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1
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Bagheri SM, Hakimizadeh E, Allahtavakoli M. Nephroprotective Effect of Ferula assa-foetida Oleo Gum Resin on Type 2 Diabetic Rats. Curr Pharm Des 2024; 30:2485-2492. [PMID: 38910415 DOI: 10.2174/0113816128303631240530045628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Accepted: 04/01/2024] [Indexed: 06/25/2024]
Abstract
OBJECTIVE Diabetic nephropathy is one of the main causes of kidney failure in the end stage of diabetes worldwide. On the other hand, asafoetida is a gum whose hypoglycemic effects have been proven. The present study was conducted with the aim of using asafoetida to prevent diabetic nephropathy. METHODS Diabetes was induced by a high-fat diet (60%) and streptozotocin injection (35 mg/kg) in rats. Diabetic rats were treated with an oral dose of 50 mg/kg of asafoetida for 8 weeks. At the end of the experiment, serum and urine parameters were examined. Antioxidant enzymes and lipid peroxidation levels in the kidney were also determined along with its histological examination. The expression levels of tumor necrosis factor-alpha and Transforming growth factor beta genes were also evaluated. RESULTS Glucose, cholesterol, triglyceride, and HbA1c concentrations were significantly reduced in the asafoetida 50. On the other hand, in the treatment group, serum creatinine, urea, and albumin levels decreased and increased in urine. Antioxidant enzymes in the kidney improved significantly, and the expression of tumour necrosis factor-alpha and transforming growth factor-beta genes decreased. Histopathological examination also showed that necrosis, epithelial damage, and leukocyte infiltration increased in the diabetic and decreased in the treatment group. CONCLUSION The result of biochemical analysis, enzymatic, and histological examinations showed that asafoetida may delay the progression of diabetic nephropathy due to the presence of anti-inflammatory and antioxidant activities.
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Affiliation(s)
- Seyyed Majid Bagheri
- Physiology-Pharmacology Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Elham Hakimizadeh
- Physiology-Pharmacology Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Mohammad Allahtavakoli
- Physiology-Pharmacology Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
- Department of Physiology and Pharmacology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
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2
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Jiang H, Jiang FX. Human pluripotent stem cell-derived β cells: Truly immature islet β cells for type 1 diabetes therapy? World J Stem Cells 2023; 15:182-195. [PMID: 37180999 PMCID: PMC10173812 DOI: 10.4252/wjsc.v15.i4.182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 01/30/2023] [Accepted: 03/20/2023] [Indexed: 04/26/2023] Open
Abstract
A century has passed since the Nobel Prize winning discovery of insulin, which still remains the mainstay treatment for type 1 diabetes mellitus (T1DM) to this day. True to the words of its discoverer Sir Frederick Banting, “insulin is not a cure for diabetes, it is a treatment”, millions of people with T1DM are dependent on daily insulin medications for life. Clinical donor islet transplantation has proven that T1DM is curable, however due to profound shortages of donor islets, it is not a mainstream treatment option for T1DM. Human pluripotent stem cell derived insulin-secreting cells, pervasively known as stem cell-derived β cells (SC-β cells), are a promising alternative source and have the potential to become a T1DM treatment through cell replacement therapy. Here we briefly review how islet β cells develop and mature in vivo and several types of reported SC-β cells produced using different ex vivo protocols in the last decade. Although some markers of maturation were expressed and glucose stimulated insulin secretion was shown, the SC-β cells have not been directly compared to their in vivo counterparts, generally have limited glucose response, and are not yet fully matured. Due to the presence of extra-pancreatic insulin-expressing cells, and ethical and technological issues, further clarification of the true nature of these SC-β cells is required.
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Affiliation(s)
- Helen Jiang
- Sir Charles Gairdner Hospital, University of Western Australia, Perth 6009, Australia
| | - Fang-Xu Jiang
- School of Biomedical Sciences, University of Western Australia, Perth 6009, Australia
- School of Health and Medical Sciences, Edith Cowan University, Perth 6027, Australia
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3
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The microenvironment of silk/gelatin nanofibrous scaffold improves proliferation and differentiation of Wharton's jelly-derived mesenchymal cells into islet-like cells. Gene 2022; 833:146586. [PMID: 35597530 DOI: 10.1016/j.gene.2022.146586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 05/03/2022] [Accepted: 05/16/2022] [Indexed: 11/22/2022]
Abstract
The use of umbilical cord-derived mesenchymal stem cells along with three-dimensional (3D) scaffolds in pancreatic tissue engineering can be considered as a treatment for diabetes. This study aimed to investigate the differentiation of Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) into pancreatic islet-insulin producing cells (IPCs) on silk/gelatin nanofibers as a 3D scaffold. Mesenchymal markers were evaluated at the mesenchymal stem cells (MSCs) level by flow cytometry. WJ-MSCs were then cultured on 3D scaffolds and treated with a differential medium. Immunocytochemical assays showed efficient differentiation of WJ-MSCs into IPCs. Also, Real-time PCR results showed a significant increase in the expression of pancreatic genes in the 3D culture group compared to the two-dimensional (2D) culture group. Despite these cases, the secretion of insulin and C-peptide in response to different concentrations of glucose in the 3D group was significantly higher than in the 2D culture. The results of our study showed that silk/gelatin scaffold with WJ-MSCs could be a good option in the production of IPCs in regenerative medicine and pancreatic tissue engineering.
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Hashemi J, Barati G, Bibak B. Decellularized Matrix Bioscaffolds: Implementation of Native Microenvironment in Pancreatic Tissue Engineering. Pancreas 2021; 50:942-951. [PMID: 34643609 DOI: 10.1097/mpa.0000000000001868] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
ABSTRACT Type 1 diabetes is an autoimmune disease, and its incidence is usually estimated in the range of 5% to 10%. Currently, the administration of exogenous insulin is the standard of care therapy. However, this therapy is not effective in some patients who may develop some chronic complications. Islet transplantation into the liver is another therapy with promising outcomes; however, the long-term efficacy of this therapeutic option is limited to a small number of patients. Because native extracellular matrix (ECM) components provide a suitable microenvironment for islet functions, engineering a 3-dimensional construct that recapitulates the native pancreatic environment could address these obstacles. Many attempts have been conducted to mimic an in vivo microenvironment to increase the survival of islets or islet-like clusters. With the advent of decellularization technology, it is possible to use a native ECM in organ engineering. Pancreatic decellularized bioscaffold provides proper cell-cell and cell-ECM interactions and retains growth factors that are critical in the determination of cell fate within a native organ. This review summarizes the current knowledge of decellularized matrix technology and addresses its possible limitations before use in the clinic.
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Affiliation(s)
- Javad Hashemi
- From the Department of Pathobiology and Laboratory Sciences, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd
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5
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A new shortened protocol to obtain islet-like cells from hESC-derived ductal cells. In Vitro Cell Dev Biol Anim 2021; 57:587-597. [PMID: 34212340 DOI: 10.1007/s11626-021-00580-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Accepted: 04/06/2021] [Indexed: 10/21/2022]
Abstract
Conventional methods for obtaining pancreatic β cells are based on simulating the embryonic development phase of endocrine cells via hierarchical differentiation of pluripotent stem cells (PSCs). Accordingly, we attempted to modify the protocols for obtaining insulin-secreting cells (ISCs) by sequential differentiation of a human embryonic stem cell (hESC), using the HS181 cell line. Furthermore, we hypothesize that actual pancreatic endocrine cells may arise from trans-differentiation of mature ductal cells after the embryonic developmental stage and throughout the rest of life. According to the hypothesis, ductal cells are trans-differentiated into endocrine and exocrine cells, undergoing a partial epithelial to mesenchymal transition (EMT). To address this issue, we developed two new protocols based on hESC differentiation to obtain ductal cells and then induce EMT in cells to obtain hormone-secreting islet-like cells (HSCs). The ductal (pre-EMT exocrine) cells were then induced to undergo partial EMT by treating with Wnt3a and activin A, in hypoxia. The cell derived from the latter method significantly expressed the main endocrine cell-specific markers and also β cells, in particular. These experiments not only support our hypothetical model but also offer a promising approach to develop new methods to compensate β cell depletion in patients with type 1 diabetes mellitus (T1DM). Although this protocol of generating islet-like cells from ductal cells has a potential to treat T1DM, this strategy may be exploited to optimize the function of these cells in an animal model and future clinical applications.
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Shaheen R, Gurlin RE, Gologorsky R, Blaha C, Munnangi P, Santandreu A, Torres A, Carnese P, Nair GG, Szot G, Fissell WH, Hebrok M, Roy S. Superporous agarose scaffolds for encapsulation of adult human islets and human stem-cell-derived β cells for intravascular bioartificial pancreas applications. J Biomed Mater Res A 2021; 109:2438-2448. [PMID: 34196100 DOI: 10.1002/jbm.a.37236] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/14/2021] [Accepted: 05/11/2021] [Indexed: 12/12/2022]
Abstract
Type 1 diabetic patients with severe hypoglycemia unawareness have benefitted from cellular therapies, such as pancreas or islet transplantation; however, donor shortage and the need for immunosuppression limits widespread clinical application. We previously developed an intravascular bioartificial pancreas (iBAP) using silicon nanopore membranes (SNM) for immunoprotection. To ensure ample nutrient delivery, the iBAP will need a cell scaffold with high hydraulic permeability to provide mechanical support and maintain islet viability and function. Here, we examine the feasibility of superporous agarose (SPA) as a potential cell scaffold in the iBAP. SPA exhibits 66-fold greater hydraulic permeability than the SNM along with a short (<10 μm) diffusion distance to the nearest islet. SPA also supports short-term functionality of both encapsulated human islets and stem-cell-derived enriched β-clusters in a convection-based system, demonstrated by high viability (>95%) and biphasic insulin responses to dynamic glucose stimulus. These findings suggest that the SPA scaffold will not limit nutrient delivery in a convection-based bioartificial pancreas and merits continued investigation.
