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Yamada S, Terada K, Ueno Y, Sugiyama T, Seno M, Kojima I. Differentiation of Adult Hepatic Stem-Like Cells into Pancreatic Endocrine Cells. Cell Transplant 2017; 14:647-53. [PMID: 16405075 DOI: 10.3727/000000005783982738] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
To apply cell transplantation for treatment of diabetes mellitus, a sufficient number of β-cell sources are required. In the present study, we examined whether an epithelial cell line obtained from normal adult rat liver, namely hepatic stem-like (HSL) cells, which can be converted to both hepatocytes and billiary epithelial cells, could be a potential β-cell source. The growth speed of HSL cells was rapid and these cells were easily expanded in vitro. Bipotential hepatic stem cells, HSL cells, also expressed PGP9.5, which is expressed in neurons, β-cells, and progenitor cells of the pancreatic endocrine cells as well. Sodium butyrate induced morphological changes in HSL cells and converted them into flattened cells with large cytoplasm. When HSL cells were incubated with a combination of 5 mM sodium butyrate and 1 nM betacellulin, most of the cells were converted into morphologically neuron-like cells. RT-PCR analysis revealed that a series of transcriptional factors involved in differentiation of pancreatic endocrine cells was induced by the treatment with sodium butyrate and betacellulin. mRNAs for insulin, pancreatic polypeptide, and somatostatin were also observed. Immunoreactive pancreatic polypeptide, somatostatin, and insulin were detected in sodium butyrate and betacellulin-treated HSL cells. In conclusion, HSL cells obtained from adult normal liver also have the potential to differentiate into pancreatic endocrine cells in vitro. HSL cells may be one of the potential β-cell sources for cell transplant therapy for insulin-dependent diabetes.
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Affiliation(s)
- Satoko Yamada
- Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan
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2
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Acarregui A, Ciriza J, Saenz del Burgo L, Gurruchaga Iribar H, Yeste J, Illa X, Orive G, Hernández RM, Villa R, Pedraz JL. Characterization of an encapsulated insulin secreting human pancreatic beta cell line in a modular microfluidic device. J Drug Target 2017; 26:36-44. [DOI: 10.1080/1061186x.2017.1334208] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Argia Acarregui
- NanoBioCel Group, Laboratory of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, Vitoria-Gasteiz, Spain
| | - Jesús Ciriza
- NanoBioCel Group, Laboratory of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, Vitoria-Gasteiz, Spain
| | - Laura Saenz del Burgo
- NanoBioCel Group, Laboratory of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, Vitoria-Gasteiz, Spain
| | - Haritz Gurruchaga Iribar
- NanoBioCel Group, Laboratory of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, Vitoria-Gasteiz, Spain
| | - José Yeste
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, Vitoria-Gasteiz, Spain
- Institut de Microelectrònica de Barcelona, IMB-CNM (CSIC), Barcelona, Spain
| | - Xavi Illa
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, Vitoria-Gasteiz, Spain
- Institut de Microelectrònica de Barcelona, IMB-CNM (CSIC), Barcelona, Spain
| | - Gorka Orive
- NanoBioCel Group, Laboratory of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, Vitoria-Gasteiz, Spain
| | - Rosa M. Hernández
- NanoBioCel Group, Laboratory of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, Vitoria-Gasteiz, Spain
| | - Rosa Villa
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, Vitoria-Gasteiz, Spain
- Institut de Microelectrònica de Barcelona, IMB-CNM (CSIC), Barcelona, Spain
| | - Jose Luis Pedraz
- NanoBioCel Group, Laboratory of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain
- Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, Vitoria-Gasteiz, Spain
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Kim D, Jun HS. In Vivo Imaging of Transplanted Pancreatic Islets. Front Endocrinol (Lausanne) 2017; 8:382. [PMID: 29403437 PMCID: PMC5786518 DOI: 10.3389/fendo.2017.00382] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Accepted: 12/26/2017] [Indexed: 01/08/2023] Open
Abstract
The beta-cells in the islets of Langerhans in the pancreas secrete insulin and play an important role in glucose homeostasis. Diabetes, characterized by hyperglycemia, results from an absolute or a relative deficiency of the pancreatic beta-cell mass. Islet transplantation has been considered to be a useful therapeutic approach, but it is largely unsuccessful because most of the transplanted islets are lost in the early stage of transplantation. To evaluate the efficacy of intervention methods for the improvement of islet survival, monitoring of the functional islet mass is needed. Various techniques to image and track transplanted islets have been investigated to assess islets after transplantation. In this review, recent progresses in imaging methods to visualize islets are discussed.
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Affiliation(s)
- Donghee Kim
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, South Korea
| | - Hee-Sook Jun
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, South Korea
- College of Pharmacy, Gachon Institute of Pharmaceutical Science, Gachon University, Incheon, South Korea
- Gachon Medical Research Institute, Gil Hospital, Incheon, South Korea
- *Correspondence: Hee-Sook Jun,
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Sunitha MM, Srikanth L, Santhosh Kumar P, Chandrasekhar C, Sarma PVGK. In vitro differentiation potential of human haematopoietic CD34(+) cells towards pancreatic β-cells. Cell Biol Int 2016; 40:1084-93. [PMID: 27514733 DOI: 10.1002/cbin.10654] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Accepted: 07/17/2016] [Indexed: 11/06/2022]
Abstract
Haematopoietic stem cells (HSCs) possess multipotent ability to differentiate into various types of cells on providing appropriate niche. In the present study, the differentiating potential of human HSCs into β-cells of islets of langerhans was explored. Human HSCs were apheretically isolated from a donor and cultured. Phenotypic characterization of CD34 glycoprotein in the growing monolayer HSCs was confirmed by immunocytochemistry and flow cytometry techniques. HSCs were induced by selection with beta cell differentiating medium (BDM), which consists of epidermal growth factor (EGF), fibroblast growth factor (FGF), transferrin, Triiodo-l-Tyronine, nicotinamide and activin A. Distinct morphological changes of differentiated cells were observed on staining with dithizone (DTZ) and expression of PDX1, insulin and synaptophysin was confirmed by immunocytochemistry. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis revealed distinct expression of specific β-cell markers, pancreatic and duodenal homeobox-1 (PDX1), glucose transporter-2 (GLUT-2), synaptophysin (SYP) and insulin (INS) in these differentiated cells compared to HSCs. Further, these cells exhibited elevated expression of INS gene at 10 mM glucose upon inducing with different glucose concentrations. The prominent feature of the obtained β-cells was the presence of glucose sensors, which was determined by glucokinase activity and high glucokinase activity compared with CD34(+) stem cells. These findings illustrate the differentiation of CD34(+) HSCs into β-cells of islets of langerhans.
