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BETA
Barbu, Andreea R
Alternative names
Publications (10 of 13) Show all publications
Asif, S., Ekdahl, K. N., Fromell, K., Gustafson, E., Barbu, A., Le Bland, K., . . . Teramura, Y. (2016). Heparinization of cell surfaces with short pepetide-conjugated PEG-lipid regulates thromboinflammation in thransplantation of human MSCs and hepatocytes. Acta Biomaterialia, 35, 194-205
Open this publication in new window or tab >>Heparinization of cell surfaces with short pepetide-conjugated PEG-lipid regulates thromboinflammation in thransplantation of human MSCs and hepatocytes
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2016 (English)In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 35, p. 194-205Article in journal (Refereed) Published
Abstract [en]

Infusion of therapeutic cells into humans is associated with immune responses, including thromboinflammation, which result in a large loss of transplanted cells\ To address these problems, heparinization of the cell surfaces was achieved by a cell-surface modification technique using polyethylene glycol conjugated phospholipid (PEG-lipid) derivatives. A short heparin-binding peptide was conjugated to the PEG-lipid for immobilization of heparin conjugates on the surface of human mesenchymal stem cells (hMSCs) and human hepatocytes. Here three kinds of heparin-binding peptides were used for immobilizing heparin conjugates and examined for the antithrombogenic effects on the cell surface. The heparinized cells were incubated in human whole blood to evaluate their hemocompatibility by measuring blood parameters such as platelet count, coagulation markers, complement markers, and Factor Xa activity. We found that one of the heparin-binding peptides did not show cytotoxicity after the immobilization with heparin conjugates. The degree of binding of the heparin conjugates on the cell surface (analyzed by flow cytometer) depended on the ratio of the active peptide to control peptide. For both human MSCs and hepatocytes in whole-blood experiments, no platelet aggregation was seen in the heparin conjugate-immobilized cell group vs. the controls (non-coated cells or control peptide). Also, the levels of thrombin-antithrombin complex (TAT), C3a, and sC5b-9 were significantly lower than those of the controls, indicating a lower activation of coagulation and complement. Factor Xa analysis indicated that the heparin conjugate was still active on the cell surface at 24 h post-coating. It is possible to immobilize heparin conjugates onto hMSC and human hepatocyte surfaces and thereby protect the cell surfaces from damaging thromboinflammation. Statement of Signigficance We present a promising approach to enhance the biocompatibility of therapeutic cells. Here we used short peptide-conjugated PEG-lipid for cell surface modification and heparin conjugates for the coating of human hepatocytes and MSCs. We screened the short peptides to find higher affinity for heparinization of cell surface and performed hemocompatibility assay of heparinized human hepatocytes and human MSCs in human whole blood. Using heparin-binding peptide with higher affinity, not only coagulation activation but also complement activation was significantly suppressed. Thus, it was possible to protect human hepatocytes and human MSCs from the attack of thromboinflammatory activation, which can contribute to the improvement graft survival.

Keywords
Cell surface modification; Heparinization; Thromboinflammation; MSCs; Hepatocyte; Polyethylene glycol-conjugated phospholipid (PEG-lipid)
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-279420 (URN)10.1016/j.actbio.2016.02.018 (DOI)000375162200018 ()26876877 (PubMedID)
Funder
Swedish Research CouncilThe Swedish Foundation for International Cooperation in Research and Higher Education (STINT)
Available from: 2016-03-01 Created: 2016-03-01 Last updated: 2017-11-30Bibliographically approved
Jansson, L., Barbu, A., Bodin, B., Drott, C. J., Espes, D., Gao, X., . . . Carlsson, P.-O. (2016). Pancreatic islet blood flow and its measurement. Upsala Journal of Medical Sciences, 121(2), 81-95
Open this publication in new window or tab >>Pancreatic islet blood flow and its measurement
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2016 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 121, no 2, p. 81-95Article, review/survey (Refereed) Published
Abstract [en]

Pancreatic islets are richly vascularized, and islet blood vessels are uniquely adapted to maintain and support the internal milieu of the islets favoring normal endocrine function. Islet blood flow is normally very high compared with that to the exocrine pancreas and is autonomously regulated through complex interactions between the nervous system, metabolites from insulin secreting beta-cells, endothelium derived mediators, and hormones. The islet blood flow is normally coupled to the needs for insulin release and is usually disturbed during glucose intolerance and overt diabetes. The present review provides a brief background on islet vascular function and especially focuses on available techniques to measure islet blood perfusion. The gold standard for islet blood flow measurements in experimental animals is the microsphere technique, and its advantages and disadvantages will be discussed. In humans there are still no methods to measure islet blood flow selectively, but new developments in radiological techniques hold great hopes for the future.