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Affiliation(s)
- Rebecca Shaheen
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California, USA
| | - Rachel E Gurlin
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California, USA
| | - Rebecca Gologorsky
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California, USA
| | - Charles Blaha
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California, USA.,Silicon Kidney, San Francisco, California, USA
| | - Pujita Munnangi
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California, USA
| | - Ana Santandreu
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California, USA
| | - Alonso Torres
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California, USA
| | - Phichitpol Carnese
- Diabetes Center, Department of Medicine, University of California, San Francisco, California, USA
| | - Gopika G Nair
- Diabetes Center, Department of Medicine, University of California, San Francisco, California, USA
| | - Gregory Szot
- Diabetes Center, Department of Medicine, University of California, San Francisco, California, USA
| | - William H Fissell
- Silicon Kidney, San Francisco, California, USA.,Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Matthias Hebrok
- Diabetes Center, Department of Medicine, University of California, San Francisco, California, USA
| | - Shuvo Roy
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California, USA.,Silicon Kidney, San Francisco, California, USA
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7
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Navaeian M, Asadian S, Ahmadpour Yazdi H, Gheibi N. ANGPTL8 roles in proliferation, metabolic diseases, hypothyroidism, polycystic ovary syndrome, and signaling pathways. Mol Biol Rep 2021; 48:3719-3731. [PMID: 33864588 DOI: 10.1007/s11033-021-06270-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Accepted: 03/05/2021] [Indexed: 12/18/2022]
Abstract
A new and atypical member of the ANGPTL family is angiopoietin-like protein 8 (ANGPTL8). This newly discovered hormone is a drug target that can be used to treat diabetes and dyslipidemia. The protein, as a hepatocyte-derived circulating factor, can control the triglyceride level of plasma. ANGPTL8 is significantly associated with inflammation and metabolic syndrome consequences such as obesity, diabetes, hypothyroidism, and PCOS. ANGPTL8 gene has four exons encoding a 22/5 kDa weight of 198 amino acid polypeptides. A highly preserved ANGPTL8 gene among mammals exhibits the essential hormone functions of ANGPTL8. Nevertheless, the physiological function of this hormone in the body is poorly understood. Studies published in PubMed (2008-2020), Google Scholar (2004-2020), and Scopus (2004-2020) databases of clinical trials were reviewed. This analysis is aimed at collecting information on ANGPTL8. The emphasis of this review was on gathering information about the role of ANGPTL8 in the metabolism of glucose and lipids and cell proliferation. It addition to the different roles of ANGPTL8 in diabetes and lipid metabolism, this review emphasized on the protein role in signaling pathways. The study also proposes the signaling pathways that may be considered as a new target for treatment.
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Affiliation(s)
- Maryam Navaeian
- Student Research Committee, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Samieh Asadian
- Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Hossein Ahmadpour Yazdi
- Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran.
| | - Nematollah Gheibi
- Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran.
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8
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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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9
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Scarl RT, Corbin KL, Vann NW, Smith HM, Satin LS, Sherman A, Nunemaker CS. Intact pancreatic islets and dispersed beta-cells both generate intracellular calcium oscillations but differ in their responsiveness to glucose. Cell Calcium 2019; 83:102081. [PMID: 31563790 DOI: 10.1016/j.ceca.2019.102081] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 09/12/2019] [Accepted: 09/14/2019] [Indexed: 01/19/2023]
Abstract
Pancreatic islets produce pulses of insulin and other hormones that maintain normal glucose homeostasis. These micro-organs possess exquisite glucose-sensing capabilities, allowing for precise changes in pulsatile insulin secretion in response to small changes in glucose. When communication among these cells is disrupted, precision glucose sensing falters. We measured intracellular calcium patterns in 6-mM-steps between 0 and 16 mM glucose, and also more finely in 2-mM-steps from 8 to 12 mM glucose, to compare glucose sensing systematically among intact islets and dispersed islet cells derived from the same mouse pancreas in vitro. The calcium activity of intact islets was uniformly low (quiescent) below 4 mM glucose and active above 8 mM glucose, whereas dispersed beta-cells displayed a broader activation range (2-to-10 mM). Intact islets exhibited calcium oscillations with 2-to-5-min periods, yet beta-cells exhibited longer 7-10 min periods. In every case, intact islets showed changes in activity with each 6-mM-glucose step, whereas dispersed islet cells displayed a continuum of calcium responses ranging from islet-like patterns to stable oscillations unaffected by changes in glucose concentration. These differences were also observed for 2-mM-glucose steps. Despite the diversity of dispersed beta-cell responses to glucose, the sum of all activity produced a glucose dose-response curve that was surprisingly similar to the curve for intact islets, arguing against the importance of "hub cells" for function. Beta-cells thus retain many of the features of islets, but some are more islet-like than others. Determining the molecular underpinnings of these variations could be valuable for future studies of stem-cell-derived beta-cell therapies.
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Affiliation(s)
- Rachel T Scarl
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, United States
| | - Kathryn L Corbin
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, United States; Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, United States
| | - Nicholas W Vann
- Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, United States
| | - Hallie M Smith
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, United States
| | - Leslie S Satin
- Brehm Diabetes Research Center, University of Michigan Medical School, Ann Arbor, MI, United States; Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Arthur Sherman
- Laboratory of Biological Modeling, NIDDK, NIH, Bethesda, MD, United States
| | - Craig S Nunemaker
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, United States; Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, United States.
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El-naseery NI, Elewa YHA, Ichii O, Kon Y. An experimental study of menopause induced by bilateral ovariectomy and mechanistic effects of mesenchymal stromal cell therapy on the parotid gland of a rat model. Ann Anat 2018; 220:9-20. [DOI: 10.1016/j.aanat.2018.06.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2018] [Revised: 06/18/2018] [Accepted: 06/21/2018] [Indexed: 12/14/2022]
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11
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Wang R, Zhang D, Zhang T, Zhao F, Lang H, Lin X, Pang X. The differentiation of human MSCs derived from adipose and amniotic tissues into insulin-producing cells, induced by PEI@Fe3O4 nanoparticles-mediated NRSF and SHH silencing. Int J Mol Med 2018; 42:2831-2838. [PMID: 30132574 DOI: 10.3892/ijmm.2018.3827] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2018] [Accepted: 08/06/2018] [Indexed: 11/05/2022] Open
Abstract
Type 1 diabetes involves the immunologically mediated destruction of insulin‑producing cells (IPCs) in the pancreatic islet. Mesenchymal stem cells (MSCs) have the ability to differentiate into IPCs and have become the most promising means for diabetes therapy. The present study demonstrated that human adipose‑derived stem cells (hADSCs) and human amniotic MSCs (hAMSCs) are able to differentiate into functional IPCs by knocking down neuronal restrictive silencing factor (NRSF) and Sonic hedgehog (SHH). In the current study, PEI@Fe3O4 nanoparticles (NPs) were used to deliver NRSF small interfering (si)RNA and SHH siRNA to hADSCs and hAMSCs. Following infection with PEI@Fe3O4 NPs containing NRSF siRNA and SHH siRNA, the MSCs were induced to differentiate into IPCs. Four specific genes for islet cells were expressed in the differentiated cells. These cells also produced and released insulin in a glucose‑responsive manner. These findings indicated that hADSCs and hAMSCs may be induced to differentiate into IPCs via PEI@Fe3O4 NP‑mediated NRSF and SHH silencing.
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Affiliation(s)
- Rui Wang
- Key Laboratory of Cell Biology and Medical Cell Biology, Department of Stem Cells and Regenerative Medicine, National Health Commission of China, Ministry of Education of China, China Medical University, Shenyang, Liaoning 110122, P.R. China
| | - Dianbao Zhang
- Key Laboratory of Cell Biology and Medical Cell Biology, Department of Stem Cells and Regenerative Medicine, National Health Commission of China, Ministry of Education of China, China Medical University, Shenyang, Liaoning 110122, P.R. China
| | - Tao Zhang
- Key Laboratory of Cell Biology and Medical Cell Biology, Department of Stem Cells and Regenerative Medicine, National Health Commission of China, Ministry of Education of China, China Medical University, Shenyang, Liaoning 110122, P.R. China
| | - Feng Zhao
- Key Laboratory of Cell Biology and Medical Cell Biology, Department of Stem Cells and Regenerative Medicine, National Health Commission of China, Ministry of Education of China, China Medical University, Shenyang, Liaoning 110122, P.R. China
| | - Hongxin Lang
- Key Laboratory of Cell Biology and Medical Cell Biology, Department of Stem Cells and Regenerative Medicine, National Health Commission of China, Ministry of Education of China, China Medical University, Shenyang, Liaoning 110122, P.R. China
| | - Xuewen Lin
- Key Laboratory of Cell Biology and Medical Cell Biology, Department of Stem Cells and Regenerative Medicine, National Health Commission of China, Ministry of Education of China, China Medical University, Shenyang, Liaoning 110122, P.R. China
| | - Xining Pang
- Key Laboratory of Cell Biology and Medical Cell Biology, Department of Stem Cells and Regenerative Medicine, National Health Commission of China, Ministry of Education of China, China Medical University, Shenyang, Liaoning 110122, P.R. China
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12
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Wehbe T, Chahine NA, Sissi S, Abou-Joaude I, Chalhoub L. Bone marrow derived stem cell therapy for type 2 diabetes mellitus. Stem Cell Investig 2016; 3:87. [PMID: 28066789 DOI: 10.21037/sci.2016.11.14] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Accepted: 11/21/2016] [Indexed: 12/19/2022]
Abstract
In this study, 6 patients with type 2 diabetes (T2D) underwent autologous bone marrow mononuclear stem cell (BM-MNSC) infusion into the celiac and superior mesenteric arteries without pretreatment with any myeloablative or immune-suppressive therapy. Five of 6 (83%) showed normalization of their fasting glucose and the glycosylated hemoglobin (HbA1C) with significant reduction of their medication requirements. The HbA1C dropped on average 2.2 points. The three patients with diabetic complications showed improvement or stabilization and most patients reported improved energy and stamina. The durations of response varied between 6 months and 2 years. No patients had any significant adverse effects.