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Affiliation(s)
- Manne Mudhu Sunitha
- Stem Cell laboratory, Department of Biotechnology, Sri Venkateswara Institute of Medical Sciences, Tirupati, 517 507, Andhra Pradesh, India
| | - Lokanathan Srikanth
- Stem Cell laboratory, Department of Biotechnology, Sri Venkateswara Institute of Medical Sciences, Tirupati, 517 507, Andhra Pradesh, India
| | - Pasupuleti Santhosh Kumar
- Stem Cell laboratory, Department of Biotechnology, Sri Venkateswara Institute of Medical Sciences, Tirupati, 517 507, Andhra Pradesh, India
| | - Chodimella Chandrasekhar
- Department of Haematology, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India
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Iacovacci V, Ricotti L, Menciassi A, Dario P. The bioartificial pancreas (BAP): Biological, chemical and engineering challenges. Biochem Pharmacol 2016; 100:12-27. [DOI: 10.1016/j.bcp.2015.08.107] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2015] [Accepted: 08/26/2015] [Indexed: 01/05/2023]
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Luo LG, Xiong F, Ravassard P, Luo JZ. Human Bone Marrow Subpopulations Sustain Human Islet Function and Viability In vitro. ACTA ACUST UNITED AC 2015; 8:576-587. [PMID: 27110541 PMCID: PMC4837454 DOI: 10.9734/bjmmr/2015/17536] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
AIMS Allogeneic bone marrow (BM) has been shown to support human islet survival and function in long-term culture by initiating human islet vascularization and β-cell regeneration. Various BM subpopulations may play different roles in human islet functions and survival. In this paper we investigated the effects of BM and its subpopulations, endothelial progenitor cells (E) and mesenchymal (M) cells on human islet's β-cell function and regeneration. STUDY DESIGN Isolation and identification of subpopulations from human bone marrow and culture with allogeneic human islet to investigate effects of different cell population on human islet function and regeneration. PLACE AND DURATION OF STUDY Department of Medicine, Center for Stem Cell & Diabetes Research, RWMC, Providence, RI, USA, between 2010 - 2014. METHODOLOGY Human islets were distributed from Integrated Islet Distribution Program (IIDP) and human bone marrow (BM) was harvested by Bone marrow transplantation center at Roger Williams Hospital. BM subpopulation was identified cell surface markers through Fluorescence-activated cell sorting, applied in flow cytometry (FACS), islet function was evaluated by human ELISA kit and β cell regeneration was evaluated by three methods of Cre-Loxp cell tracing, β cell sorting and RT-PCR for gene expression. RESULTS Four different BM and seven different islet donates contributed human tissues. We observed islet β-cell having self regeneration capability in short term culture (3∼5 days) using a Cre-Loxp cell tracing. BM and its subtype E, M have similar benefits on β cell function during co-culture with human islet comparison to islet only. However, only whole BM enables to sustain the capability of islet β-cell self regeneration resulting in increasing β cell population while single E and M individual do not significantly affect on that. Mechanism approach to explore β-cell self regeneration by evaluating transcription factor expressions, we found that BM significantly increases the activations of β-cell regeneration relative transcription factors, the LIM homeodomain protein (Isl1), homologue to zebrafish somite MAF1 (MAFa), the NK-homeodomain factor 6.1 (NKX6.1), the paired box family factors 6 (PAX6), insulin promoter factor 1 (IPF1) and kinesin family member 4A (KIF4a). CONCLUSION These results suggest that BM and its derived M and E cells enable to support human islet β-cell function. However, only BM can sustain the capability of β-cell self regeneration through initiating β-cell transcriptional factors but not individual E and M cells suggesting pure E and M cells less supportive for islet long-term survival in vitro.
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Affiliation(s)
- Lu Guang Luo
- Department of Medicine/Research, Roger Williams Medical Center, Boston University, USA
| | - Fang Xiong
- Department of Medicine/Research, Roger Williams Medical Center, Boston University, USA
| | - Philippe Ravassard
- Department of Molecular Biology, ICM, Biotechnology & Biotherapy Group 47 Bd de Hospital, Paris France
| | - John Zq Luo
- Department of Medicine/Research, Roger Williams Medical Center, Boston University, USA; Department of Medicine, Brown University, Alpert Medical School, Providence, Rhode Island, USA
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7
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Li D, Peng SY, Zhang ZW, Feng RC, Li L, Liang J, Tai S, Teng CB. Complete disassociation of adult pancreas into viable single cells through cold trypsin-EDTA digestion. J Zhejiang Univ Sci B 2014; 14:596-603. [PMID: 23825145 DOI: 10.1631/jzus.b1200226] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
The in vitro isolation and analysis of pancreatic stem/progenitor cells are necessary for understanding their properties and function; however, the preparation of high-quality single-cell suspensions from adult pancreas is prerequisite. In this study, we applied a cold trypsin-ethylenediaminetetraacetic acid (EDTA) digestion method to disassociate adult mouse pancreata into single cells. The yield of single cells and the viability of the harvested cells were much higher than those obtained via the two commonly used warm digestion methods. Flow cytometric analysis showed that the ratio of ductal or BCRP1-positive cells in cell suspensions prepared through cold digestion was consistent with that found in vivo. Cell culture tests showed that pancreatic epithelial cells prepared by cold digestion maintained proliferative capacity comparable to those derived from warm collagenase digestion. These results indicate that cold trypsin-EDTA digestion can effectively disassociate an adult mouse pancreas into viable single cells with minimal cell loss, and can be used for the isolation and analysis of pancreatic stem/progenitor cells.