Keywords
Blood flow measurements, islet blood flow, microspheres, pancreatic islets
National Category
General Practice
Identifiers
urn:nbn:se:uu:diva-299775 (URN)10.3109/03009734.2016.1164769 (DOI)000376695600004 ()27124642 (PubMedID)
Funder
Swedish Research CouncilSwedish Diabetes AssociationSwedish Childhood Cancer FoundationNovo Nordisk
Available from: 2016-07-27 Created: 2016-07-27 Last updated: 2018-01-10Bibliographically approved
Barbu, A., Lejonklou, M. H. & Skogseid, B. (2016). Progranulin Stimulates Proliferation of Mouse Pancreatic Islet Cells and Is Overexpressed in the Endocrine Pancreatic Tissue of an MEN1 Mouse Model. Pancreas, 45(4), 533-540
Open this publication in new window or tab >>Progranulin Stimulates Proliferation of Mouse Pancreatic Islet Cells and Is Overexpressed in the Endocrine Pancreatic Tissue of an MEN1 Mouse Model
2016 (English)In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 45, no 4, p. 533-540Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: Progranulin (PGRN) promotes cell growth and cell cycle progression in several cell types and contributes to tumorigenesis in diverse cancers. We have recently reported PGRN expression in islets and tumors developed in an MEN1 transgenic mouse. Here we sought to investigate PGRN expression and regulation after exposure to hypoxia as well as its effects on pancreatic islet cells and neuroendocrine tumors (NETs) in MEN1 mice.

METHODS: Gene and protein expression were analyzed by quantitative polymerase chain reaction, immunohistochemistry, and Western blot. We also investigated PGRN expression in samples from patients carrying pancreatic NETs associated or not with the multiple endocrine neoplasia 1 syndrome, using enzyme-linked immunosorbent assay and immunohistochemistry analysis.

RESULTS: Progranulin is upregulated in tumors and islets of the MEN1 mouse as well as in the serum of patients with pancreatic NETs associated with glucagonoma syndrome. In normal mice islets and pancreatic tumors, PGRN expression was strongly potentiated by hypoxia. Progranulin promotes cell proliferation in islet cells and βTC-6 cells, a process paralleled by activation of the mitogen-activated protein kinase signaling cascade.

CONCLUSIONS: Our findings identify PGRN as an effective inducer of pancreatic islet cell proliferation and a possible important factor for pancreatic endocrine tumor development.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-273805 (URN)10.1097/MPA.0000000000000509 (DOI)000372350500008 ()26495792 (PubMedID)
Funder
Swedish Cancer Society, 110674Swedish Research Council, M-521-2011-3668Swedish Society for Medical Research (SSMF)Swedish Society of Medicine
Available from: 2016-01-18 Created: 2016-01-18 Last updated: 2018-01-10Bibliographically approved
Zang, G., Sandberg, M., Carlsson, P.-O., Welsh, N., Jansson, L. & Barbu, A. (2015). Activated pancreatic stellate cells can impair pancreatic islet function in mice. Upsala Journal of Medical Sciences, 120(3), 169-180
Open this publication in new window or tab >>Activated pancreatic stellate cells can impair pancreatic islet function in mice
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2015 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 120, no 3, p. 169-180Article in journal (Refereed) Published
Abstract [en]

Background. Pancreatic or islet fibrosis is often associated with activated pancreatic stellate cells (PSCs). PSCs are considered not only to promote fibrosis, but also to be associated with glucose intolerance in some diseases. We therefore evaluated morphological and functional relationships between islets and PSCs in the normal mouse pancreas and transplanted islets. Methods. Immunohistochemistry was used to map the presence of PSCs in the normal mouse pancreas and islets implanted under the renal capsule. We isolated and cultured mouse PSCs and characterized them morphologically by immunofluorescence staining. Furthermore, we measured their cytokine production and determined their effects on insulin release from simultaneously cultured islets. Results. PSCs were scattered throughout the pancreas, with occasional cells within the islets, particularly in the islet capsule. In islet transplants they were found mainly in the graft periphery. Cultured PSCs became functionally activated and produced several cytokines. Throughout the culture period they linearly increased their production of interleukin-6 and mammalian keratinocyte-derived chemokine. PSC cytokine production was not affected by acute hyperglycemia. Syngeneic islets cocultured with PSCs for 24-48 h increased their insulin release and lowered their insulin content. However, short-term insulin release in batch-type incubations was unaffected after 48 h of co-culture. Increased islet cell caspase-3 activation and a decreased islet cell replication were consistently observed after co-culture for 2 or 7 days. Conclusion. Activated PSCs may contribute to impaired islet endocrine function seen in exocrine pancreatitis and in islet fibrosis associated with some cases of type 2 diabetes.