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Affiliation(s)
- Tarek Wehbe
- Hematology Department, the Lebanese Canadian and Notre Dame University Hospitals, Beirut, Lebanon
| | - Nassim Abi Chahine
- Neurosurgery Department, the Lebanese Canadian Hospital, Beirut, Lebanon
| | - Salam Sissi
- Endocrinology Department, Al-Saydet Hospital, Zgharta, Lebanon
| | - Isabelle Abou-Joaude
- Endocrinology Department, The Middle East and Notre Dame University Hospitals, Beirut, Lebanon
| | - Louis Chalhoub
- Endocrinology Department, the Lebanese Canadian Hospital, Beirut, Lebanon
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Progenitor cells may aid successful islet compensation in metabolically healthy obese individuals. Med Hypotheses 2016; 86:97-9. [DOI: 10.1016/j.mehy.2015.10.027] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2015] [Accepted: 10/26/2015] [Indexed: 12/29/2022]
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14
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Allahverdi A, Abroun S, Jafarian A, Soleimani M, Taghikhani M, Eskandari F. Differentiation of Human Mesenchymal Stem Cells into Insulin Producing Cells by Using A Lentiviral Vector Carrying PDX1. CELL JOURNAL 2015. [PMID: 26199902 PMCID: PMC4503837 DOI: 10.22074/cellj.2016.3721] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Objective Type I diabetes is an immunologically-mediated devastation of insulin producing cells (IPCs) in the pancreatic islet. Stem cells that produce β-cells are a new
promising tool. Adult stem cells such as mesenchymal stem cells (MSCs) are self renewing multi potent cells showing capabilities to differentiate into ectodermal, mesodermal and endodermal tissues. Pancreatic and duodenal homeobox factor 1 (PDX1)
is a master regulator gene required for embryonic development of the pancreas and
is crucial for normal pancreatic islets activities in adults.
Materials and Methods We induced the over-expression of the PDX1 gene in human
bone marrow MSCs (BM-MSCs) by Lenti-PDX1 in order to generate IPCs. Next, we examine the ability of the cells by measuring insulin/c-peptide production and INSULIN and
PDX1 gene expressions.
Results After transduction, MSCs changed their morphology at day 5 and gradually differentiated into IPCs. INSULIN and PDX1 expressions were confirmed by real time polymerase chain reaction (RT-PCR) and immunostaining. IPC secreted insulin and C-peptide
in the media that contained different glucose concentrations.
Conclusion MSCs differentiated into IPCs by genetic manipulation. Our result
showed that lentiviral vectors could deliver PDX1 gene to MSCs and induce pancreatic differentiation.
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Affiliation(s)
- Amir Allahverdi
- Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Saied Abroun
- Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Arefeh Jafarian
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Masoud Soleimani
- Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mohammad Taghikhani
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Fatemeh Eskandari
- Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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Arivazhagan A, Krishna S, Yadav S, Shah HR, Kumar P, Ambasta RK. Synergy of bone marrow transplantation and curcumin ensue protective effects at early onset of diabetes in mice. J Diabetes 2015; 7:473-84. [PMID: 25060836 DOI: 10.1111/1753-0407.12204] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2013] [Revised: 06/21/2014] [Accepted: 07/13/2014] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The aim of this study was to investigate the early onset effects of diabetes on pro-angiogenic signaling pathway, total number of bone marrow cells, organs (pancreas and kidney) damage and the reversal effect of diabetes by combinatorial treatment of curcumin and bone marrow transplantation in streptozotocin (STZ) induced diabetic mice. METHODS In the present study, Streptozotocin induced diabetic mice were transplanted with bone marrow cells (2 × 10(6) ) followed by the administration of curcumin (80 mg/kg bodyweight). Effect of diabetes on the different organs was studied by H&E, Western blotting and immunofluorescence using vascular endothelial growth factor (VEGF), platelet/endothelial cell adhesion molecule (PECAM), insulin, Caspase-9 and Caspase-3 antibodies. RESULTS The effect of diabetes results in the reduction of the total cell number and viability of the bone marrow cells, organ degeneration and lower VEGF/PECAM expression. However, transplantation with normal bone marrow cells significantly reduced the blood glucose levels (above normal range) and initiated the organ regeneration via the VEGF/PECAM mediated manner. Curcumin treatment further reduced the blood glucose level (near normal); and accelerated the organ regeneration, enhanced VEGF/PECAM expression and decreased caspase expression level in the organs. Curcumin also had a protective role against the glucotoxicity test performed on the bone marrow cells. CONCLUSION This study suggests that bone marrow transplantation and curcumin administration is an effective treatment in reversing the early onset effects of diabetes via the VEGF/PECAM signaling pathway.
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Affiliation(s)
| | - Soni Krishna
- School of Biosciences and Technology, VIT University, Vellore, India
| | - Shivangi Yadav
- School of Biosciences and Technology, VIT University, Vellore, India
- Department of Experimental Medicine, La Sapienza University De Roma, Rome, Italy
| | - Harshit Rajesh Shah
- School of Biosciences and Technology, VIT University, Vellore, India
- Department of Clinical Immunology and Rheumatology, Hannover Medical School, Hannover, Germany
| | - Pravir Kumar
- School of Biosciences and Technology, VIT University, Vellore, India
- Department of Biotechnology, Delhi Technological University, Delhi, India
- Adjunct Faculty, Neurology Department, Tufts University School of Medicine, Boston, Massachusetts, USA
| | - Rashmi Kumar Ambasta
- School of Biosciences and Technology, VIT University, Vellore, India
- Department of Biotechnology, Delhi Technological University, Delhi, India
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16
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Dadheech N, Srivastava A, Paranjape N, Gupta S, Dave A, Shah GM, Bhonde RR, Gupta S. Swertisin an Anti-Diabetic Compound Facilitate Islet Neogenesis from Pancreatic Stem/Progenitor Cells via p-38 MAP Kinase-SMAD Pathway: An In-Vitro and In-Vivo Study. PLoS One 2015; 10:e0128244. [PMID: 26047129 PMCID: PMC4457488 DOI: 10.1371/journal.pone.0128244] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2014] [Accepted: 04/23/2015] [Indexed: 12/12/2022] Open
Abstract
Transplanting islets serves best option for restoring lost beta cell mass and function. Small bio-chemical agents do have the potential to generate new islets mass, however lack of understanding about mechanistic action of these small molecules eventually restricts their use in cell-based therapies for diabetes. We recently reported "Swertisin" as a novel islet differentiation inducer, generating new beta cells mass more effectively. Henceforth, in the present study we attempted to investigate the molecular signals that Swertisin generate for promoting differentiation of pancreatic progenitors into islet cells. To begin with, both human pancreatic progenitors (PANC-1 cells) and primary cultured mouse intra-islet progenitor cells (mIPC) were used and tested for Swertisin induced islet neogenesis mechanism, by monitoring immunoblot profile of key transcription factors in time dependent manner. We observed Swertisin follow Activin-A mediated MEPK-TKK pathway involving role of p38 MAPK via activating Neurogenin-3 (Ngn-3) and Smad Proteins cascade. This MAP Kinase intervention in differentiation of cells was confirmed using strong pharmacological inhibitor of p38 MAPK (SB203580), which effectively abrogated this process. We further confirmed this mechanism in-vivo in partial pancreatectomised (PPx) mice model, where we could show Swertisin exerted potential increase in insulin transcript levels with persistent down-regulation of progenitor markers like Nestin, Ngn-3 and Pancreatic Duodenal Homeobox Gene-1 (PDX-1) expression, within three days post PPx. With detailed molecular investigations here in, we first time report the molecular mode of action of Swertisin for islet neogenesis mediated through MAP Kinase (MEPK-TKK) pathway involving Ngn-3 and Smad transcriptional regulation. These findings held importance for developing Swertisin as potent pharmacological drug candidate for effective and endogenous differentiation of islets in cell based therapy for diabetes.
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Affiliation(s)
- Nidheesh Dadheech
- Molecular Endocrinology and Stem Cell Research Lab, Department of Biochemistry, Faculty of Science, The M S University of Baroda, Vadodara, Gujarat, India
| | - Abhay Srivastava
- Molecular Endocrinology and Stem Cell Research Lab, Department of Biochemistry, Faculty of Science, The M S University of Baroda, Vadodara, Gujarat, India
| | - Neha Paranjape
- Hislope College of Biotechnology, Nagpur, Maharashtra, India
| | - Shivika Gupta
- Hislope College of Biotechnology, Nagpur, Maharashtra, India
| | - Arpita Dave
- Molecular Endocrinology and Stem Cell Research Lab, Department of Biochemistry, Faculty of Science, The M S University of Baroda, Vadodara, Gujarat, India
| | - Girish M. Shah
- Skin Cancer Research Laboratory, Centre de Recherche du CHUL, CHUQ, Univerisity Laval, Quebec City, Quebec, Canada
| | - Ramesh R. Bhonde
- Manipal Hospital and Regenerative Medicine Centre, Manipal Hospital, Manipal, Karnataka, India
| | - Sarita Gupta
- Molecular Endocrinology and Stem Cell Research Lab, Department of Biochemistry, Faculty of Science, The M S University of Baroda, Vadodara, Gujarat, India
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17
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Lee KS, Kim TJ, Pratx G. Single-cell tracking with PET using a novel trajectory reconstruction algorithm. IEEE TRANSACTIONS ON MEDICAL IMAGING 2015; 34:994-1003. [PMID: 25423651 PMCID: PMC4392854 DOI: 10.1109/tmi.2014.2373351] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/05/2023]
Abstract
Virtually all biomedical applications of positron emission tomography (PET) use images to represent the distribution of a radiotracer. However, PET is increasingly used in cell tracking applications, for which the "imaging" paradigm may not be optimal. Here, we investigate an alternative approach, which consists in reconstructing the time-varying position of individual radiolabeled cells directly from PET measurements. As a proof of concept, we formulate a new algorithm for reconstructing the trajectory of one single moving cell directly from list-mode PET data. We model the trajectory as a 3-D B-spline function of the temporal variable and use nonlinear optimization to minimize the mean-square distance between the trajectory and the recorded list-mode coincidence events. Using Monte Carlo simulations (GATE), we show that this new algorithm can track a single source moving within a small-animal PET system with 3 mm accuracy provided that the activity of the cell [Bq] is greater than four times its velocity [mm/s]. The algorithm outperforms conventional ML-EM as well as the "minimum distance" method used for positron emission particle tracking (PEPT). The new method was also successfully validated using experimentally acquired PET data. In conclusion, we demonstrated the feasibility of a new method for tracking a single moving cell directly from PET list-mode data, at the whole-body level, for physiologically relevant activities and velocities.