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Affiliation(s)
- Dan Li
- Laboratory of Animal Development Biology, College of Life Science, Northeast Forestry University, Harbin 150040, China
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Schweicher J, Nyitray C, Desai TA. Membranes to achieve immunoprotection of transplanted islets. FRONT BIOSCI-LANDMRK 2014; 19:49-76. [PMID: 24389172 PMCID: PMC4230297 DOI: 10.2741/4195] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Transplantation of islet or beta cells is seen as the cure for type 1 diabetes since it allows physiological regulation of blood glucose levels without requiring any compliance from the patients. In order to circumvent the use of immunosuppressive drugs (and their side effects), semipermeable membranes have been developed to encapsulate and immunoprotect transplanted cells. This review presents the historical developments of immunoisolation and provides an update on the current research in this field. A particular emphasis is laid on the fabrication, characterization and performance of membranes developed for immunoisolation applications.
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Affiliation(s)
- Julien Schweicher
- Therapeutic Micro and Nanotechnology Laboratory, Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco (UCSF), 1700 4 Street, Box 2520, San Francisco, CA, 94158, USA
| | - Crystal Nyitray
- Therapeutic Micro and Nanotechnology Laboratory, Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco (UCSF), 1700 4 Street, Box 2520, San Francisco, CA, 94158, USA
| | - Tejal A. Desai
- Therapeutic Micro and Nanotechnology Laboratory, Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco (UCSF), 1700 4 Street, Box 2520, San Francisco, CA, 94158, USA
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Auer VJ, Janas E, Ninichuk V, Eppler E, Weiss TS, Kirchner S, Otto AM, Stangl MJ. Extracellular factors and immunosuppressive drugs influencing insulin secretion of murine islets. Clin Exp Immunol 2013; 170:238-47. [PMID: 23039895 DOI: 10.1111/j.1365-2249.2012.04645.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Approximately 60% of transplanted islets undergo apoptosis within the first week post-transplantation into the liver attributed to poor engraftment, immune rejection and toxicity of immunosuppressive drugs. Understanding how extracellular matrix (ECM) components, immunosuppressive drugs and proinflammatory cytokines affect insulin secretion will contribute to an improved clinical outcome of islet transplantations. In this study, functional activity of isolated murine islets was measured by glucose-stimulated insulin secretion (GSIS) and by electrophysiological measurements using patch-clamp. Cultivating islets with soluble fibronectin or laminin, as opposed to with coated laminin, markedly increased GSIS. Addition of cyclosporin A reduced GSIS and suppressed glucose-induced spike activity. Tacrolimus affected neither GSIS nor spike activity, indicating a different mechanism. To evaluate the influence of proinflammatory cytokines, islets were incubated with interleukin (IL)-1β, tumour necrosis factor (TNF)-α or with supernatants from cultured Kupffer cells, the main mediators of inflammation in the hepatic sinusoids. IL-1β exerted a bimodal effect on insulin secretion, stimulating below 2 ng/ml and suppressing above 10 ng/ml. Soluble laminin in combination with a stimulatory IL-1β concentration further increased insulin secretion by 20% compared to IL-1β alone, while with high IL-1β concentrations soluble laminin slightly attenuated GSIS inhibition. TNF-α alone did not affect GSIS, but with stimulatory IL-1β concentrations completely abolished it. Similarly, supernatants derived from Kupffer cells exerted a bimodal effect on GSIS. Our data suggest that improved insulin secretion of transplanted islets could be achieved by including soluble laminin and low IL-1β concentrations in the islet cultivation medium, and by a simultaneous inhibition of cytokine secretion from Kupffer cells.
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Affiliation(s)
- V J Auer
- Institute of Medical Engineering, Technische Universität München (IMETUM), Garching Center for Liver Cell Research, Department of Pediatrics and Adolescent Medicine, University of Regensburg Hospital Hepacult GmbH, Biopark Regensburg, Regensburg, Switzerland.
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Wu C, Ma G, Li J, Zheng K, Dang Y, Shi X, Sun Y, Li F, Zhu Z. In vivo cell tracking via ¹⁸F-fluorodeoxyglucose labeling: a review of the preclinical and clinical applications in cell-based diagnosis and therapy. Clin Imaging 2013; 37:28-36. [PMID: 23206605 DOI: 10.1016/j.clinimag.2012.02.023] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2012] [Accepted: 02/29/2012] [Indexed: 12/17/2022]
Abstract
The rising interest in using functional cells for diagnosis and treatment has created an urgent need for in vivo cell-tracking techniques. Certain advanced techniques, such as those involving reporter genes or nanoparticles, are still awaiting confirmation of their safety and feasibility in human patients. Tracking cells by labeling them with (18)F-fluorodeoxyglucose, a tracer clinically used in positron emission tomography (PET), may be one way to rapidly translate some of these principles from bench to bedside. The preliminary results are exciting, although further development, optimization, and validation are required. Here, several applications of the technique are surveyed: finding inflammatory foci, targeting cancer immunotherapies, tracking transplanted islet cells, and monitoring cardiac stem cells. Advantages, limitations, and prospects of the technique are discussed. These early experiences only highlight the existing need to improve cell-labeling techniques using PET tracers. This method may finally lead to the development of effective and convenient methods for clinical cell-tracking techniques involving PET/computed tomography.
