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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 [en]
Decidual stromal cells, Type 1 diabetes, Islets of Langerhans, Gene expression
National Category
Cell and Molecular Biology
Research subject
Medical Cell Biology
Identifiers
URN: urn:nbn:se:uu:diva-402499OAI: oai:DiVA.org:uu-402499DiVA, id: diva2:1386257
Available from: 2020-01-17 Created: 2020-01-17 Last updated: 2020-02-04Bibliographically approved
In thesis
1. Challenges in Islet Transplantation and Strategies to Improve Beta-Cell Function
Open this publication in new window or tab >>Challenges in Islet Transplantation and Strategies to Improve Beta-Cell Function
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
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
Islet transplantation, Type 1 diabetes, Mesenchymal stem cells
National Category
Cell and Molecular Biology
Research subject
Medical Cell Biology
Identifiers
urn:nbn:se:uu:diva-402501 (URN)978-91-513-0858-6 (ISBN)
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

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