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Affiliation(s)
- Keum Sil Lee
- Department of Radiology, Stanford University, CA 94305 USA
| | - Tae Jin Kim
- Department of Radiation Oncology, Stanford University, CA 94305 USA
| | - Guillem Pratx
- Department of Radiation Oncology, Stanford University, CA 94305 USA
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18
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Han SH, Cho E, Lee DK, Cho G, Kim YR, Cho H. Simulational validation of color magnetic particle imaging (cMPI). Phys Med Biol 2014; 59:6521-36. [DOI: 10.1088/0031-9155/59/21/6521] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
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Lu J, Dong H, Lin L, Wang Q, Huang L, Tan J. miRNA-302 facilitates reprogramming of human adult hepatocytes into pancreatic islets-like cells in combination with a chemical defined media. Biochem Biophys Res Commun 2014; 453:405-10. [PMID: 25268319 DOI: 10.1016/j.bbrc.2014.09.095] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Accepted: 09/22/2014] [Indexed: 01/09/2023]
Abstract
The direct conversion of one cell type to another without an intermediate pluripotent stage is required for regenerative therapies. The ventral pancreas and liver share a common developmental origin. Recent studies have shown that hepatocytes could be induced to transdifferentiate into insulin-producing cells. In this paper, we showed a new strategy to achieve the direct conversion of human hepatocytes into surrogate β cells. Hepatocytes were transfected with microRNA-302 (miR-302) mimic and Pdx1, Ngn3 and MafA expressed plasmids, followed by a chemical-defined culture system for maturation of insulin-secreting cells. Co-transfection of miR-302 mimic increased the transcription of pancreatic development-related genes (Sox17, Foxa2, and endogenous Pdx1). Furthermore, at the end of this treatment, hepatocytes became insulin expressed cells that released the hormone in response to a physiological glucose change in vitro. This work shows that miR-302 participation may facilitates the conversion of adult hepatocytes into pancreatic islets-like cells.
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Affiliation(s)
- Jun Lu
- FuJian Provincial Key Laboratory of Transplant Biology, Fuzhou General Hospital/ or Dongfang Hospital, Xiamen University, Fuzhou 350025, China.
| | - Huiyue Dong
- FuJian Provincial Key Laboratory of Transplant Biology, Fuzhou General Hospital/ or Dongfang Hospital, Xiamen University, Fuzhou 350025, China
| | - Lingjing Lin
- FuJian Provincial Key Laboratory of Transplant Biology, Fuzhou General Hospital/ or Dongfang Hospital, Xiamen University, Fuzhou 350025, China
| | - Qinghua Wang
- FuJian Provincial Key Laboratory of Transplant Biology, Fuzhou General Hospital/ or Dongfang Hospital, Xiamen University, Fuzhou 350025, China
| | - Lianghu Huang
- FuJian Provincial Key Laboratory of Transplant Biology, Fuzhou General Hospital/ or Dongfang Hospital, Xiamen University, Fuzhou 350025, China
| | - Jianming Tan
- FuJian Provincial Key Laboratory of Transplant Biology, Fuzhou General Hospital/ or Dongfang Hospital, Xiamen University, Fuzhou 350025, China.
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20
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Bahar Halpern K, Vana T, Walker MD. Paradoxical role of DNA methylation in activation of FoxA2 gene expression during endoderm development. J Biol Chem 2014; 289:23882-92. [PMID: 25016019 DOI: 10.1074/jbc.m114.573469] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The transcription factor FoxA2 is a master regulator of endoderm development and pancreatic beta cell gene expression. To elucidate the mechanisms underlying the activation of the FoxA2 gene during differentiation, we have compared the epigenetic status of undifferentiated human embryonic stem cells (hESCs), hESC-derived early endoderm stage cells (CXCR4+ cells), and pancreatic islet cells. Unexpectedly, a CpG island in the promoter region of the FoxA2 gene displayed paradoxically high levels of DNA methylation in expressing tissues (CXCR4+, islets) and low levels in nonexpressing tissues. This CpG island region was found to repress reporter gene expression and bind the Polycomb group protein SUZ12 and the DNA methyltransferase (DNMT)3b preferentially in undifferentiated hESCs as compared with CXCR4+ or islets cells. Consistent with this, activation of FoxA2 gene expression, but not CXCR4 or SOX17, was strongly inhibited by 5-aza-2'-deoxycytidine and by knockdown of DNMT3b. We hypothesize that in nonexpressing tissues, the lack of DNA methylation allows the binding of DNA methyltransferases and repressing proteins, such as Polycomb group proteins; upon differentiation, DNMT activation leads to CpG island methylation, causing loss of repressor protein binding. These results suggest a novel and unexpected role for DNA methylation in the activation of FoxA2 gene expression during differentiation.
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Affiliation(s)
- Keren Bahar Halpern
- From the Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Tal Vana
- From the Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Michael D Walker
- From the Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel
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21
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Sulé-Suso J, Forsyth N, Untereiner V, Sockalingum G. Vibrational spectroscopy in stem cell characterisation: is there a niche? Trends Biotechnol 2014; 32:254-62. [DOI: 10.1016/j.tibtech.2014.03.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2013] [Revised: 03/04/2014] [Accepted: 03/05/2014] [Indexed: 11/29/2022]
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Bose B, Katikireddy KR, Shenoy PS. Regenerative medicine for diabetes: differentiation of human pluripotent stem cells into functional β-cells in vitro and their proposed journey to clinical translation. VITAMINS AND HORMONES 2014; 95:223-48. [PMID: 24559920 DOI: 10.1016/b978-0-12-800174-5.00009-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
Diabetes is a group of metabolic diseases, rising globally at an alarming rate. Type 1 (juvenile diabetes) is the autoimmune version of diabetes where the pancreas is unable to produce insulin, whereas type 2 (adult onset diabetes) is caused due to insulin resistance of the cells. In either of the cases, elevated blood glucose levels are observed which leads to progressive comorbidity like renal failure, cardiovascular disease, retinopathy, etc. Metformin, sulphonyl urea group of drugs, as well as insulin injections are the available therapies. In advanced cases of diabetes, the drug alone or drug in combination with insulin injections are not able to maintain a steady level of blood glucose. Moreover, frequent insulin injections are rather cumbersome for the patient. So, regenerative medicine could be a permanent solution for fighting diabetes. Islet transplantation has been tried with a limited amount of success on a large population of diabetics because of the shortage of cadaveric pancreas. Therefore, the best proposed alternative is regenerative medicine involving human pluripotent stem cell (hPSC)-derived beta islet transplantation which can be obtained in large quantities. Efficient protocols for in vitro differentiation of hPSC into a large number of sustained insulin-producing beta cells for transplantation will be considered to be a giant leap to address global rise in diabetic cases. Although most of the protocols mimic in vivo pancreatic development in humans, considerable amount of lacuna persists for near-perfect differentiation strategies. Moreover, beta islets differentiated from hPSC have not yet been successfully translated under clinical scenario.
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Affiliation(s)
- Bipasha Bose
- Nanyang Technological University, School of Biological Sciences, NTU Lab Location @ Level 2 Singapore Institute for Clinical Sciences, Brenner Centre for Molecular Medicine, Singapore, Singapore.
| | | | - P Sudheer Shenoy
- Nanyang Technological University, School of Biological Sciences, NTU Lab Location @ Level 2 Singapore Institute for Clinical Sciences, Brenner Centre for Molecular Medicine, Singapore, Singapore
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23
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Ilie I, Ilie R, Mocan T, Tabaran F, Iancu C, Mocan L. Nicotinamide-functionalized multiwalled carbon nanotubes increase insulin production in pancreatic beta cells via MIF pathway. Int J Nanomedicine 2013; 8:3345-53. [PMID: 24039418 PMCID: PMC3770514 DOI: 10.2147/ijn.s48223] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Recent data in the literature support the role of nicotinamide (NA) as a pharmacologic agent that stimulates pancreatic beta-cells to produce insulin in vitro. There are data showing that carbon nanotubes may be useful in initiating and maintaining cellular metabolic responses. This study shows that administration of multiwalled carbon nanotubes (MWCNTs) functionalized with nicotinamide (NA-MWCNTs) leads to significant insulin production compared with individual administration of NA, MWCNTs, and a control solution. Treatment of 1.4E7 cells for 30 minutes with NA-MWCNTs at concentrations ranging from 1 mg/L to 20 mg/L resulted in significantly increased insulin release (0.18 ± 0.026 ng/mL for 1 mg/L, 0.21 ± 0.024 ng/mL for 5 mg/L, and 0.27 ± 0.028 ng/mL for 20 mg/L). Thus, compared with cells treated with NA only (0.1 ± 0.01 ng/mL for 1 mg/L, 0.12 ± 0.017 ng/mL for 5 mg/L, and 0.17 ± 0.01 ng/mL for 20 mg/L) we observed a significant positive effect on insulin release in cells treated with NA-MWCNTs. The results were confirmed using flow cytometry, epifluorescence microscopy combined with immunochemistry staining, and enzyme-linked immunosorbent assay techniques. In addition, using immunofluorescence microscopy techniques, we were able to demonstrate that MWCNTs enhance insulin production via the macrophage migration inhibitory factor pathway. The application and potential of NA combined with MWCNTs as an antidiabetic agent may represent the beginning of a new chapter in the nanomediated treatment of diabetes mellitus.