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Affiliation(s)
- Chenxi Wu
- Department of Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
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Molecular imaging: a promising tool to monitor islet transplantation. J Transplant 2011; 2011:202915. [PMID: 22013504 PMCID: PMC3195545 DOI: 10.1155/2011/202915] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2011] [Accepted: 07/29/2011] [Indexed: 12/18/2022] Open
Abstract
Replacement of insulin production by pancreatic islet transplantation has great potential as a therapy for type 1 diabetes mellitus. At present, the lack of an effective approach to islet grafts assessment limits the success of this treatment. The development of molecular imaging techniques has the potential to fulfill the goal of real-time noninvasive monitoring of the functional status and viability of the islet grafts. We review the application of a variety of imaging modalities for detecting endogenous and transplanted beta-cell mass. The review also explores the various molecular imaging strategies for assessing islet delivery, the metabolic effects on the islet grafts as well as detection of immunorejection. Here, we highlight the use of combined imaging and therapeutic interventions in islet transplantation and the in vivo monitoring of stem cells differentiation into insulin-producing cells.
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Choi JH, Lee MY, Kim Y, Shim JY, Han SM, Lee KA, Choi YK, Jeon HM, Baek KH. Isolation of genes involved in pancreas regeneration by subtractive hybridization. Biol Chem 2011; 391:1019-29. [PMID: 20536387 DOI: 10.1515/bc.2010.101] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
The deterioration of β cells in the pancreas is a crucial factor in the progression of diabetes mellitus; therefore, the recovery of β cells is of vital importance for effective diabetic therapeutic strategies. Partially pancreatectomized rats have been used for the investigation of pancreatic regeneration. Because it was determined that tissue extract from the partially-dissected pancreas induces pancreatic differentiation in embryonic stem cells, paracrine factors were thought to be involved in the regeneration. In this study, we screened for genes that had higher mRNA levels 2 days after 60%-pancreatectomy. The genes were isolated using subtractive hybridization and DNA sequencing. Twelve genes (adipsin, Aplp2, Clu, Col1a2, Glul, Krt8, Lgmn, LOC299907, LOC502894, Pla2g1b, Reg3α and Xbp1) were identified, and RT-PCR and real-time PCR analyses were performed to validate their expression levels. Among the genes identified, three genes (Glul, Lgmn and Reg3a) were selected for further analyses. Assays revealed that Glul and Reg3α enhance cell growth. Glul, Lgmn and Reg3α change the expression level of islet marker genes, where NEUROD, NKX2.2, PAX4 and PAX6 are up-regulated and somatostatin is down-regulated. Thus, we believe that Glul, Lgmn and Reg3a can serve as novel targets in diabetes mellitus genetic therapy.
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Affiliation(s)
- Jong-Ho Choi
- College of Medicine, CHA University, CHA General Hospital, Seoul 135-081, Korea
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Boroujeni NB, Hashemi SM, Khaki Z, Soleimani M. The reversal of hyperglycemia after transplantation of mouse embryonic stem cells induced into early hepatocyte-like cells in streptozotocin-induced diabetic mice. Tissue Cell 2011; 43:75-82. [DOI: 10.1016/j.tice.2010.12.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2010] [Revised: 12/12/2010] [Accepted: 12/17/2010] [Indexed: 01/26/2023]
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Perán M, Sánchez-Ferrero A, Tosh D, Marchal JA, Lopez E, Alvarez P, Boulaiz H, Rodríguez-Serrano F, Aranega A. Ultrastructural and molecular analyzes of insulin-producing cells induced from human hepatoma cells. Cytotherapy 2011; 13:193-200. [DOI: 10.3109/14653249.2010.501791] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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Van Belle TL, Coppieters KT, Von Herrath MG. Type 1 Diabetes: Etiology, Immunology, and Therapeutic Strategies. Physiol Rev 2011; 91:79-118. [DOI: 10.1152/physrev.00003.2010] [Citation(s) in RCA: 679] [Impact Index Per Article: 48.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disease in which destruction or damaging of the beta-cells in the islets of Langerhans results in insulin deficiency and hyperglycemia. We only know for sure that autoimmunity is the predominant effector mechanism of T1D, but may not be its primary cause. T1D precipitates in genetically susceptible individuals, very likely as a result of an environmental trigger. Current genetic data point towards the following genes as susceptibility genes: HLA, insulin, PTPN22, IL2Ra, and CTLA4. Epidemiological and other studies suggest a triggering role for enteroviruses, while other microorganisms might provide protection. Efficacious prevention of T1D will require detection of the earliest events in the process. So far, autoantibodies are most widely used as serum biomarker, but T-cell readouts and metabolome studies might strengthen and bring forward diagnosis. Current preventive clinical trials mostly focus on environmental triggers. Therapeutic trials test the efficacy of antigen-specific and antigen-nonspecific immune interventions, but also include restoration of the affected beta-cell mass by islet transplantation, neogenesis and regeneration, and combinations thereof. In this comprehensive review, we explain the genetic, environmental, and immunological data underlying the prevention and intervention strategies to constrain T1D.
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Affiliation(s)
- Tom L. Van Belle
- Center for Type 1 Diabetes Research, La Jolla Institute for Allergy and Immunology, La Jolla, California
| | - Ken T. Coppieters
- Center for Type 1 Diabetes Research, La Jolla Institute for Allergy and Immunology, La Jolla, California
| | - Matthias G. Von Herrath
- Center for Type 1 Diabetes Research, La Jolla Institute for Allergy and Immunology, La Jolla, California
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16
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Brown L, Edelman ER. Optimal control of blood glucose: the diabetic patient or the machine? Sci Transl Med 2010; 2:27ps18. [PMID: 20393187 DOI: 10.1126/scitranslmed.3001083] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
In this issue of Science Translational Medicine, El-Khatib et al. describe a "closed-loop" bihormonal artificial pancreas, designed to avert episodes of low blood sugar in patients with insulin-dependent diabetes. We discuss the benefits and challenges of therapy directed at tight control of blood glucose and ask whether this and similar technological breakthroughs can address as yet unanswered questions in the biology of diabetes.
