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Liljebäck, H., Quach, M., Carlsson, P.-O. & Lau, J. (2019). Fewer Islets Survive from a First Transplant than a Second Transplant: Evaluation of Repeated Intraportal Islet Transplantation in Mice. Cell Transplantation, 28(11), 1455-1460
Open this publication in new window or tab >>Fewer Islets Survive from a First Transplant than a Second Transplant: Evaluation of Repeated Intraportal Islet Transplantation in Mice
2019 (English)In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 28, no 11, p. 1455-1460Article in journal (Refereed) Published
Abstract [en]

Beta cell replacement is an exciting field where new beta cell sources and alternative sites are widely explored. The liver has been the implantation site of choice in the clinic since the advent of islet transplantation. However, in most cases, repeated islet transplantation is needed to achieve normoglycemia in diabetic recipients. This study aimed to investigate whether there are differences in islet survival and engraftment between a first and a second transplantation, performed 1 week apart, to the liver. C57BL/6 mice were accordingly transplanted twice with an initial infusion of syngeneic islets expressing green fluorescent protein (GFP). The second islet transplant was performed 1 week later and consisted of islets isolated from non-GFP C57BL/6-mice. Animals were sacrificed either 1 day or 1 month after the second transplantation. A control group received a saline infusion instead of GFP-expressing islets, 1 week later obtained a standard non-GFP islet transplant, and was subsequently sacrificed 1 month later. Islet engraftment in the liver was assessed by immunohistochemistry and serum was analyzed for angiogenic factors induced by the first islet transplantation. Almost 70% of islets found in the liver following repeated islet transplantation originated from the second transplantation. The vascular density in the transplanted non-GFP-expressing islets did not differ depending on whether their transplantation was preceded by a primary islet transplantation or saline administration only nor did angiogenic factors in serum prior to the transplantation of non-GFP islets differ between animals that had received a previous islet transplantation or a saline infusion. We conclude that first islet transplantation creates, by unknown mechanisms, favorable conditions for the survival of a second transplant to the liver.

Keywords
GFP, engraftment, islet transplantation, type 1 diabetes
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-398599 (URN)10.1177/0963689719866685 (DOI)000479643300001 ()31359771 (PubMedID)
Funder
Swedish Child Diabetes FoundationSwedish Research Council, 2017-01343EXODIAB - Excellence of Diabetes Research in SwedenSwedish Diabetes Association
Available from: 2019-12-07 Created: 2019-12-07 Last updated: 2020-01-17Bibliographically approved
Liljebäck, H., Espes, D. & Carlsson, P.-O. (2019). Unsurpassed Intrahepatic Islet Engraftment: the Quest for New Sites for Beta Cell Replacement. Cell Medicine, 11, Article ID 2155179019857662.
Open this publication in new window or tab >>Unsurpassed Intrahepatic Islet Engraftment: the Quest for New Sites for Beta Cell Replacement
2019 (English)In: Cell Medicine, ISSN 2155-1790, E-ISSN 2155-1790, Vol. 11, article id 2155179019857662Article in journal, Editorial material (Other academic) Published
Abstract [en]

The liver is currently the site of choice for clinical islet transplantation, even though many alternative implantation sites have lately been proposed as more ideal for graft survival. The suggested sites, for example intramuscular space, omentum, bone marrow, and spleen, are sometimes difficult to compare due to differences in animal model, islet isolation procedure, and islet quality. In addition, the variation in transplanted islet mass is vast. The aim of this commentary is to review alternative implantation sites tested experimentally as well as in clinical islet transplantation. Although many sites have been investigated, none have convincingly proved better suited for clinical islet transplantation than intraportal injection to the liver, regardless of whether it is autologous or allogeneic transplantation. However, in order to fully evaluate upcoming bioengineering techniques, such as scaffolds containing insulin-producing cells derived from stem cells, the need of an alternative site has arisen to enable cellular monitoring, which currently cannot be achieved within the liver.

Place, publisher, year, edition, pages
Sage Publications, 2019
Keywords
intraportal islet transplantation, type 1 diabetes, beta cell replacement
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-390334 (URN)10.1177/2155179019857662 (DOI)000472913100001 ()
Available from: 2019-08-09 Created: 2019-08-09 Last updated: 2019-08-09Bibliographically 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: 2020-01-17
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
Espes, D., Martinell, M., Liljebäck, H. & Carlsson, P.-O. (2015). Betatrophin in Diabetes Mellitus: the Epidemiological Evidence in Humans. Current Diabetes Reports, 15(12), Article ID 104.
Open this publication in new window or tab >>Betatrophin in Diabetes Mellitus: the Epidemiological Evidence in Humans
2015 (English)In: Current Diabetes Reports, ISSN 1534-4827, E-ISSN 1539-0829, Vol. 15, no 12, article id 104Article, review/survey (Refereed) Published
Abstract [en]

The prevalence of type 2 diabetes is increasing worldwide, and while numerous treatments exist, none of the current pharmacologic therapies is curative. Pharmacologic approaches that increase beta cell mass may present an avenue for actual cure. There have been numerous reports on factors that can induce beta cell proliferation in rodents, whereas there are still very limited data on the occurrence of beta cell proliferation in humans. The recent discovery of the hormone betatrophin, which in mice counteracted glucose intolerance induced by insulin resistance by potently stimulating beta cell proliferation, has boosted the hope for a new target for drug development for the treatment of diabetes mellitus in humans. With the encouraging preclinical findings as a background, this review presents the available clinical data on betatrophin and discusses its possible role in humans.

Keywords
Betatrophin; Diabetes; Humans; Beta cell proliferation; Islet; Liver
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-270683 (URN)10.1007/s11892-015-0676-4 (DOI)000366806700002 ()26458375 (PubMedID)
Funder
Swedish Research Council, K2013-55X-15043Novo NordiskAFA InsuranceSwedish Diabetes AssociationSwedish Child Diabetes FoundationStiftelsen Olle Engkvist ByggmästareNovo Nordisk
Available from: 2016-01-03 Created: 2016-01-03 Last updated: 2017-12-01Bibliographically 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
Espes, D., Liljebäck, H., Lau, J., Franzén, P., Quach, M. & Carlsson, P.-O.Function and Gene Expression of Islets Experimentally Transplanted to Muscle or Omentum.
Open this publication in new window or tab >>Function and Gene Expression of Islets Experimentally Transplanted to Muscle or Omentum
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(English)Manuscript (preprint) (Other academic)
Keywords
Islet transplantation, muscle, omentum, engraftment, gene expression, laser capture microdissection
National Category
Cell and Molecular Biology
Research subject
Medical Cell Biology
Identifiers
urn:nbn:se:uu:diva-282952 (URN)
Available from: 2016-04-08 Created: 2016-04-08 Last updated: 2020-01-17
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-4804-5091

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