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Challenges in Islet Transplantation and Strategies to Improve Beta-Cell Function
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.ORCID iD: 0000-0003-4804-5091
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Description
Abstract [en]

The incidence of type 1 diabetes is increasing worldwide and therapies of islet transplantation and potential cell-based therapies are rapidly evolving. Choosing the optimal site for such therapies is crucial for safety and for obtaining the best possible outcome. The liver is currently the site of choice, but is unfortunately associated with disadvantages for graft survival.

In paper I, intraportally transplanted human islets were evaluated for hypoxia, apoptosis, and beta-cell survival. This revealed a substantial graft loss of approximately 50 % of transplanted islet mass at one month posttransplantation. At the same time, revascularization was increased, yet still lower than that of native islets. The highest rate of apoptosis was associated with prolonged time in culture prior transplantation.

Due to progressive loss of graft function, repeated islet transplantation is often performed. A mouse model, used in paper II, demonstrated an increased survival rate of islets transplanted one week after a first transplant. This finding may reflect an improved engraftment environment “primed” by the first islet injection. No difference in islet vascular density could be ascribed to it.   

As stem cell-based therapies improve, graft monitoring possibilities and retrieval are of importance for safely introducing these techniques into the clinic. Islet grafts to omentum and muscle cured diabetic mice in paper III. Gene expression was unaltered or increased for genes important for beta-cell function.

Decidual stromal cells (DSCs) have immunomodulatory properties that could prove useful for treatments of autoimmune or inflammatory conditions. In paper IV, DSCs were found to be easily isolated from human placenta. The cells were characterized by surface markers, differentiation capacity and gene expression during culture. Co-culture with human pancreatic islets was also conducted. DSCs were observed to be very similar to other types of mesenchymal stromal cells. Greatest change in gene expression was seen between passage 2 and 5. The effect on human islet function may depend on islet viability prior to co-culture.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2020. , p. 52
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1633
Keywords [en]
Islet transplantation, Type 1 diabetes, Mesenchymal stem cells
National Category
Cell and Molecular Biology
Research subject
Medical Cell Biology
Identifiers
URN: urn:nbn:se:uu:diva-402501ISBN: 978-91-513-0858-6 (print)OAI: oai:DiVA.org:uu-402501DiVA, id: diva2:1386289
Public defence
2020-03-06, Room B22, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2020-02-14 Created: 2020-01-17 Last updated: 2020-02-14
List of papers
1. Extensive Loss of Islet Mass Beyond the First Day After Intraportal Human Islet Transplantation in a Mouse Model
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: 2020-02-04Bibliographically approved
2. Fewer Islets Survive from a First Transplant than a Second Transplant: Evaluation of Repeated Intraportal Islet Transplantation in Mice
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
3. 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
Show others...
(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
4. Alterations of Decidual Stromal Cells in Culture and their Effect on Human Pancreatic Islets in Vitro
Open this publication in new window or tab >>Alterations of Decidual Stromal Cells in Culture and their Effect on Human Pancreatic Islets in Vitro
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Several studies have shown improved outcome of islet transplantation after co-culture or co-transplantation with mesenchymal stromal cells (MSCs). Since there is no standardized MSC source or protocol, studies revealing the mechanism behind these promising results are fundamental for further advances and for the implementation of this treatment in clinical practice. In this study, we investigated the features of decidual stromal cells (DSCs), a type of MSCs isolated from the decidual layer of human placentas, their alterations in culture and their effect on human beta-cells in vitro.

Human DSCs were isolated after planned caesarian sections and characterized during culture up to passage 10. Inflammatory biomarkers were analyzed in culture medium and in lysates of DSCs and human islets. After 48 hours of co-culture, assessment of islet function by high glucose and forskolin perifusion and gene expression analysis of DSCs and islets were performed. Additionally, islets were co-cultured with pro-inflammatory cytokines to evaluate the cytoprotective ability of DSCs in different co-culture systems.

DSCs were easily isolated and of maternal origin. The cells retained the typical MSC surface marker expression up to 10 passages and were to some extent able to differentiate into three mesenchymal lineages. Gene expression analysis, after culture, showed the highest number of altered genes between passage 2 and 5. DSCs had variable effect on human islet function after co-culture, where the impact appeared dependent on islet quality of the donor. DSCs increased human islet cell death when combined with cytokine stress.

DSCs are an eligible MSC source, easily isolated and expanded in culture. We report on changes in gene expression during culture and an ambiguous effect on human islet function.

Keywords
Decidual stromal cells, Type 1 diabetes, Islets of Langerhans, Gene expression
National Category
Cell and Molecular Biology
Research subject
Medical Cell Biology
Identifiers
urn:nbn:se:uu:diva-402499 (URN)
Available from: 2020-01-17 Created: 2020-01-17 Last updated: 2020-02-04Bibliographically approved

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Liljebäck, Hanna

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