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Affiliation(s)
- Larry Brown
- Harvard MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, E25-438, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
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17
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Affiliation(s)
- David M Harlan
- National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health, Diabetes Branch, Bethesda, Maryland, USA.
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18
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Abstract
Type 1 diabetes (insulin-dependent, IDDM) results in immune-mediated destruction of pancreatic beta cells, which leads to a deficiency in insulin secretion and as a result, to hyperglycaemia. Keeping blood glucose levels under tight control represents the most effective way either to prevent the onset or to reduce the progression of the chronic complications of IDDM. At present, pancreatic islet transplantation is emerging as the most promising clinical modality, which can stop diabetes progression without increasing the incidence of hypoglycaemic events. Although early results of clinical trials using the Edmonton Protocol and its variations are very encouraging, it is still unclear how long the islets will survive and how often the transplantation procedure will be successful. In order to monitor transplantation efficiency and graft survival, reliable non-invasive imaging methods are critically needed. If such methods are introduced clinically, essential information regarding the location, function and viability of transplanted islets can be obtained repeatedly and non-invasively. This review will focus on the latest advancements in the field of in vivo imaging of islet transplantation and describe various islet labelling and imaging techniques. In addition, we will critically look into limitations and obstacles currently present on the way to successful clinical implementation of this approach.
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Affiliation(s)
- Z Medarova
- Molecular Imaging Program, MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02129, USA
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19
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Abstract
Transplantation of pancreatic tissue, as either the intact whole pancreas or isolated pancreatic islets has become a clinical option to be considered in the treatment of patients with type 1 insulin-dependant diabetes mellitus. A successful whole pancreas or islet transplant offers the advantages of attaining normal or near normal blood glucose control and normal hemoglobin A1c levels without the risks of severe hypoglycemia associate with intensive insulin therapy. Both forms of transplants are also effective at eliminating the occurrence of significant hypoglycemic events (even with only partial islet function evident). Whereas whole pancreas transplantation has also been shown to be very effective at maintaining a euglycemic state over a sustained period of time, thus providing an opportunity for a recipient to benefit from improvement of their blood glucose control, it is associated with a significant risk of surgical and post-operative complications. Islet transplantation is attractive as a less invasive alternative to whole pancreas transplant and offers the future promise of immunosuppression-free transplantation through pre-transplant culture. Islet transplantation however, may not always achieve the sustained level of tight glucose control necessary for reducing the risk of secondary diabetic complications and exposes the patient to the adverse effects of immunosuppression. Although recent advances have led to an increased rate of obtaining insulin-independence following islet transplantation, further developments are needed to improve the long-term viability and function of the graft to maintain improved glucose control over time.
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Affiliation(s)
- R Mark Meloche
- Department of Surgery, University of British Columbia, 5th Floor Diamond Centre, 2775 Laurel Street, Vancouver, BC, V5Z 1M9, Canada.
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20
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Pasquali L, Giannoukakis N, Trucco M. Induction of immune tolerance to facilitate beta cell regeneration in type 1 diabetes. Adv Drug Deliv Rev 2008; 60:106-13. [PMID: 18053613 DOI: 10.1016/j.addr.2007.08.032] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2007] [Accepted: 08/01/2007] [Indexed: 01/12/2023]
Abstract
A definitive cure for type 1 diabetes is currently being pursued with enormous effort by the scientific community. Different strategies are followed to restore physiologic production of insulin in diabetic patients. Restoration of self-tolerance remains the milestone that must be reached in order to move a step further and recover a cell source capable of independent and functional insulin production. Multiple strategies aimed at modulation of both central and peripheral immunity must be considered. Promising results now show that the immune system can be modulated in a way that acquisition of a "diabetes-suppressive" phenotype is possible. Once self-tolerance is achieved, reversal of the disease may be obtained by simply allowing physiologic rescue and/or regeneration of the beta cells to take place. Given that these outcomes have already been confirmed in humans, refinement of existing protocols along with novel methods adapted to T1DM reversal will allow translation into clinical trials.
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Affiliation(s)
- Lorenzo Pasquali
- Division of Immunogenetics, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA
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21
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Abstract
Transplantation of pancreatic tissue, as either the intact whole pancreas or isolated pancreatic islets has become a clinical option to be considered in the treatment of patients with type 1 insulin-dependant diabetes mellitus. A successful whole pancreas or islet transplant offers the advantages of attaining normal or near normal blood glucose control and normal hemoglobin A1c levels without the risks of severe hypoglycemia associate with intensive insulin therapy. Both forms of transplants are also effective at eliminating the occurrence of significant hypoglycemic events (even with only partial islet function evident). Whereas whole pancreas transplantation has also been shown to be very effective at maintaining a euglycemic state over a sustained period of time, thus providing an opportunity for a recipient to benefit from improvement of their blood glucose control, it is associated with a significant risk of surgical and post-operative complications. Islet transplantation is attractive as a less invasive alternative to whole pancreas transplant and offers the future promise of immunosuppression-free transplantation through pre-transplant culture. Islet transplantation however, may not always achieve the sustained level of tight glucose control necessary for reducing the risk of secondary diabetic complications and exposes the patient to the adverse effects of immunosuppression. Although recent advances have led to an increased rate of obtaining insulin-independence following islet transplantation, further developments are needed to improve the long-term viability and function of the graft to maintain improved glucose control over time.
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22
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Warnock GL, Liao YHT, Wang X, Ou D, Ao Z, Johnson JD, Verchere CB, Thompson D. An odyssey of islet transplantation for therapy of type 1 diabetes. World J Surg 2007; 31:1569-76. [PMID: 17562107 DOI: 10.1007/s00268-007-9125-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2007] [Accepted: 03/27/2007] [Indexed: 12/22/2022]
Abstract
Canadian surgical contributions to the field of islet transplantation have a rich heritage and a promising future. In this article, some seminal Canadian contributions to this field are reviewed, including contributions at the basic research laboratory and translational applications to bedside therapy of type 1 diabetes.