Keywords
Beta-cell replication, insulin release, pancreatic islets, stellate cells
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-261989 (URN)10.3109/03009734.2015.1032453 (DOI)000359819800004 ()25854824 (PubMedID)
Funder
Swedish Research Council, 521-2011-3777
Available from: 2015-09-07 Created: 2015-09-07 Last updated: 2017-12-04Bibliographically approved
Barbu, A., Hamad, O. A., Lind, L., Ekdahl, K. N. & Nilsson, B. (2015). The role of complement factor C3 in lipid metabolism. Molecular Immunology, 67(1), 101-107
Open this publication in new window or tab >>The role of complement factor C3 in lipid metabolism
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2015 (English)In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 67, no 1, p. 101-107Article, review/survey (Refereed) Published
Abstract [en]

Abundant reports have shown that there is a strong relationship between C3 and C3a-desArg levels, adipose tissue, and risk factors for cardiovascular disease, metabolic syndrome and diabetes. The data indicate that complement components, particularly C3, are involved in lipid metabolism. The C3 fragment, C3a-desArg, functions as a hormone that has insulin-like effects and facilitates triglyceride metabolism. Adipose tissue produces and regulates the levels of complement components, which promotes generation of inflammatory initiators such as the anaphylatoxins C3a and C5a. The anaphylatoxins trigger a cyto/chemokine response in proportion to the amount of adipose tissue present, and induce inflammation and mediate metabolic effects such as insulin resistance. These observations support the concept that complement is an important participant in lipid metabolism and in obesity, contributing to the metabolic syndrome and to the low-grade inflammation associated with obesity.

Keywords
C3, C3a-desArg, Obesity, Metabolic syndrome (MetS), Apolipoproteins
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-261039 (URN)10.1016/j.molimm.2015.02.027 (DOI)000357144100011 ()25746915 (PubMedID)
Available from: 2015-09-01 Created: 2015-08-28 Last updated: 2018-01-11Bibliographically approved
Barbu, A., Jansson, L., Sandberg, M., Quach, M. & Palm, F. (2015). The use of hydrogen gas clearance for blood flow measurements in single endogenous and transplanted pancreatic islets. Microvascular Research, 97, 124-129
Open this publication in new window or tab >>The use of hydrogen gas clearance for blood flow measurements in single endogenous and transplanted pancreatic islets
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2015 (English)In: Microvascular Research, ISSN 0026-2862, E-ISSN 1095-9319, Vol. 97, p. 124-129Article in journal (Refereed) Published
Abstract [en]

The blood perfusion of pancreatic islets is regulated independently from that of the exocrine pancreas, and is of importance for multiple aspects of normal islet function, and probably also during impaired glucose tolerance. Single islet blood flow has been difficult to evaluate due to technical limitations. We therefore adapted a hydrogen gas washout technique using microelectrodes to allow such measurements. Platinum micro-electrodes monitored hydrogen gas clearance from individual endogenous and transplanted islets in the pancreas of male Lewis rats and in human and mouse islets implanted under the renal capsule of male athymic mice. Both in the rat endogenous pancreatic islets as well as in the intra-pancreatically transplanted islets, the vascular conductance and blood flow values displayed a highly heterogeneous distribution, varying by factors 6-10 within the same pancreas. The blood flow of human and mouse islet grafts transplanted in athymic mice was approximately 30% lower than that in the surrounding renal parenchyma. The present technique provides unique opportunities to study the islet vascular dysfunction seen after transplantation, but also allows for investigating the effects of genetic and environmental perturbations on islet blood flow at the single islet level in vivo. (C) 2014 The Authors. Published by Elsevier Inc.

Keywords
Blood flow, Hydrogen gas washout, Pancreatic islets, Transplanted islets, In vivo
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-243450 (URN)10.1016/j.mvr.2014.10.002 (DOI)000346895400018 ()
Note

Andrea Barbu and Leif Jansson contributed equally to this work.

