexed: 12/24/2022] Open
Abstract
Transcription factor mediated lineage reprogramming of human pancreatic exocrine tissue could conceivably provide an unlimited supply of islets for transplantation in the treatment of diabetes. Exocrine tissue can be efficiently reprogrammed to islet-like cells using a cocktail of transcription factors: Pdx1, Ngn3, MafA and Pax4 in combination with growth factors. We show here that overexpression of exogenous Pax4 in combination with suppression of the endogenous transcription factor ARX considerably enhances the production of functional insulin-secreting β-like cells with concomitant suppression of α-cells. The efficiency was further increased by culture on laminin-coated plates in media containing low glucose concentrations. Immunocytochemistry revealed that reprogrammed cultures were composed of ~45% islet-like clusters comprising >80% monohormonal insulin+ cells. The resultant β-like cells expressed insulin protein levels at ~15–30% of that in adult human islets, efficiently processed proinsulin and packaged insulin into secretory granules, exhibited glucose responsive insulin secretion, and had an immediate and prolonged effect in normalising blood glucose levels upon transplantation into diabetic mice. We estimate that approximately 3 billion of these cells would have an immediate therapeutic effect following engraftment in type 1 diabetes patients and that one pancreas would provide sufficient tissue for numerous transplants.
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Affiliation(s)
- Maria J. Lima
- School of Medical Sciences, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom
- * E-mail:
| | - Kenneth R. Muir
- School of Medical Sciences, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom
| | - Hilary M. Docherty
- School of Medical Sciences, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom
| | - Neil W. A. McGowan
- Department of Surgery, University of Edinburgh, Edinburgh Royal Infirmary, Edinburgh, EH16 4SU, United Kingdom
| | - Shareen Forbes
- Endocrinology Unit, University/BHF Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, EH16 4TJ, United Kingdom
| | - Yves Heremans
- Diabetes Research Centre, Vrije Universiteit Brussel, B1090 Brussels, Belgium
| | - Harry Heimberg
- Diabetes Research Centre, Vrije Universiteit Brussel, B1090 Brussels, Belgium
| | - John Casey
- Department of Surgery, University of Edinburgh, Edinburgh Royal Infirmary, Edinburgh, EH16 4SU, United Kingdom
| | - Kevin Docherty
- School of Medical Sciences, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom
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Zhang S, Bai C, Ma Y, Li X, Gao Y, Fan Y, Guan W, Zheng D. The characterisation and functional β-cell differentiation of duck pancreas-derived mesenchymal cells. Br Poult Sci 2016; 57:201-10. [DOI: 10.1080/00071668.2015.1135505] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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Genome Editing of the CYP1A1 Locus in iPSCs as a Platform to Map AHR Expression throughout Human Development. Stem Cells Int 2016; 2016:2574152. [PMID: 27148368 PMCID: PMC4842384 DOI: 10.1155/2016/2574152] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Accepted: 03/17/2016] [Indexed: 12/12/2022] Open
Abstract
The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that increases the expression of detoxifying enzymes upon ligand stimulation. Recent studies now suggest that novel endogenous roles of the AHR exist throughout development. In an effort to create an optimized model system for the study of AHR signaling in several cellular lineages, we have employed a CRISPR/CAS9 genome editing strategy in induced pluripotent stem cells (iPSCs) to incorporate a reporter cassette at the transcription start site of one of its canonical targets, cytochrome P450 1A1 (CYP1A1). This cell line faithfully reports on CYP1A1 expression, with luciferase levels as its functional readout, when treated with an endogenous AHR ligand (FICZ) at escalating doses. iPSC-derived fibroblast-like cells respond to acute exposure to environmental and endogenous AHR ligands, and iPSC-derived hepatocytes increase CYP1A1 in a similar manner to primary hepatocytes. This cell line is an important innovation that can be used to map AHR activity in discrete cellular subsets throughout developmental ontogeny. As further endogenous ligands are proposed, this line can be used to screen for safety and efficacy and can report on the ability of small molecules to regulate critical cellular processes by modulating the activity of the AHR.
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49
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Baker K. Comparison of bioartificial and artificial pancreatic transplantation as promising therapies for Type I Diabetes Mellitus. ACTA ACUST UNITED AC 2016. [DOI: 10.1093/biohorizons/hzw002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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50
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Takahashi Y, Takebe T, Taniguchi H. Engineering pancreatic tissues from stem cells towards therapy. Regen Ther 2016; 3:15-23. [PMID: 31245468 PMCID: PMC6581807 DOI: 10.1016/j.reth.2016.01.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Revised: 12/17/2015] [Accepted: 01/20/2016] [Indexed: 12/20/2022] Open
Abstract
Pancreatic islet transplantation is performed as a potential treatment for type 1 diabetes mellitus. However, this approach is significantly limited due to the critical shortage of islet sources. Recently, a number of publications have developed protocols for directed β-cell differentiation of pluripotent cells, such as embryonic stem (ES) or induced pluripotent stem (iPS) cells. Decades of studies have led to the development of modified protocols that recapitulate molecular developmental cues by combining various growth factors and small molecules with improved efficiency. However, the later step of pancreatic differentiation into functional β-cells has yet to be satisfactory in vitro, highlighting alternative approach by recapitulating spatiotemporal multicellular interaction in three-dimensional (3D) culture. Here, we summarize recent progress in the directed differentiation into pancreatic β-cells with a focus on both two-dimensional (2D) and 3D differentiation settings. We also discuss the potential transplantation strategies in combination with current bioengineering approaches towards diabetes therapy.
Transplantation of stem cell derived pancreatic progenitors is a possible approach for generating mature β-cell in vivo. Promise of 3-D (or 4-D) culture has started to be explored by reconstituting pancreatic tissue structures. Self-condensation culture is a basic technique of integrating multiple heterotypic lineages including vasculatures. Bioengineering approach has been combined for developing effective transplant strategies.
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Key Words
- 2D, two-dimensional
- 3D, three-dimensional
- BMP, bone morphogenic protein
- Diabetes
- ES, embryonic stem
- FGF, fibroblast growth factors
- Heterotypic cellular interaction
- IBMIR, instant blood-mediated reaction
- ILV, indolactam V
- Ngn3, neurogenin 3
- PEG, polyethylene glycol
- PI3K, phosphatidylinositol-3 kinase
- PIPAAm, poly-N-isopropylacrylamide
- PVA, polyvinyl alcohol
- Pancreas
- Pdx1, pancreatic and duodenal homeobox 1
- Ptf1a, pancreatic transcription factor 1a
- Regenerative medicine
- VEGF, vascular endothelial growth factor
- Vascularization
- iPS, induced pluripotent stem
- iPS/ES cell
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Affiliation(s)
- Yoshinobu Takahashi
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Kanazawa-ku 3-9, Yokohama, Kanagawa, 236-0004, Japan
| | - Takanori Takebe
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Kanazawa-ku 3-9, Yokohama, Kanagawa, 236-0004, Japan.,Advanced Medical Research Center, Yokohama City University, Kanazawa-ku 3-9, Yokohama, Kanagawa, 236-0004, Japan.,PRESTO, Japan Science and Technology Agency, 4-1-8, Honcho, Kawaguchi, Saitama, 332-0012, Japan.,Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, 3333 Burnet Avenue, Cincinnati, OH, 45229- 3039, USA
| | - Hideki Taniguchi
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Kanazawa-ku 3-9, Yokohama, Kanagawa, 236-0004, Japan.,Advanced Medical Research Center, Yokohama City University, Kanazawa-ku 3-9, Yokohama, Kanagawa, 236-0004, Japan
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