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Affiliation(s)
- Garth L Warnock
- Department of Surgery, University of British Columbia Medical Center, 910 West 10th Avenue, Vancouver, British Columbia V5Z 4E3.
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23
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Chen XB, Li YX, Jiao Y, Dong WP, Li G, Chen J, Tan JM. Influence of heme oxygenase-1 gene transfer on the viability and function of rat islets in in vitro culture. World J Gastroenterol 2007; 13:1053-9. [PMID: 17373739 PMCID: PMC4146867 DOI: 10.3748/wjg.v13.i7.1053] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the influence of heme oxygenase-1 (HO-1) gene transfer on the viability and function of cultured rat islets in vitro.
METHODS: Islets were isolated from the pancreata of Sprague-Dawley rats by intraductal collagenase digestion, and purified by discontinuous Ficoll density gradient centrifugation. Purified rat islets were transfected with adenoviral vectors containing human HO-1 gene (Ad-HO-1) or enhanced green fluorescent protein gene (Ad-EGFP), and then cultured for seven days. Transfection was confirmed by fluorescence microscopy and Western blot. Islet viability was evaluated by acridine orange/ propidium iodide fluorescent staining. Glucose-stimulated insulin release was detected using insulin radioimmunoassay kits and was used to assess the function of islets. Stimulation index (SI) was calculated by dividing the insulin release upon high glucose stimulation by the insulin release upon low glucose stimulation.
RESULTS: After seven days culture, the viability of cultured rat islets decreased significantly (92% ± 6% vs 52% ± 13%, P < 0.05), and glucose-stimulated insulin release also decreased significantly (6.47 ± 0.55 mIU/L/30IEQ vs 4.57 ± 0.40 mIU/L/30IEQ, 14.93 ± 1.17 mIU/L/30IEQ vs 9.63 ± 0.71 mIU/L/30IEQ, P < 0.05). Transfection of rat islets with adenoviral vectors at an MOI of 20 was efficient, and did not impair islet function. At 7 d post-transfection, the viability of Ad-HO-1 transfected islets was higher than that of control islets (71% ± 15% vs 52% ± 13%, P < 0.05). There was no significant difference in insulin release upon low glucose stimulation (2.8 mmol/L) among Ad-HO-1 transfected group, Ad-EGFP transfected group, and control group (P > 0.05), while when stimulated by high glucose (16.7 mmol/L) solution, insulin release in Ad-HO-1 transfected group was significantly higher than that in Ad-EGFP transfected group and control group, respectively (12.50 ± 2.17 mIU/L/30IEQ vs 8.87 ± 0.65 mIU/L/30IEQ; 12.50 ± 2.17 mIU/L/30IEQ vs 9.63 ± 0.71 mIU/L/30IEQ, P < 0.05). The SI of Ad-HO-1 transfected group was also significantly higher than that of Ad-EGFP transfected group and control group, respectively (2.21 ± 0.02 vs 2.08 ± 0.05; 2.21 ± 0.02 vs 2.11 ± 0.03, P < 0.05).
CONCLUSION: The viability and function of rat islets decrease over time in in vitro culture, and heme oxygenase-1 gene transfer could improve the viability and function of cultured rat islets.
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Affiliation(s)
- Xiao-Bo Chen
- Department of Renal Transplantation and Urology, the First People's Hospital, Shanghai Jiao Tong University, China
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24
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Singh AK, Gudehithlu KP, Litbarg NO, Sethupathi P, Arruda JAL, Dunea G. Transplanting fragments of diabetic pancreas into activated omentum gives rise to new insulin producing cells. Biochem Biophys Res Commun 2007; 355:258-62. [PMID: 17292859 DOI: 10.1016/j.bbrc.2007.01.152] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2007] [Accepted: 01/29/2007] [Indexed: 12/19/2022]
Abstract
To determine if pancreatic progenitor cells can be induced to form insulin producing cells in vivo, we auto-transplanted fragments of streptozotocin-induced diabetic pancreas into omentum pre-injected with a foreign material. As shown previously, omentum pre-activated in this manner becomes rich in growth factors and progenitor cells. After auto-transplanting diabetic pancreas in the activated omentum, new insulin secreting cells appeared in the omentum in niches surrounding the foreign particles--a site previously shown to harbor progenitor cells. Extracts of these omenta contained measurable insulin. Four of eight diabetic animals treated in this manner became normoglycemic. This shows that new insulin producing cells can be regenerated from diabetic pancreas by auto-transplanting pancreatic fragments into the activated omentum, an environment rich in growth factors and progenitor cells.
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Affiliation(s)
- Ashok K Singh
- The Division of Nephrology, Stroger Hospital of Cook County, 637 South Wood Street (Durand Bldg 2nd Floor), Chicago, IL 60612, USA.
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25
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Kim SJ, Doudet DJ, Studenov AR, Nian C, Ruth TJ, Gambhir SS, McIntosh CHS. Quantitative micro positron emission tomography (PET) imaging for the in vivo determination of pancreatic islet graft survival. Nat Med 2006; 12:1423-8. [PMID: 17143277 DOI: 10.1038/nm1458] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2006] [Accepted: 06/27/2006] [Indexed: 11/09/2022]
Abstract
Islet transplantation is an attractive approach for treating type-1 diabetes, but there is a massive loss of transplanted islets. It is currently only possible to estimate islet mass indirectly, through measurement of circulating C-peptide and insulin levels. This type of estimation, however, is not sufficiently sensitive or reproducible for follow-up of individuals who have undergone islet transplantation. Here we show that islet graft survival could be assessed for 1 month in diabetic NOD mice using 9-(4-[(18)F]-fluoro-3-hydroxymethylbutyl)guanine ([(18)F]FHBG)-positron emission tomography (PET) technology, the PET signal reflecting insulin secretory capacity of transplanted islets. Expression of the gene encoding viral interleukin-10 (vIL-10), was measurable in real time with PET scanning. Additionally, we addressed the clinical potential of this approach by visualizing transplanted islets in the liver, the preferred clinical transplantation site. We conclude that quantitative in vivo PET imaging is a valid method for facilitating the development of protocols for prolonging islet survival, with the potential for tracking human transplants.
