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Olerud, Johan
Publications (10 of 16) Show all publications
Eich, T., Ståhle, M. U., Gustafsson, B., Horneland, R., Lempinen, M., Lundgren, T., . . . Korsgren, O. (2018). Calcium: A Crucial Potentiator for Efficient Enzyme Digestion of the Human Pancreas. Cell Transplantation, 27(7), 1031-1038
Open this publication in new window or tab >>Calcium: A Crucial Potentiator for Efficient Enzyme Digestion of the Human Pancreas
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2018 (English)In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 27, no 7, p. 1031-1038Article in journal (Refereed) Published
Abstract [en]

Background: Effective digestive enzymes are crucial for successful islet isolation. Supplemental proteases are essential because they synergize with collagenase for effective pancreatic digestion. The activity of these enzymes is critically dependent on the presence of Ca2+ ions at a concentration of 5–10 mM. The present study aimed to determine the Ca2+ concentration during human islet isolation and to ascertain whether the addition of supplementary Ca2+ is required to maintain an optimal Ca2+ concentration during the various phases of the islet isolation process.

Methods: Human islets were isolated according to standard methods and isolation parameters. Islet quality control and the number of isolations fulfilling standard transplantation criteria were evaluated. Ca2+ was determined by using standard clinical chemistry routines. Islet isolation was performed with or without addition of supplementary Ca2+ to reach a Ca2+ of 5 mM.

Results: Ca2+ concentration was markedly reduced in bicarbonate-based buffers, especially if additional bicarbonate was used to adjust the pH as recommended by the Clinical Islet Transplantation Consortium. A major reduction in Ca2+ concentration was also observed during pancreatic enzyme perfusion, digestion, and harvest. Additional Ca2+ supplementation of media used for dissolving the enzymes and during digestion, perfusion, and harvest was necessary in order to obtain the concentration recommended for optimal enzyme activity and efficient liberation of a large number of islets from the human pancreas.

Conclusions: Ca2+ is to a large extent consumed during clinical islet isolation, and in the absence of supplementation, the concentration fell below that recommended for optimal enzyme activity. Ca2+ supplementation of the media used during human pancreas digestion is necessary to maintain the concentration recommended for optimal enzyme activity. Addition of Ca2+ to the enzyme blend has been implemented in the standard isolation protocols in the Nordic Network for Clinical Islet Transplantation.

Keywords
calcium, clinical islet transplantation, diabetes, islet isolation
National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-364508 (URN)10.1177/0963689718779350 (DOI)000440338700003 ()29945463 (PubMedID)
Available from: 2018-11-05 Created: 2018-11-05 Last updated: 2018-11-05Bibliographically approved
Carlsson, P.-O., Espes, D., Sedigh, A., Rotem, A., Zimermann, B., Grinberg, H., . . . Korsgren, O. (2018). Transplantation of Macro-encapsulated Human Islets within the Bioartificial Pancreas β Air to Patients with Type 1 Diabetes Mellitus. American Journal of Transplantation, 18(7), 1735-1744
Open this publication in new window or tab >>Transplantation of Macro-encapsulated Human Islets within the Bioartificial Pancreas β Air to Patients with Type 1 Diabetes Mellitus
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2018 (English)In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 18, no 7, p. 1735-1744Article in journal (Refereed) Published
Abstract [en]

Macroencapsulation devices provide the dual possibility to immunoprotect transplanted cells while also being retrievable; the latter bearing importance for safety in future trials with stem-cell derived cells. However, macroencapsulation entails a problem with oxygen supply to the encapsulated cells. The βAir device solves this with an incorporated refillable oxygen tank. This phase 1 study evaluated the safety and efficacy of implanting the βAir device containing allogeneic human pancreatic islets to patients with type 1 diabetes. Four patients were transplanted with 1-2 βAir devices, each containing 155000-180000 IEQ (i.e. 1800-4600 IEQ per kg body weight), and monitored for 3-6 months, followed by the recovery of devices. Implantation of the βAir device was safe and successfully prevented immunization and rejection of the transplanted tissue. However, although beta cells survived in the device, only minute levels of circulating C-peptide were observed with no impact on metabolic control. Fibrotic tissue with immune cells was formed in capsule surroundings. Recovered devices displayed a blunted glucose-stimulated insulin response, and amyloid formation in the endocrine tissue. We conclude that the βAir device is safe and can support survival of allogeneic islets for several months, although the function of the transplanted cells was limited.