Available from: 2015-02-09 Created: 2015-02-09 Last updated: 2017-12-04Bibliographically approved
Chu, X., Gao, X., Jansson, L., Quach, M., Skogseid, B. & Barbu, A. (2013). Multiple Microvascular Alterations in Pancreatic Islets and Neuroendocrine Tumors of a Men1 Mouse Model. American Journal of Pathology, 182(6), 2355-2367
Open this publication in new window or tab >>Multiple Microvascular Alterations in Pancreatic Islets and Neuroendocrine Tumors of a Men1 Mouse Model
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2013 (English)In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 182, no 6, p. 2355-2367Article in journal (Refereed) Published
Abstract [en]

Vascular therapeutic targeting requires thorough evaluation of the mechanisms activated in the specific context of each particular tumor type. We highlight structural, molecular, and functional microvascular aberrations contributing to development and maintenance of pancreatic neuroendocrine tumors (NETs), with special reference to multiple endocrine neoplasia 1 (MEN1) syndrome, using a Men1 mouse model. Tissue samples were analyzed by immunofluorescence to detect vessel density and pericyte distribution within the endocrine pancreas; expression of angiogenic factors was assessed by immunohistochemistry and quantitative real-time PCR in isolated islets and adenomas cultured under normoxic or hypoxic conditions. The increased vascular density of pancreatic NETs developed in Men1 mice was paralleled by an early and extensive redistribution of pericytes within endocrine tissue. These morphological alterations are supported by, and in some cases preceded by, fine-tuned variations in expression of several angiogenic regulators and are further potentiated by hypoxia. By combining two novel ex vivo and in vivo single-islet and tumor perfusion techniques, we demonstrated that both vascular reactivity and blood perfusion of tumor arterioles are significantly altered in response to glucose and L-nitro-arginine methyl ester. Our findings unravel multiple potential molecular and physiological targets differentially activated in the endocrine pancreas of Men1 mice and highlight the need for in-depth functional studies to fully understand the contribution of each component to development of pancreatic NETs in MEN1 syndrome.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-203534 (URN)10.1016/j.ajpath.2013.02.023 (DOI)000319781800038 ()
Available from: 2013-07-16 Created: 2013-07-15 Last updated: 2017-12-06Bibliographically approved
Lejonklou, M. H., Barbu, A., Stålberg, P. & Skogseid, B. (2012). Accelerated Proliferation and Differential Global Gene Expression in Pancreatic Islets of Five-Week-Old Heterozygous Men1 Mice: Men1 Is a Haploinsufficient Suppressor. Endocrinology, 153(6), 2588-2598
Open this publication in new window or tab >>Accelerated Proliferation and Differential Global Gene Expression in Pancreatic Islets of Five-Week-Old Heterozygous Men1 Mice: Men1 Is a Haploinsufficient Suppressor
2012 (English)In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 153, no 6, p. 2588-2598Article in journal (Refereed) Published
Abstract [en]