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Affiliation(s)
- Su-Jin Kim
- Department of Cellular & Physiological Sciences and the Diabetes Research Group, Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada
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26
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Zhang Y, Li SZ, Li J, Pan X, Cahoon RE, Jaworski JG, Wang X, Jez JM, Chen F, Yu O. Using Unnatural Protein Fusions to Engineer Resveratrol Biosynthesis in Yeast and Mammalian Cells. J Am Chem Soc 2006; 128:13030-1. [PMID: 17017764 DOI: 10.1021/ja0622094] [Citation(s) in RCA: 137] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Resveratrol is a naturally occurring defense compound produced by a limited number of plants in response to stresses. Besides cardiovascular benefits, this health-promoting compound has been reported to extend life spans in yeasts, flies, worms, and fish. To biosynthesize resveratrol de novo, tyrosine ammonia lyase (TAL), 4-coumarate CoA-ligase (4CL), and stilbene synthase (STS) were isolated from Rhodobacter sphaeroides, Arabidopsis thaliana, and Vitis vinifera, respectively. Yeast cells expressing 4CL and STS produce resveratrol when fed with 4-coumaric acid, the substrate of 4CL. When a translational fusion protein joining 4CL and STS was used, yeast cells produced 15-fold more resveratrol than the cotransformed cells, suggesting that physical localization of 4CL and STS facilitate resveratrol production. When the resveratrol pathway was introduced into human HEK293 cells, de novo biosynthesis was detected, leading to intracellular accumulation of resveratrol. We successfully engineered an entire plant natural product pathway into a mammalian host.
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Affiliation(s)
- Yansheng Zhang
- Donald Danforth Plant Science Center, St. Louis, Missouri 63132, USA
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Carter J, Karmiol S, Nagy M, McElreath R, Calloway C, Motley A, Neill A, Jang HJ, Posselt A, Stock P. Pretransplant islet culture: a comparison of four serum-free media using a murine model of islet transplantation. Transplant Proc 2006; 37:3446-9. [PMID: 16298624 DOI: 10.1016/j.transproceed.2005.09.073] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
INTRODUCTION Human islet transplant protocols frequently incorporate a brief period of islet culture before transplantation. The optimal medium for pretransplant islet culture is unknown. METHODS We compared four serum-free media formulated for human islets: Miami (MM1), Memphis (M-SFM), Edmonton (EDM), and hCell OCZEM-SF/AF (hCell). Islets isolated from a single human pancreas with purity >80% were cultured in 2500-islet-equivalent (IE) fractions using the media listed. After 7 days, each 2500-IE fraction was grafted under the kidney capsule of a streptozocin-diabetic rag1 mouse (n = 4 per group). Mice were evaluated with serum glucose monitoring, stimulated C-peptide release, and glucose tolerance tests. Islet fractions transplanted immediately after isolation (n = 4 mice) served as controls. In vitro islet function was assessed on days 0 and 3 and included insulin release (after static glucose stimulation), total cellular C-peptide content, cell count, and viability. RESULTS Glucose control was improved in all cohorts of mice after transplant, but only islet grafts cultured in MM1 were statistically indistinguishable from fresh islets. MM1- and hCell-cultured islet grafts showed improved glucose tolerance compared with fresh islets; C-peptide release was similar among the four cohorts. In vitro, only islets cultured in MM1 had similar stimulation index to fresh islets, whereas only hCell- and MM1-cultured islets demonstrated recovery of C-peptide content and insulin release. CONCLUSIONS Media choice before transplant can influence islet quality, even when culture periods are short. Miami MM1 and hCell media may provide better islet protection than alternative media.
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Affiliation(s)
- J Carter
- Transplantation Research Lab, University of California-San Francisco, San Francisco, CA 94143, USA.
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28
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Rood PPM, Bottino R, Balamurugan AN, Fan Y, Cooper DKC, Trucco M. Facilitating physiologic self-regeneration: a step beyond islet cell replacement. Pharm Res 2006; 23:227-42. [PMID: 16323065 DOI: 10.1007/s11095-005-9095-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2005] [Accepted: 10/13/2005] [Indexed: 01/06/2023]
Abstract
Type 1 diabetes (T1D) is an autoimmune disease, the clinical onset of which most frequently presents in children and adolescents who are genetically predisposed. T1D is characterized by specific insulin-producing beta cell destruction. The well-differentiated and specialized islet beta cells seem to physiologically retain the ability to compensate for the cells lost by reproducing themselves, whereas undifferentiated cell sources may help in generating new ones, even while the autoimmune process takes place. Diabetes clinical onset, i.e., establishment of a detectable, chronic hyperglycemia, occurs at a critical stage when autoimmunity, having acted for a while, supersedes the regenerative effort and reduces the number of beta cells below the physiologic threshold at which the produced insulin becomes insufficient for the body's needs. Clinical solutions aimed at avoiding cumbersome daily insulin administrations by the reestablishment of physiologic insulin production, like whole pancreas or pancreatic islet allotransplantation, are limited by the scarcity of pancreas donors and by the toxic effects of the immunosuppressive drugs administered to prevent rejection. However, new accumulating evidence suggests that, once autoimmunity is abrogated, the endocrine pancreas properties may be sufficient to allow the physiological regenerative process to restore endogenous insulin production, even after the disease has become clinically manifest. Knowledge of these properties of the endocrine pancreas suggests the testing of reliable and clinically translatable protocols for obliterating autoimmunity, thus allowing the regeneration of the patient's own endocrine cells. The safe induction of an autoimmunity-free status might become a new promising therapy for T1D.