National Category
Endocrinology and Diabetes Surgery Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-337701 (URN)10.1111/ajt.14642 (DOI)29288549 (PubMedID)
Funder
Ernfors FoundationSwedish Diabetes AssociationSwedish Research Council, 921-2014-7054Swedish Research Council, K2013-55X-15043Swedish Research Council, K2015-54X-12219-19-4Swedish Research Council, K2016-01040Swedish Research Council, K2016-GTWNovo NordiskSwedish Child Diabetes Foundation
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2018-01-03 Created: 2018-01-03 Last updated: 2018-09-21Bibliographically approved
Shah, P., Lueschen, N., Ardestani, A., Oberholzer, J., Olerud, J., Carlsson, P.-O. & Maedler, K. (2016). Angiopoetin-2 Signals Do Not Mediate the Hypervascularization of Islets in Type 2 Diabetes. PLoS ONE, 11(9), Article ID e0161834.
Open this publication in new window or tab >>Angiopoetin-2 Signals Do Not Mediate the Hypervascularization of Islets in Type 2 Diabetes
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2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 9, article id e0161834Article in journal (Refereed) Published
Abstract [en]

Aims Changes in the islet vasculature have been implicated in the regulation of beta-cell survival and function during the progression to type 2 diabetes (T2D). Failure of the beta-cell to compensate for the increased insulin demand in obesity eventually leads to diabetes; as a result of the complex interplay of genetic and environmental factors (e.g. ongoing inflammation within the islets) and impaired vascular function. The Angiopoietin/Tie (Ang/Tie) angiogenic system maintains vasculature and is closely related to organ inflammation and angiogenesis. In this study we aimed to identify whether the vessel area within the islets changes in diabetes and whether such changes would be triggered by the Tie-antagonist Ang-2. Methods Immunohistochemical and qPCR analyses to follow islet vascularization and Ang/Tie levels were performed in human pancreatic autopsies and isolated human and mouse islets. The effect of Ang-2 was assessed in beta-cell-specific Ang-2 overexpressing mice during high fat diet (HFD) feeding. Results Islet vessel area was increased in autopsy pancreases from patients with T2D. The vessel markers Tie-1, Tie-2 and CD31 were upregulated in mouse islets upon HFD feeding from 8 to 24 weeks. Ang-2 was transiently upregulated in mouse islets at 8 weeks of HFD and under glucolipotoxic conditions (22.2mMglucose/0.5 mMpalmitate) in vitro in human and mouse islets, in contrast to its downregulation by cytokines (IL-1 beta, IFN-gamma and TNF-alpha). Ang-1 on the other hand was oppositely regulated, with a significant loss under glucolipotoxic condition, a trend to reduce in islets from patients with T2D and an upregulation by cytokines. Modulation of such changes in Ang-2 by its overexpression or the inhibition of its receptor Tie-2 impaired beta-cell function at basal conditions but protected islets from cytokine induced apoptosis. In vivo, beta-cell-specific Ang-2 overexpression in mice induced hypervascularization under normal diet but contrastingly led to hypovascularized islets in response to HFD together with increased apoptosis and reduced beta-cell mass. Conclusions Islet hypervascularization occurs in T2D. A balanced expression of the Ang1/Ang2 system is important for islet physiology. Ang-2 prevents beta-cell mass and islet vascular adaptation in response to HFD feeding with no major influence on glucose homeostasis.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-311613 (URN)10.1371/journal.pone.0161834 (DOI)000383653100010 ()27617438 (PubMedID)
Funder
EU, European Research CouncilGerman Research Foundation (DFG)
Available from: 2016-12-30 Created: 2016-12-30 Last updated: 2017-11-29Bibliographically approved
Liljebäck, H., Grapensparr, L., Olerud, J. & Carlsson, P.-O. (2016). Extensive Loss of Islet Mass Beyond the First Day After Intraportal Human Islet Transplantation in a Mouse Model. Cell Transplantation, 25(3), 481-489
Open this publication in new window or tab >>Extensive Loss of Islet Mass Beyond the First Day After Intraportal Human Islet Transplantation in a Mouse Model
2016 (English)In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 25, no 3, p. 481-489Article in journal (Refereed) Published
Abstract [en]

Clinical islet transplantation is characterized by a progressive deterioration of islet graft function, which renders many patients once again dependent on exogenous insulin administration within a couple of years. In this study, we aimed to investigate possible engraftment factors limiting the survival and viability of experimentally transplanted human islets beyond the first day after their transplantation to the liver. Human islets were transplanted into the liver of nude mice and characterized 1 or 30 days after transplantation by immunohistochemistry. The factors assessed were endocrine mass, cellular death, hypoxia, vascular density and amyloid formation in the transplanted islets. One day posttransplantation, necrotic cells, as well as apoptotic cells, were commonly observed. In contrast to necrotic death, apoptosis rates remained high 1 month posttransplantation, and the total islet mass was reduced by more than 50% between 1 and 30 days posttransplantation. Islet mass at 30 days posttransplantation correlated negatively to apoptotic death. Vascular density within the transplanted islets remained less than 30% of that in native human islets up to 30 days posttransplantation and was associated with prevailing hypoxia. Amyloid formation was rarely observed in the 1-day-old transplants, but was commonly observed in the 30-day-old islet transplants. We conclude that substantial islet cell death occurs beyond the immediate posttransplantation phase, particularly through apoptotic events. Concomitant low vascularization with prevailing hypoxia and progressive amyloid development was observed in the human islet grafts. Strategies to improve engraftment at the intraportal site or change of implantation site in the clinical setting are needed.