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Affiliation(s)
- Ioana Ilie
- Department of Endocrinology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Razvan Ilie
- Department of Microbiology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Teodora Mocan
- Department of Physiology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Flaviu Tabaran
- Third Surgery Clinic, Department of Nanomedicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Cornel Iancu
- Third Surgery Clinic, Department of Nanomedicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Lucian Mocan
- Third Surgery Clinic, Department of Nanomedicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
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24
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Mesenchymal stem cell therapy in diabetes mellitus: progress and challenges. J Nucleic Acids 2013; 2013:194858. [PMID: 23762531 PMCID: PMC3666198 DOI: 10.1155/2013/194858] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2013] [Accepted: 04/18/2013] [Indexed: 02/07/2023] Open
Abstract
Advanced type 2 diabetes mellitus is associated with significant morbidity and mortality due to cardiovascular, nervous, and renal complications. Attempts to cure diabetes mellitus using islet transplantation have been successful in providing a source for insulin secreting cells. However, limited donors, graft rejection, the need for continued immune suppression, and exhaustion of the donor cell pool prompted the search for a more sustained source of insulin secreting cells. Stem cell therapy is a promising alternative for islet transplantation in type 2 diabetic patients who fail to control hyperglycemia even with insulin injection. Autologous stem cell transplantation may provide the best outcome for those patients, since autologous cells are readily available and do not entail prolonged hospital stays or sustained immunotoxic therapy. Among autologous adult stem cells, mesenchymal stem cells (MSCs) therapy has been applied with varying degrees of success in both animal models and in clinical trials. This review will focus on the advantages of MSCs over other types of stem cells and the possible mechanisms by which MSCs transplant restores normoglycemia in type 2 diabetic patients. Sources of MSCs including autologous cells from diabetic patients and the use of various differentiation protocols in relation to best transplant outcome will be discussed.
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25
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Human embryonic stem cell differentiation into insulin secreting β-cells for diabetes. Cell Biol Int 2013; 36:1013-20. [PMID: 22897387 DOI: 10.1042/cbi20120210] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
hESC (human embryonic stem cells), when differentiated into pancreatic β ILC (islet-like clusters), have enormous potential for the cell transplantation therapy for Type 1 diabetes. We have developed a five-step protocol in which the EBs (embryoid bodies) were first differentiated into definitive endoderm and subsequently into pancreatic lineage followed by formation of functional endocrine β islets, which were finally matured efficiently under 3D conditions. The conventional cytokines activin A and RA (retinoic acid) were used initially to obtain definitive endoderm. In the last step, ILC were further matured under 3D conditions using amino acid rich media (CMRL media) supplemented with anti-hyperglycaemic hormone-Glp1 (glucagon-like peptide 1) analogue Liraglutide with prolonged t(½) and Exendin 4. The differentiated islet-like 3D clusters expressed bonafide mature and functional β-cell markers-PDX1 (pancreatic and duodenal homoeobox-1), C-peptide, insulin and MafA. Insulin synthesis de novo was confirmed by C-peptide ELISA of culture supernatant in response to varying concentrations of glucose as well as agonist and antagonist of functional 3D β islet cells in vitro. Our results indicate the presence of almost 65% of insulin producing cells in 3D clusters. The cells were also found to ameliorate hyperglycaemia in STZ (streptozotocin) induced diabetic NOD/SCID (non-obese diabetic/severe combined immunodeficiency) mouse up to 96 days of transplantation. This protocol provides a basis for 3D in vitro generation of long-term in vivo functionally viable islets from hESC.
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26
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Bose B, Shenoy P S. Non insulin producing cell line, MIA PaCa-2 is rendered insulin producing in vitro via mesenchymal epithelial transition. J Cell Biochem 2013; 114:1642-52. [PMID: 23386380 DOI: 10.1002/jcb.24506] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2012] [Accepted: 01/16/2013] [Indexed: 11/12/2022]
Abstract
We used non-insulin producing pancreatic carcinoma cell line, MIA PaCa-2 and have modulated its culture conditions by using 1% matrigel as extracellular matrix, N2, B27 growth supplements and serum free conditions. Expression of markers was analyzed using qRT-PCR, immunofluorescence and in vitro functional assay for insulin and C-peptide release was assessed using insulin and C-peptide ELISA, respectively. The cells grown under this altered culture conditions have exhibited a transition in the morphology from mesenchymal to epithelial with extensive piling up of cells. A reduction in doubling time from 40 to 18 h, upregulation of beta islet specific markers like pancreatic duodenal homeobox-1 (Pdx-1), C-peptide, insulin, and disappearance of markers like vimentin were observed. On the functional level, the altered morphology bearing cells released high levels of insulin in response to 10 µM tolbutamide (an activator of insulin pathway) and reduced insulin secretion in response to 50 µM nifedipine (inhibitor of the pathway). On the contrary, the original cells (mesenchymal morphology) had failed to release any insulin in response to varying concentrations of glucose and also the activators and inhibitors of the insulin pathway. This investigation thus provides a basis for using this basic developmental biology phenomenon mesenchymal to epithelial transition as a strategy to generate a large number of functional islets from stem cells of mesenchymal origin.
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Affiliation(s)
- Bipasha Bose
- Embryonic Stem Cell Group Reliance Life Sciences Pvt. Ltd. Dhirubhai Ambani Life Sciences Centre, Navi Mumbai, India.
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27
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Hosseinkhani M, Shirazi R, Rajaei F, Mahmoudi M, Mohammadi N, Abbasi M. Engineering of the embryonic and adult stem cell niches. IRANIAN RED CRESCENT MEDICAL JOURNAL 2013; 15:83-92. [PMID: 23682319 PMCID: PMC3652509 DOI: 10.5812/ircmj.7541] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/01/2012] [Accepted: 01/08/2013] [Indexed: 12/15/2022]
Abstract
CONTEXT Stem cells have the potential to generate a renewable source of cells for regenerative medicine due to their ability to self-renew and differentiate to various functional cell types of the adult organism. The extracellular microenvironment plays a pivotal role in controlling stem cell fate responses. Therefore, identification of appropriate environmental stimuli that supports cellular proliferation and lineage-specific differentiation is critical for the clinical application of the stem cell therapies. EVIDENCE ACQUISITION Traditional methods for stem cells culture offer limited manipulation and control of the extracellular microenvironment. Micro engineering approaches are emerging as powerful tools to control stem cell-microenvironment interactions and for performing high-throughput stem cell experiments. RESULTS In this review, we provided an overview of the application of technologies such as surface micropatterning, microfluidics, and engineered biomaterials for directing stem cell behavior and determining the molecular cues that regulate cell fate decisions. CONCLUSIONS Stem cells have enormous potential for therapeutic and pharmaceutical applications, because they can give rise to various cell types. Despite their therapeutic potential, many challenges, including the lack of control of the stem cell microenvironment remain. Thus, a greater understanding of stem cell biology that can be used to expand and differentiate embryonic and adult stem cells in a directed manner offers great potential for tissue repair and regenerative medicine.
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Affiliation(s)
- Mohsen Hosseinkhani
- Department of Anatomy, Qazvin University of Medical Science, Qazvin, IR Iran
- Corresponding author: Mohsen Hosseinkhani, Department of Anatomy, Qazvin University of Medical Science, Qazvin, IR Iran. Tel: +98-2188274683, Fax: +98-2188274683, E-mail:
| | - Reza Shirazi
- Department of Anatomy, Qazvin University of Medical Science, Qazvin, IR Iran
| | - Farzad Rajaei
- Department of Anatomy, Qazvin University of Medical Science, Qazvin, IR Iran
| | - Masoud Mahmoudi
- Department of Anatomy, Qazvin University of Medical Science, Qazvin, IR Iran
| | - Navid Mohammadi
- Department of Community Medicine, Tehran University of Medical Science, Tehran, IR Iran
| | - Mahnaz Abbasi
- Department of Rheumatology, Qazvin University of Medical Science, Qazvin, IR Iran
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Gálvez P, Clares B, Hmadcha A, Ruiz A, Soria B. Development of a cell-based medicinal product: regulatory structures in the European Union. Br Med Bull 2013. [PMID: 23184855 DOI: 10.1093/bmb/lds036] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
INTRODUCTION New therapies with genes, tissues and cells have taken the emerging field for the treatment of many diseases. Advances on stem cell therapy research have led to international regulatory agencies to harmonize and regulate the development of new medicines with stem cells. SOURCES OF DATA European Medicines Agency on September 15, 2012. AREAS OF AGREEMENT Cell therapy medicinal products should be subjected to the same regulatory principles than any other medicine. AREAS OF CONTROVERSY Their technical requirements for quality, safety and efficacy must be more specific and stringent than other biologic products and medicines. GROWING POINTS Cell therapy medicinal products are at the cutting edge of innovation and offer a major hope for various diseases for which there are limited or no therapeutic options. AREAS TIMELY FOR DEVELOPING RESEARCH The development of cell therapy medicinal products constitutes an alternative therapeutic strategy to conventional clinical therapy, for which no effective cure was previously available.
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Stanekzai J, Isenovic ER, Mousa SA. Treatment options for diabetes: potential role of stem cells. Diabetes Res Clin Pract 2012; 98:361-8. [PMID: 23020931 DOI: 10.1016/j.diabres.2012.09.010] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2012] [Revised: 06/27/2012] [Accepted: 09/04/2012] [Indexed: 01/09/2023]
Abstract
There are diseases and injuries in which a patient's cells or tissues are destroyed that can only be adequately corrected by tissue or organ transplants. Stem cells may be able to generate new tissue and even cure diseases for which there is no adequate therapy. Type 1 diabetes (T1DM), an insulin-dependent diabetes, is a chronic disease affecting genetically predisposed individuals, in which insulin-secreting beta (β)-cells within pancreatic islets of Langerhans are selectively and irreversibly destroyed by autoimmune assault. Type 2 diabetes (T2DM) is characterized by a gradual decrease in insulin sensitivity in peripheral tissues and the liver (insulin resistance), followed by a gradual decline in β-cell function and insulin secretion. Successful replacing of damaged β-cells has shown considerable potential in treating T1DM, but lack of adequate donors is a barrier. The literature suggests that embryonic and adult stem cells are promising alternatives in long-term treatment of diabetes. However, any successful strategy should address both the need for β-cell replacement and controlling the autoimmune response to cells that express insulin. This review summarizes the current knowledge of options and the potential of stem cell transplantation in diabetes treatment.