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Affiliation(s)
- Pleunie P M Rood
- Division of Immunogenetics, Department of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, Pennsylvania, USA
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29
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Lobo PI, Spencer C, Simmons WD, Hagspiel KD, Angle JF, Deng S, Markmann J, Naji A, Kirk SE, Pruett T, Brayman KL. Development of anti-human leukocyte antigen class 1 antibodies following allogeneic islet cell transplantation. Transplant Proc 2005; 37:3438-3440. [PMID: 16298621 DOI: 10.1016/j.transproceed.2005.09.065] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Currently there is minimal concern that islet allograft failure could result from the development of anti-human leukocyte antigen (HLA) antibodies reactive to the allograft. We report here a case of islet allograft failure where the recipient developed immunoglobulin G anti-HLA class I antibodies reactive to HLA antigens present in two of the three islet cell donors. The patient had no detectable anti-HLA antibodies prior to the transplant but these antibodies were detected approximately 4 months posttransplant. Of concern, these antibodies developed despite induction with anti-IL2R antibodies (Zenapex) prior to intraportal islet cell infusion, low-dose tacrolimus (12-hour troughs 3 to 5 ng/mL) and rapammune (target troughs 12 to 15 ng/mL). The patient was not presensitized with blood products or a previous allograft. Her husband, however, shared antigens present in one of the islet donors and the recipient could have been presensitized to her husband during her two pregnancies. This case clearly demonstrates that islet allografts can lead to development of anti-HLA antibodies, which can cause islet allograft failure, as is the case with solid organ transplants, and hence emphasizes the need to monitor for such antibodies pre- and posttransplant. Additionally it appears that currently recommended immunosuppression may not be sufficient to inhibit a humoral response to both alloantigens and autoantigens.
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Affiliation(s)
- P I Lobo
- Department of Internal Medicine and Surgery, University of Virginia Health System, Charlottesville, VA 22908, USA.
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Ende N, Chen R, Reddi AS. Effect of human umbilical cord blood cells on glycemia and insulitis in type 1 diabetic mice. Biochem Biophys Res Commun 2005; 325:665-9. [PMID: 15541340 DOI: 10.1016/j.bbrc.2004.10.091] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2004] [Indexed: 12/26/2022]
Abstract
Several studies have shown that transplantation of embryonic stem cells into diabetic animals either improved or normalized blood glucose levels. In this study, we examined the dose-dependent effect of early (prediabetic stage) intravenous administration of human umbilical cord blood (HUCB) mononuclear cells on blood glucose levels, survival, and insulitis in nonobese diabetic (NOD) mice with autoimmune type 1 diabetes. The results show that mice treated with HUCB cells significantly lowered their blood glucose levels and increased their lifespan, as compared with untreated mice. Also, a significant reduction in insulitis was observed in treated than in untreated mice. The mice that received the highest dosage (200 x 10(6)) of cells had greater reduction in blood glucose levels and the degree of insulitis than the mice that received lower dosage (100-150 x 10(6)) of cells. Prolonged lifespan in the former group of mice seems to be related to better control of blood glucose levels. Thus, administration of HUCB cells in the prediabetic stage without any immunosuppression improves type 1 diabetes by protecting the islets from insulitis in NOD mice.
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Affiliation(s)
- Norman Ende
- Department of Pathology and Laboratory Medicine, UMDNJ-New Jersey Medical School, 185 South Orange Ave, Newark, NJ 07103, USA
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31
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Abstract
The blood vessels of the pancreatic islets are of crucial importance for oxygen and metabolite supply, and dispersal of secreted hormones. In addition to this, endothelial cells have an important role in the revascularization process after islet transplantation. Studies have reported signs of poor engraftment of transplanted islets, presumably due to impaired revascularization. The aims of this study were to investigate islet endothelial cells and the revascularization process of transplanted islets. The lectin Bandeiraea simplicifolia was found to consistently stain endothelium of both endogenous and transplanted pancreatic islets. By using this marker, we investigated the vascular density of both endogenous and transplanted islets of C57BL/6 mice. One month post-transplantation, a time point when the implants are assumed to be completely revascularized, the graft vascular density was decreased at all investigated implantation sites when compared to endogenous islets. Furthermore, most of the blood vessels were located in the graft connective tissue stroma. Similar results were obtained six months post-transplantation and in cured diabetic animals after one month. In order to evaluate the function of intraportally transplanted islets, we developed a method to retrieve such islets. Enzymatic and mechanic treatment of the liver enabled us to re-isolate the transplanted islets for further in vitro studies. These islets had decreased insulin release, insulin content and glucose oxidation rate when compared to non-transplanted control islets. To understand the role of islet endothelium in the revascularization of transplanted islets we performed angiogenesis microarray studies on islet endothelial cells, from non-cultured, cultured and transplanted islets. We found that the islet endothelium expressed mRNA for both inhibitors and inducers of angiogenesis, and that this expression differed with time. In conclusion, these results provide a useful platform for further studies on the islet endothelium.
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Affiliation(s)
- Göran Mattsson
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
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32
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Abstract
Type 1 diabetes affects an estimated 150 million people worldwide and results from an autoimmune-mediated destruction of insulin-producing beta-cells. In the United States alone more than 16 million people are affected by this disease and it is estimated that spending for diabetes management accounts for one out of every eight healthcare dollars. In this context, scientists are proposing novel therapeutic strategies that might allow a perfect glycemic control of most patients with diabetes.
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Affiliation(s)
- Gorka Orive
- Laboratory of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of the Basque Country, Vitoria-Gasteiz, 01002, Spain
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