Keywords
Islet transplantation, Diabetes, Amyloid, Engraftment
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-294600 (URN)10.3727/096368915X688902 (DOI)000372669200005 ()26264975 (PubMedID)
Funder
Swedish Research CouncilSwedish Diabetes AssociationSwedish Child Diabetes FoundationNovo Nordisk
Available from: 2016-05-26 Created: 2016-05-25 Last updated: 2017-11-30Bibliographically approved
Maedler, K., Shah, P., Lueschen, N., Ardestani, A., Olerud, J. & Carlsson, P.-O. (2016). The hypervascularisation of islets in type 2 diabetes is not mediated by angiopoetin-2. Paper presented at 52nd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), SEP 12-16, 2016, Munich, GERMANY. Diabetologia, 59, S203-S203
Open this publication in new window or tab >>The hypervascularisation of islets in type 2 diabetes is not mediated by angiopoetin-2
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2016 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, p. S203-S203Article in journal (Refereed) Published
Place, publisher, year, edition, pages
SPRINGER, 2016
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-322047 (URN)000398373701219 ()
Conference
52nd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), SEP 12-16, 2016, Munich, GERMANY
Available from: 2017-05-16 Created: 2017-05-16 Last updated: 2017-05-16Bibliographically approved
Grapensparr, L., Vasylovska, S., Li, Z., Olerud, J., Jansson, L., Kozlova, E. & Carlsson, P.-O. (2015). Co-transplantation of Human Pancreatic Islets With Post-migratory Neural Crest Stem Cells Increases beta-Cell Proliferation and Vascular And Neural Regrowth. Journal of Clinical Endocrinology and Metabolism, 100(4), E583-E590
Open this publication in new window or tab >>Co-transplantation of Human Pancreatic Islets With Post-migratory Neural Crest Stem Cells Increases beta-Cell Proliferation and Vascular And Neural Regrowth
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2015 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 100, no 4, p. E583-E590Article in journal (Refereed) Published
Abstract [en]

Context: Neural crest stem cells (NCSCs) are capable of substantially improving murine islet function by promoting beta-cell proliferation. Objective: The present study aimed to investigate the potential of NCSCs to stimulate human beta-cell proliferation, and improve neural and vascular engraftment of human islets. Design, Setting, and Subjects: Human pancreatic islets from 18 brain-dead cadaveric donors (age range, 19-78 y) were obtained through the Nordic Network for Clinical Islet Transplantation. beta-cell proliferation and graft function was investigated at our experimental laboratory. Intervention and Main Outcome Measures: Human islets were transplanted, either alone or together with spheres of NCSCs. beta-cell proliferation, as well as islet neuralandvascular densities, were assessed by immunohistochemistry. Graft blood perfusion and oxygen tension were measured using laser-Doppler flowmetry and Clark microelectrodes, respectively. Results: Two days posttransplantation, the number of Ki67-positive beta-cells was doubled in human islets that had been exposed to NCSCs. Similar findings were obtained in vitro, as well as with EdU as proliferation marker. Four weeks posttransplantation, NCSC-exposed human islet grafts had much higher neural and vascular densities. The newly formed blood vessels were also functional, given that these human islets had a substantially higher blood perfusion and oxygen tension when compared with control transplants. Conclusion: We conclude that exposure to NCSCs stimulates human beta-cell proliferation, andthat these cells improve both the neural and vascular engraftment of transplanted human islets. NCSCs are a promising cellular therapy for translation into clinical use.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-253267 (URN)10.1210/jc.2014-4070 (DOI)000353361500009 ()25668197 (PubMedID)
Available from: 2015-05-25 Created: 2015-05-25 Last updated: 2017-12-04Bibliographically approved
Shah, P., Olerud, J., Kerr-Conte, J., Carlsson, P.-O. & Maedler, K. (2013). Angiogenic factors regulate beta cell function. Paper presented at 49th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), SEP 23-27, 2013, Barcelona, SPAIN. Diabetologia, 56, S193-S193
Open this publication in new window or tab >>Angiogenic factors regulate beta cell function
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2013 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 56, p. S193-S193Article in journal, Meeting abstract (Other academic) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-218010 (URN)000329196901121 ()
Conference
49th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), SEP 23-27, 2013, Barcelona, SPAIN
Available from: 2014-02-07 Created: 2014-02-06 Last updated: 2017-12-06Bibliographically approved
Liljebäck, H., Olerud, J. & Carlsson, P.-O. (2013). Engraftment Factors Limiting Human Islet Survival and Function After Experimental Intraportal Islet Transplantation. Paper presented at 14th World Congress of the International-Pancreas-and-Islet-Transplant-Association (IPITA), SEP 24-27, 2013, Monterey, CA. Transplantation, 96(6), S130-S130
Open this publication in new window or tab >>Engraftment Factors Limiting Human Islet Survival and Function After Experimental Intraportal Islet Transplantation
2013 (English)In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 96, no 6, p. S130-S130Article in journal, Meeting abstract (Other academic) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-220754 (URN)000330443500236 ()
Conference
14th World Congress of the International-Pancreas-and-Islet-Transplant-Association (IPITA), SEP 24-27, 2013, Monterey, CA
Available from: 2014-03-21 Created: 2014-03-20 Last updated: 2017-12-05Bibliographically approved
Teramura, Y., Podiyan, O., Olerud, J., Hilborn, J. & Nilsson, B. (2013). Microencapsulation of cells, including islets, within stable ultra-thin membranes of maleimide-conjugated PEG-lipid with multifunctional crosslinkers. Biomaterials, 34(11), 2683-2693
Open this publication in new window or tab >>Microencapsulation of cells, including islets, within stable ultra-thin membranes of maleimide-conjugated PEG-lipid with multifunctional crosslinkers
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2013 (English)In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 34, no 11, p. 2683-2693Article in journal (Refereed) Published
Abstract [en]