Individuals carrying heterozygous (hz) MEN1 (Multiple Endocrine Neoplasia Syndrome Type 1) germ line mutations develop endocrine tumors as a result of somatic loss of the wild-type (wt) allele. However, endocrine cell proliferation has been observed despite wt allele retention, indicating haploinsufficiency. To study downstream molecular effects of the hz haplotype, a germ line Men1 hz mouse model was used to explore differences in global endocrine pancreatic gene expression. Because islet cells of 5-wk-old hz mice express Menin from the retained wt Men1 allele, these were isolated after collagenase digestion of the pancreas, and used for global gene expression array. Wild-type littermates were used for comparison. Array findings were corroborated by quantitative PCR, Western blotting, in situ proximity ligation assay, and immunohistochemistry. The hz islets show increased proliferation: the Ki-67 index was twice as high as in wt islets (3.48 vs. 1.74%; P = 0.024). The microarray results demonstrated that several genes were differentially expressed. Some selected genes were studied on the protein level, e.g. the cytoskeletal regulator myristoylated alanine-rich protein kinase C substrate (Marcks) was significantly less expressed in hz islets, using in situ proximity ligation assay and Western blotting (P < 0.001 and P < 0.01, respectively). Further, gene ontology analysis showed that genes with higher mRNA expression in the hz endocrine pancreas were associated with e.g. chromatin maintenance and apoptosis. Lower mRNA was observed for genes involved in growth factor binding. In conclusion, despite retained Menin expression, proliferation was accelerated, and numerous genes were differentially expressed in the endocrine pancreas of 5-wk-old hz Men1 mice, corroborating the hypothesis that MEN1 is a haploinsufficient suppressor.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-174062 (URN)10.1210/en.2011-1924 (DOI)000304370700011 ()22492302 (PubMedID)
Available from: 2012-05-10 Created: 2012-05-10 Last updated: 2017-12-07Bibliographically approved
Barbu, A., Johansson, Å., Bodin, B., Källskog, Ö., Carlsson, P.-O., Sandberg, M., . . . Jansson, L. (2012). Blood flow in endogenous and transplanted pancreatic islets in anesthetized rats: Effects of lactate and pyruvate. Pancreas, 41(8), 1263-1271
Open this publication in new window or tab >>Blood flow in endogenous and transplanted pancreatic islets in anesthetized rats: Effects of lactate and pyruvate
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2012 (English)In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 41, no 8, p. 1263-1271Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: The objective of this study was to evaluate the effects of exogenously administered lactate and pyruvate on blood perfusion in endogenous and transplanted islets. METHODS: Anesthetized Wistar-Furth rats were given lactate or pyruvate intravenously, and regional blood perfusion was studied 3 or 30 minutes later with a microsphere technique. Separate rats received a 30-minute infusion of pyruvate or lactate into the portal vein before blood flow measurements. We also administered these substances to islet-implanted rats 4 weeks after transplantation and measured graft blood flow with laser Doppler flowmetry. The expression of monocarboxylate transporter 1 and lactate dehydrogenase A was analyzed. RESULTS: The expression of monocarboxylate transporter 1 and lactate dehydrogenase A was markedly up-regulated in transplanted as compared with endogenous islets. Administration of pyruvate, but not lactate, increased mesenteric blood flow after 3 minutes. Pyruvate decreased mesenteric blood flow after 30 minutes, whereas lactate decreased only islet blood flow. These responses were absent in transplanted animals. A continuous intraportal infusion of lactate or pyruvate increased selectively islet blood flow but did not affect blood perfusion of transplanted islets. CONCLUSIONS: Lactate and pyruvate affect islet blood flow through effects mediated by interactions between the liver and the nervous system. Such a response can help adjust the release of islet hormones during excess substrate concentrations.

Keywords
blood flow, lactate, pancreatic islets, pyruvate
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-186004 (URN)10.1097/MPA.0b013e31824bd97c (DOI)000310360500015 ()
Available from: 2012-11-28 Created: 2012-11-27 Last updated: 2017-12-07Bibliographically approved
Barbu, A., Persdotter Hedlund, G., Lind, J. & Carlsson, C. (2009). Pref-1 and adipokine expression inadipose tissues of GK And Zucker rats. Molecular and Cellular Endocrinology, 299(2), 163-171
Open this publication in new window or tab >>Pref-1 and adipokine expression inadipose tissues of GK And Zucker rats
2009 (English)In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 299, no 2, p. 163-171Article in journal (Refereed) Published
Abstract [en]

In view of the central role of preadipocyte factor-1, adiponectin and leptin in white adipose tissue function, the aim of the present study was to analyze the mRNA expression of these proteins and of the inflammatory markers interleukin-6 and tumor necrosis factor-α in visceral and subcutaneous fat pads of rats with different metabolic disorders.

We demonstrated highly divergent expression of preadipocyte factor-1, upregulated expression of adiponectin, interleukin-6 and TNF-α mRNA in adipose tissues of the diabetic Goto Kakizaki rat compared to the obese Zucker rat. This was correlated to an increased number of large adipocytes and serum levels of adiponectin. Furthermore, in all four strains studied (as above plus Wistar Furth and Zucker Lean), significant heterogeneity was evident in adipokine expression within specific adipose tissues previously defined as belonging to the visceral or subcutaneous fat depots.

These results suggest that significantly increased levels of inflammation and redistribution of adipocyte size are mechanisms contributing to the development of type 2 diabetes in the GK rat.

Keywords
Adipokines, Adipocytes, Fat, Diabetes, Pref-1, Goto Kakizaki, Zucker
National Category
Endocrinology and Diabetes
Research subject
Medical Cell Biology
Identifiers
urn:nbn:se:uu:diva-102205 (URN)10.1016/j.mce.2008.11.019 (DOI)000263662500004 ()
Available from: 2009-05-05 Created: 2009-05-05 Last updated: 2017-12-13Bibliographically approved
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