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Affiliation(s)
- Jamil Stanekzai
- Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, 1 Discovery Drive, Rensselaer, NY 12144, USA
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Liang QL, Mo Z, Li XF, Wang XX, Li RM. Pdx1 protein induces human embryonic stem cells into the pancreatic endocrine lineage. Cell Biol Int 2012; 37:2-10. [PMID: 23339089 DOI: 10.1002/cbin.10001] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2012] [Accepted: 09/05/2012] [Indexed: 12/24/2022]
Affiliation(s)
- Qing Le Liang
- Hubei Key Laboratory of Clinic Centre, Tai-He Hospital; Hubei University of Medicine; 32 S. Renmin Road, Shiyan, Hubei 442000 China
| | - Zhengying Mo
- Oncology Department of Tai-He Hospital; Hubei University of Medicine; 32 S. Renmin Road, Shiyan, Hubei 442000 China
| | - Xue Feng Li
- Endocrine Department of Tai-He Hospital; Hubei University of Medicine; 32 S. Renmin Road, Shiyan, Hubei 442000 China
| | - Xiao Xun Wang
- Hubei Key Laboratory of Clinic Centre, Tai-He Hospital; Hubei University of Medicine; 32 S. Renmin Road, Shiyan, Hubei 442000 China
| | - Rui Ming Li
- Hubei Key Laboratory of Clinic Centre, Tai-He Hospital; Hubei University of Medicine; 32 S. Renmin Road, Shiyan, Hubei 442000 China
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Hammerman MR. Pancreas and kidney transplantation using embryonic donor organs. Organogenesis 2012; 1:3-13. [PMID: 19521554 DOI: 10.4161/org.1.1.1008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2004] [Accepted: 06/01/2004] [Indexed: 01/09/2023] Open
Abstract
One novel solution to the shortage of human organs available for transplantation envisions 'growing' new organs in situ. This can be accomplished by transplantation of developing organ anlagen/primordia. We and others have shown that renal anlagen (metanephroi) transplanted into animal hosts undergo differentiation and growth, become vascularized by blood vessels of host origin and exhibit excretory function. Metanephroi can be stored for up to 3 days in vitro prior to transplantation with no impairment in growth or function post-implantation. Metanephroi can be transplanted across both concordant (rat to mouse) and highly disparate (pig to rodent) xenogeneic barriers. Similarly, pancreatic anlagen can be transplanted across concordant and highly disparate barriers, and undergo growth, differentiation and secrete insulin in a physiological manner following intra-peritoneal placement. Implantation of the embryonic pancreas, is followed by selective differentiation of islet components. Here we review studies exploring the potential therapeutic applicability for organogenesis of the kidney or endocrine pancreas.
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Roche E, Burcin MM, Esser S, Rüdiger M, Soria B. The use of gating technology in bioengineering insulin-secreting cells from embryonic stem cells. Cytotechnology 2011; 41:145-51. [PMID: 19002951 DOI: 10.1023/a:1024878807264] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Embryonic stem cells display the ability to differentiate in vitro into a variety of cell types. This process is induced by embryoid body formation, addition of several soluble growth factors to the culture medium and other strategies. However, none of the used factors is capable to drive differentiation to only one specific celltype. The use of gating technology has allowed to partially overcome this problem. The rational behind this technique is based on the transfection of stem cells with a transgene carrying expression cassettes for a cell type specific promoter, regulating expression ofa selectable marker to select one cell lineage from other cell lineages.Using this system, we have obtained insulin-secreting cells by transfecting mouse embryonic stem cells with a DNA construct providing resistance to neomycin under the control of the regulatory regions of the human insulin gene. Furthermore, gating technology has been successfully used to isolate other cell types such as cardiomyocytes and neural precursors from undifferentiated embryonic stem cells. This review focuses on the possibilities offered by this technology in embryonic stem cell bioengineering, mainly to obtain insulin-secreting cells. Advantages and considerations of this selection system will be also discussed.
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Affiliation(s)
- Enrique Roche
- Institute of Bioengineering, University Miguel Hernandez, San Juan, Alicante, Spain
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Deorosan B, Nauman EA. The role of glucose, serum, and three-dimensional cell culture on the metabolism of bone marrow-derived mesenchymal stem cells. Stem Cells Int 2011; 2011:429187. [PMID: 21603146 PMCID: PMC3096318 DOI: 10.4061/2011/429187] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2010] [Accepted: 02/07/2011] [Indexed: 12/19/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have become a critical addition to all facets of tissue engineering. While most in vitro research has focused on their behavior in two-dimensional culture, relatively little is known about the cells' behavior in three-dimensional culture, especially with regard to their metabolic state. To evaluate MSC metabolism during twodimensional culture, murine bone marrow-derived MSCs were cultured for one week using twelve different medium compositions, varying in both glucose and fetal bovine serum (FBS)
concentrations. The results indicate that glucose concentration was the more important factor in sustaining cell growth and viability. To evaluate metabolic state during three-dimensional culture, MSCs were cultured for one week using two different medium compositions and two different concentrations of collagen gel matrix. The medium compositions only varied in glucose concentration. The results indicate that glucose and extracellular matrix were significant
factors in the metabolic response of the cells. However, cells cultured in low density collagen exhibited considerable cell death, likely because of physical contraction of the collagen hydrogel which was not observed in the higher density collagen. These findings will be useful to the development of in vitro cell culture models that properly mimic in vivo physiological processes.
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Affiliation(s)
- Byron Deorosan
- Weldon School of Biomedical Engineering, Purdue University, 585 Purdue Mall, West Lafayette, IN 47907-2088, USA
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Hajare M, Delphine C, Youssef H, Andree D, Jean-Claude V, nadia BJ. Osteogenic differentiation of ES cell-derived EBs mediated by embedded BMP-2 and TGF-beta-1 in a polyelectrolyte multilayer film. ACTA ACUST UNITED AC 2011. [DOI: 10.1557/proc-0950-d10-04] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
ABSTRACTIn recent years, considerable effort has been devoted to the design and controlled fabrication of structured materials with functional properties. The layer by layer buildup of polyelectrolyte multilayer films (PEM films) from oppositely charged polyelectrolytes1 offers new opportunities for the preparation of functionalized biomaterial coatings. This technique allows the preparation of supramolecular nano-architectures exhibiting specific properties in terms of control of cell activation and may also play a role in the development of local drug delivery systems. Peptides, proteins or DNA, chemically bound to polyelectrolytes, adsorbed or embedded in PEM films, have been shown to retain their biological activities. Recently, tissue engineering has merged with stem cell technology with interest to develop new sources of transplantable material for injury or disease treatment. Eminently interesting, are bone and joint injuries disorders because of the low self-regenerating capacity of the matrix secreting cells. We present here for the first time that embedded BMP-2 and TGFβ1 in a multilayered polyelectrolyte film can drive embryonic stem cells to the cartilage or bone differentiation depending on supplementary co-factors. We selected a model system made from layer by layer poly-ℓ-glutamic acid (PℓGA) and poly-ℓ-lysine succinylated (PℓLs) films into which BMP-2 and TGFβ1 have been embedded. Our results demonstrate clearly that we are able to induce osteogenesis in embryonic stem cells mediated by growth factors embedded in a polyelectrolyte multilayer film.
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Facca S, Cortez C, Mendoza-Palomares C, Messadeq N, Dierich A, Johnston APR, Mainard D, Voegel JC, Caruso F, Benkirane-Jessel N. Active multilayered capsules for in vivo bone formation. Proc Natl Acad Sci U S A 2010; 107:3406-11. [PMID: 20160118 PMCID: PMC2840428 DOI: 10.1073/pnas.0908531107] [Citation(s) in RCA: 110] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Interest in the development of new sources of transplantable materials for the treatment of injury or disease has led to the convergence of tissue engineering with stem cell technology. Bone and joint disorders are expected to benefit from this new technology because of the low self-regenerating capacity of bone matrix secreting cells. Herein, the differentiation of stem cells to bone cells using active multilayered capsules is presented. The capsules are composed of poly-L-glutamic acid and poly-L-lysine with active growth factors embedded into the multilayered film. The bone induction from these active capsules incubated with embryonic stem cells was demonstrated in vitro. Herein, we report the unique demonstration of a multilayered capsule-based delivery system for inducing bone formation in vivo. This strategy is an alternative approach for in vivo bone formation. Strategies using simple chemistry to control complex biological processes would be particularly powerful, as they make production of therapeutic materials simpler and more easily controlled.