The encapsulation of islets of Langerhans (islets) and insulin-secreting cells within a semi-permeable membrane has been suggested as a safe and simple technique for islet transplantation to attenuate early graft loss and avoid immunosuppressive therapy. The total volume of these implants tends, however, to increase upon encapsulation of the islets and cells within the polymer membrane, limiting transport between encapsulated cells and the surrounding tissue. Ultra-thin membranes could potentially overcome these diffusion limitations to provide for clinically applicable implants. Here we propose a method to encapsulate islets and cells within a stable ultra-thin polymer membrane using poly(ethylene glycol)-conjugated phospholipid bearing a maleimide group (Mal-PEG-lipids) and multiple interactive polymers (e.g., 4-arm PEG-Mal and 8-arm PEG-SH). When Mal-PEG-lipids were added to islet and cell suspensions, spontaneous incorporation into a cell surface occurred from the micelles at an equilibrium state. The addition of 4-arm PEG-Mal and 8-arm PEG-SH to the mixture induced a substantial increase in the membrane thickness because a number of Mal-PEG-lipid micelles were involved in the membrane formation at the micrometer level. No appreciable increase in islet volume was observed after microencapsulation by this method. Microencapsulation of islets with the polymer membranes, which showed semi-permeability, did not impair insulin release in response to glucose stimulation, even after 7 days. The polymer membrane structure surrounding the islets and cells was well maintained for at least 30 days. In addition, the membrane formed showed much lower thrombogenicity and inhibited complement activation upon exposure to human whole blood and serum.

Keywords
Microencapsulation, Bioartificial pancreas, Islets, Poly(ethylene glycol)-lipid (PEG-lipid), Cell surface modification, Diabetes
National Category
Medical and Health Sciences Natural Sciences
Identifiers
urn:nbn:se:uu:diva-197955 (URN)10.1016/j.biomaterials.2013.01.015 (DOI)000315748200011 ()
Available from: 2013-04-10 Created: 2013-04-08 Last updated: 2017-12-06Bibliographically approved
Grapensparr, L., Vasylovska, S., Olerud, J., Korsgren, O., Kozlova, E., Jansson, L. & Carlsson, P.-O. (2013). Neural Crest Stem Cells Induce Beta-cell Proliferation in Cultured and Transplanted Human Pancreatic Islets. Paper presented at 14th World Congress of the International-Pancreas-and-Islet-Transplant-Association (IPITA), SEP 24-27, 2013, Monterey, CA. Transplantation, 96(6), S149-S149
Open this publication in new window or tab >>Neural Crest Stem Cells Induce Beta-cell Proliferation in Cultured and Transplanted Human Pancreatic Islets
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2013 (English)In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 96, no 6, p. S149-S149Article in journal, Meeting abstract (Other academic) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-220750 (URN)000330443500270 ()
Conference
14th World Congress of the International-Pancreas-and-Islet-Transplant-Association (IPITA), SEP 24-27, 2013, Monterey, CA
Available from: 2014-03-24 Created: 2014-03-20 Last updated: 2017-12-05Bibliographically approved
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