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Affiliation(s)
- S. Facca
- a: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 977, Faculté de Médecine, 11 rue Humann, 67085 Strasbourg Cedex, France, b: Faculté de Chirurgie Dentaire Université de Strasbourg (UdS), 1 place de l’hôpital, 67084, Strasbourg, France
| | - C. Cortez
- Center for Nanoscience and Nanotechnology, Department of Chemical and Bimolecular Engineering, University of Melbourne, Victoria 3010, Australia
| | - C. Mendoza-Palomares
- a: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 977, Faculté de Médecine, 11 rue Humann, 67085 Strasbourg Cedex, France, b: Faculté de Chirurgie Dentaire Université de Strasbourg (UdS), 1 place de l’hôpital, 67084, Strasbourg, France
| | - N. Messadeq
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut Clinique de la Souris (ICS), Centre National de la Recherche Scientifique (CNRS)/Institut National de la Santé et de la Recherche Médicale INSERM/UdS, Collège de France, BP 10142, Strasbourg, France
| | - A. Dierich
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut Clinique de la Souris (ICS), Centre National de la Recherche Scientifique (CNRS)/Institut National de la Santé et de la Recherche Médicale INSERM/UdS, Collège de France, BP 10142, Strasbourg, France
| | - A. P. R. Johnston
- Center for Nanoscience and Nanotechnology, Department of Chemical and Bimolecular Engineering, University of Melbourne, Victoria 3010, Australia
| | - D. Mainard
- Unité Mixte de Recherches 7561, Center National de la Recherche Scientifique-Université de Nancy, Faculté de Médecine, Vandoeuvre les Nancy, France; and
- Center Hospitalier Universtaire de Nancy, Hôpital Central (service d’orthopédie) 29 Avenue du Maréchal de Lattre de Tassigny, 54000 Nancy, France
| | - J.-C. Voegel
- a: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 977, Faculté de Médecine, 11 rue Humann, 67085 Strasbourg Cedex, France, b: Faculté de Chirurgie Dentaire Université de Strasbourg (UdS), 1 place de l’hôpital, 67084, Strasbourg, France
| | - F. Caruso
- Center for Nanoscience and Nanotechnology, Department of Chemical and Bimolecular Engineering, University of Melbourne, Victoria 3010, Australia
| | - N. Benkirane-Jessel
- a: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 977, Faculté de Médecine, 11 rue Humann, 67085 Strasbourg Cedex, France, b: Faculté de Chirurgie Dentaire Université de Strasbourg (UdS), 1 place de l’hôpital, 67084, Strasbourg, France
- Center for Nanoscience and Nanotechnology, Department of Chemical and Bimolecular Engineering, University of Melbourne, Victoria 3010, Australia
- Center Hospitalier Universtaire de Nancy, Hôpital Central (service d’orthopédie) 29 Avenue du Maréchal de Lattre de Tassigny, 54000 Nancy, France
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Nikolic B, Faintuch S, Goldberg SN, Kuo MD, Cardella JF. Stem Cell Therapy: A Primer for Interventionalists and Imagers. J Vasc Interv Radiol 2009; 20:999-1012. [DOI: 10.1016/j.jvir.2009.04.075] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2009] [Revised: 04/24/2009] [Accepted: 04/28/2009] [Indexed: 02/06/2023] Open
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Singh P, Williams DJ. Cell therapies: realizing the potential of this new dimension to medical therapeutics. J Tissue Eng Regen Med 2008; 2:307-19. [DOI: 10.1002/term.108] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Abstract
Type 1 diabetes is characterized by the selective destruction of pancreatic β-cells caused by an autoimmune attack. Type 2 diabetes is a more complex pathology which, in addition to β-cell loss caused by apoptotic programs, includes β-cell dedifferentiation and peripheric insulin resistance. β-Cells are responsible for insulin production, storage and secretion in accordance to the demanding concentrations of glucose and fatty acids. The absence of insulin results in death and therefore diabetic patients require daily injections of the hormone for survival. However, they cannot avoid the appearance of secondary complications affecting the peripheral nerves as well as the eyes, kidneys and cardiovascular system. These afflictions are caused by the fact that external insulin injection does not mimic the tight control that pancreaticderived insulin secretion exerts on the body’s glycemia. Restoration of damaged β-cells by transplantation from exogenous sources or by endocrine pancreas regeneration would be ideal therapeutic options. In this context, stem cells of both embryonic and adult origin (including β-cell/islet progenitors) offer some interesting alternatives, taking into account the recent data indicating that these cells could be the building blocks from which insulin secreting cells could be generated in vitro under appropriate culture conditions. Although in many cases insulin-producing cells derived from stem cells have been shown to reverse experimentally induced diabetes in animal models, several concerns need to be solved before finding a definite medical application. These refer mainly to the obtainment of a cell population as similar as possible to pancreatic β-cells, and to the problems related with the immune compatibility and tumor formation. This review will summarize the different approaches that have been used to obtain insulin-producing cells from embryonic and adult stem cells, and the main problems that hamper the clinical applications of this technology.
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Abstract
Stem cells, although difficult to define, hold great promise as tools for understanding development and as therapeutic agents. However, as with any new field, uncritical enthusiasm can outstrip reality. In this review, we have listed nine common myths that we believe affect our approach to evaluating stem cells for therapy. We suggest that careful consideration needs to be given to each of these issues when evaluating a particular cell for its use in therapy. Data need to be collected and reported for failed as well as successful experiments and a rigorous scientific approach taken to evaluate the undeniable promise of stem cell biology.
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Affiliation(s)
- Tim Magnus
- Stem Cell Section, Laboratory of Neurosciences, National Institute on Aging, NIH333 Cassell Drive, Room 406A, Baltimore, MD 21224, USA
| | - Ying Liu
- Stem Cell Section, Laboratory of Neurosciences, National Institute on Aging, NIH333 Cassell Drive, Room 406A, Baltimore, MD 21224, USA
| | - Graham C Parker
- Children's Research Center of Michigan, The Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine, Children's Hospital of MichiganDetroit, MI 48201, USA
| | - Mahendra S Rao
- Stem Cell Section, Laboratory of Neurosciences, National Institute on Aging, NIH333 Cassell Drive, Room 406A, Baltimore, MD 21224, USA
- Corporate Research Laboratories, Invitrogen Corporation1620 Faraday Avenue, Carlsbad, CA 92008, USA
- Author for correspondence ()
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Soria B, Bedoya FJ, Tejedo JR, Hmadcha A, Ruiz-Salmerón R, Lim S, Martin F. Cell therapy for diabetes mellitus: an opportunity for stem cells? Cells Tissues Organs 2008; 188:70-7. [PMID: 18305378 DOI: 10.1159/000119407] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Diabetes is a chronic disease characterized by a deficit in beta cell mass and a failure of glucose homeostasis. Both circumstances result in a variety of severe complications and an overall shortened life expectancy. Thus, diabetes represents an attractive candidate for cell therapy. Reversal of diabetes can be achieved through pancreas and islet transplantation, but shortage of donor organs has prompted an intensive search for alternative sources of beta cells. This achievement has stimulated the search for appropriate stem cell sources. Both embryonic and adult stem cells have been used to generate surrogate beta cells or otherwise restore beta cell functioning. In this regard, several studies have reported the generation of insulin-secreting cells from embryonic and adult stem cells that normalized blood glucose values when transplanted into diabetic animal models. Due to beta cell complexity, insulin-producing cells generated from stem cells do not possess all beta cell attributes. This indicates the need for further development of methods for differentiation and selection of completely functional beta cells. While these problems are overcome, diabetic patients may benefit from therapeutic strategies based on autologous stem cell therapies addressing late diabetic complications. In this article, we discuss the recent progress in the generation of insulin-producing cells from embryonic and adult stem cells, together with the challenges for the clinical use of diabetes stem cell therapy.
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Affiliation(s)
- B Soria
- CABIMER (Andalusian Center for Molecular Biology and Regenerative Medicine), Isla de la Cartuja, Seville, Spain.
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Fong CY, Richards M, Manasi N, Biswas A, Bongso A. Comparative growth behaviour and characterization of stem cells from human Wharton's jelly. Reprod Biomed Online 2008; 15:708-18. [PMID: 18062871 DOI: 10.1016/s1472-6483(10)60539-1] [Citation(s) in RCA: 110] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Human embryonic stem cells (hESC) face ethical sensitivities and the problem of teratoma formation. Although Wharton's jelly stem cells (WJSC), also of embryonic origin, may not face such ethical concerns, it is not definitely known whether under hESC culture conditions they would be as pluripotent as hESC. WJSC grown on plastic showed two types of morphology (epithelioid and short fibroblastic) in primary culture depending on the culture medium used, and only fibroblastic morphology when passaged. When grown in the presence of hESC medium on mouse feeder cells, they produced atypical colonies containing hESC-like cells with high-nuclear cytoplasmic ratios and prominent nucleoli. They were positive for the hESC markers Tra-1-60, Tra-1-81, SSEA-1, SSEA-4, Oct-4 and alkaline phosphatase, negative for SSEA-3, showed normal karyotypes, developed embryoid body (EB)-like structures, did not produce teratomas in SCID mice and differentiated into neuronal derivatives. They were also positive for the mesenchymal CD markers (CD105, CD90, CD44), negative for CD34 and HLA, and although nine out of 10 embryonic stem cell genomic markers were detectable, these were expressed at low levels. WJSC are thus not as pluripotent as hESC but widely multipotent, and have the advantages of being able to be scaled up easily and not inducing teratomas.
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Affiliation(s)
- C Y Fong
- Department of Obstetrics and Gynaecology, National University of Singapore, Kent Ridge, Singapore 119074
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43
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Perin L, Giuliani S, Jin D, Sedrakyan S, Carraro G, Habibian R, Warburton D, Atala A, De Filippo RE. Renal differentiation of amniotic fluid stem cells. Cell Prolif 2007; 40:936-48. [PMID: 18021180 DOI: 10.1111/j.1365-2184.2007.00478.x] [Citation(s) in RCA: 169] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
OBJECTIVES The role of stem cells in regenerative medicine is evolving rapidly. Here, we describe the application, for kidney regeneration, of a novel non-genetically modified stem cell, derived from human amniotic fluid. We show that these pluripotent cells can develop and differentiate into de novo kidney structures during organogenesis in vitro. MATERIALS AND METHODS Human amniotic fluid-derived stem cells (hAFSCs) were isolated from human male amniotic fluid obtained between 12 and 18 weeks gestation. Green fluorescent protein and Lac-Z-transfected hAFSCs were microinjected into murine embryonic kidneys (12.5-18 days gestation) and were maintained in a special co-culture system in vitro for 10 days. Techniques of live microscopy, histology, chromogenic in situ hybridization and reverse transcriptase polymerase chain reaction were used to characterize the hAFSCs during their integration and differentiation in concert with the growing organ. RESULTS Green fluorescent protein and Lac-Z-transfected hAFSCs demonstrated long-term viability in organ culture. Histological analysis of injected kidneys revealed that hAFSCs were capable of contributing to the development of primordial kidney structures including renal vesicle, C- and S-shaped bodies. Reverse transcriptase polymerase chain reaction confirmed expression of early kidney markers for: zona occludens-1, glial-derived neurotrophic factor and claudin. CONCLUSIONS Human amniotic fluid-derived stem cells may represent a potentially limitless source of ethically neutral, unmodified pluripotential cells for kidney regeneration.
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Affiliation(s)
- L Perin
- Childrens Hospital Los Angeles, Saban Research Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA
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Stem cell potential for type 1 diabetes therapy. Open Life Sci 2007. [DOI: 10.2478/s11535-007-0035-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
AbstractStem cells have been considered as a useful tool in Regenerative Medicine due to two main properties: high rate of self-renewal, and their potential to differentiate into all cell types present in the adult organism. Depending on their origin, these cells can be grouped into embryonic or adult stem cells. Embryonic stem cells are obtained from the inner cell mass of blastocyst, which appears during embryonic day 6 of human development. Adult stem cells are present within various tissues of the organism and are responsible for their turnover and repair. In this sense, these cells open new therapeutic possibilities to treat degenerative diseases such as type 1 diabetes. This pathology is caused by the autoimmune destruction of pancreatic β-cells, resulting in the lack of insulin production. Insulin injection, however, cannot mimic β-cell function, thus causing the development of important complications. The possibility of obtaining β-cell surrogates from either embryonic or adult stem cells to restore insulin secretion will be discussed in this review.
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Mesples AD, Pretiñe B, Bellomo R. Tratamiento de la diabetes mellitus tipo 1 con implante pancreático de células madre adultas autólogas. ENDOCRINOLOGÍA Y NUTRICIÓN 2007; 54:512-518. [DOI: 10.1016/s1575-0922(07)71497-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Lin S, Xie X, Patel MR, Yang YH, Li Z, Cao F, Gheysens O, Zhang Y, Gambhir SS, Rao JH, Wu JC. Quantum dot imaging for embryonic stem cells. BMC Biotechnol 2007; 7:67. [PMID: 17925032 PMCID: PMC2174930 DOI: 10.1186/1472-6750-7-67] [Citation(s) in RCA: 116] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2007] [Accepted: 10/09/2007] [Indexed: 11/21/2022] Open
Abstract
Background Semiconductor quantum dots (QDs) hold increasing potential for cellular imaging both in vitro and in vivo. In this report, we aimed to evaluate in vivo multiplex imaging of mouse embryonic stem (ES) cells labeled with Qtracker delivered quantum dots (QDs). Results Murine embryonic stem (ES) cells were labeled with six different QDs using Qtracker. ES cell viability, proliferation, and differentiation were not adversely affected by QDs compared with non-labeled control cells (P = NS). Afterward, labeled ES cells were injected subcutaneously onto the backs of athymic nude mice. These labeled ES cells could be imaged with good contrast with one single excitation wavelength. With the same excitation wavelength, the signal intensity, defined as (total signal-background)/exposure time in millisecond was 11 ± 2 for cells labeled with QD 525, 12 ± 9 for QD 565, 176 ± 81 for QD 605, 176 ± 136 for QD 655, 167 ± 104 for QD 705, and 1,713 ± 482 for QD 800. Finally, we have shown that QD 800 offers greater fluorescent intensity than the other QDs tested. Conclusion In summary, this is the first demonstration of in vivo multiplex imaging of mouse ES cells labeled QDs. Upon further improvements, QDs will have a greater potential for tracking stem cells within deep tissues. These results provide a promising tool for imaging stem cell therapy non-invasively in vivo.
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Affiliation(s)
- Shuan Lin
- Molecular Imaging Program at Stanford (MIPS) and Bio-X Program, Department of Radiology, Stanford University, Stanford, CA 94305, USA.
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McKiernan E, O'Driscoll L, Kasper M, Barron N, O'Sullivan F, Clynes M. Directed Differentiation of Mouse Embryonic Stem Cells into Pancreatic-Like or Neuronal- and Glial-Like Phenotypes. ACTA ACUST UNITED AC 2007; 13:2419-30. [PMID: 17655486 DOI: 10.1089/ten.2006.0373] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
The derivation of definitive endoderm and in particular endocrine cell types from undifferentiated embryonic stem (ES) cells remains difficult to achieve. In this study, we investigated the potential to regulate the differentiation of ES cells into endodermal derivatives using extracellular factors previously associated with various aspects of pancreatic development. Feeder-free-cultured mouse ESD3 cells were manipulated to form embryoid bodies (EBs) in the presence of retinoic acid (RA). RA-treated EBs were subsequently exposed to sodium butyrate (SB), betacellulin (BTC) or activin A (AA). A comparative analysis was performed on these models of directed differentiation in parallel with a model of spontaneous differentiation. Lineage differentiation was determined by profiling multilineage marker transcript expression (neuronal, myogenic, exocrine and endocrine pancreas, extraembryonic and apoptotic) and subsequent protein expression within ES-derived cultures. Using a two-stage differentiation protocol developed during this study, we successfully demonstrated the derivation of an intermediate multipotential population (RA_EBs) from undifferentiated ES cells that preferentially gives rise to pancreatic endocrine insulin-expressing cell types in the presence of SB, and neuronal- and glial-like cell types in the presence of AA or BTC.
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Affiliation(s)
- Eadaoin McKiernan
- National Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland
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Hanley NA. Bone marrow-derived cells and the vasculature in diabetes: from biomarker to treatment? Diabetologia 2007; 50:2033-5. [PMID: 17653690 DOI: 10.1007/s00125-007-0773-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2007] [Accepted: 06/27/2007] [Indexed: 10/23/2022]
Affiliation(s)
- N A Hanley
- Centre for Human Development, Stem Cells & Regeneration, University of Southampton, Southampton General Hospital, Southampton, UK.
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Lock LT, Tzanakakis ES. Stem/Progenitor cell sources of insulin-producing cells for the treatment of diabetes. ACTA ACUST UNITED AC 2007; 13:1399-412. [PMID: 17550339 DOI: 10.1089/ten.2007.0047] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Patients with diabetes experience decreased insulin secretion that is linked to a significant reduction in the number of islet cells. Reversal of diabetes can be achieved through islet transplantation, but the scarcity of donor islets severely hinders wide application of this therapeutic modality. Toward that end, embryonic stem cells, adult tissue-residing progenitor cells, and regenerating native beta-cells may serve as sources of islet cell surrogates. Insulin-producing cells generated from stem or progenitor cells display subsets of native beta-cell attributes, indicating the need for further development of methods for differentiation to completely functional beta-cells. Pharmacological approaches aiming at stimulating the in vivo/ex vivo regeneration of beta-cells have also been proposed as a way of augmenting islet cell mass. We review the current state of the generation of insulin-producing cells from different sources with emphasis on embryonic stem cells and adult progenitor cells. Challenges for the clinical use of these sources are also discussed.
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Affiliation(s)
- Lye T Lock
- Department of Chemical and Biological Engineering, State University of New York at Buffalo, Buffalo, New York 14260, USA
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Kim SY, Lee S, Min BH, Park IS. Functional association of the morphogenic factors with the clusterin for the pancreatic beta-cell differentiation. Diabetes Res Clin Pract 2007; 77 Suppl 1:S122-6. [PMID: 17512083 DOI: 10.1016/j.diabres.2007.01.045] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/29/2007] [Indexed: 11/15/2022]
Abstract
Several differentiation or morphogenic factors have known to be involved in the developmental process of endocrine pancreas. However, mechanism of action and functional relation of these molecules are not well elucidated particularly in beta-cell formation from adult pancreatic stem cells. We hypothesized that adult pancreatic stem cells could be activated by the functional resumption of the morphogenic factors that were involved in embryonic development of pancreas in the duct system under the specific conditions such as tissue injuries. Besides the well-established genes including Pdx-1 and Ngn-3, we propose the nestin and clusterin as the new morphogenic factors for beta-cell neogenesis and their functional associations. We found extensive in vivo formation of ductules showing a higher replicating ability following the experimental tissue injury. These neogenic ductules were lined with low epithelial cells positive for the nestin, which has been known as neuronal stem cell marker. In in vitro culture, the nestin-rich epithelial cells of the neogenic ductules also displayed extensive self-replication leading to monolayer of epithelial cell explants and transformed into the insulin secreting beta cells as well as duct cells. Thus, we depicted them as nestin-positive duct stem (NPDS) cells. We found a neogenesis specific protein 'clusterin' in the regenerating pancreatic tissues with concomitant increase of Pdx-1 and Ngn-3 expression. The protein is expressed predominantly in the neogenic pancreas undergoing differentiation. In vitro over-expression of the clusterin gene strongly induces beta-cell transformation from neogenic ductal cells. Insulin expression, both insulin mRNA and peptide levels, was increased and showed glucose dependent manner by ectopic expression of clusterin upon the culture of neogenic ductules when compared to the mock-transfected control, implying that the duct cells transformed functional beta cells. We observed that clusterin over-expression led to up-regulation of Pdx-1 and Ngn-3, and clusterin levels were increased upon the transfection of cDNAs of Pdx-1 or Ngn-3, suggesting a close functional association of these morphogenic factors. In conclusion, we suggest that adult pancreatic stem cells can be recapitulated for neogenesis of insulin secreting beta cells not only by reactivation Pdx-1 and Ngn-3, the classical differentiation factors for pancreas development, but also by the intervention of new morphogenic factors including nestin and clusterin. In particular, by modulation of Pdx-1 and Ngn-3, clusterin induces remarkable differentiation of the functional beta cells secreting insulin in response to glucose stimulation.
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Affiliation(s)
- So-Yoon Kim
- Department of Anatomy and Center for Advanced Medical Education by BK21 project, College of Medicine, Inha University, Choong-Gu, Shinheung-Dong, Incheon 400-103, Korea
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