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An in vivo experimental model to study human immune responses towards transplanted human pluripotent stem cell-derived islets or primary human islets
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Institutionen för medicinsk cellbiologi.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
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(English)Manuscript (preprint) (Other academic)
National Category
Basic Medicine
Identifiers
URN: urn:nbn:se:uu:diva-525229OAI: oai:DiVA.org:uu-525229DiVA, id: diva2:1845628
Available from: 2024-03-19 Created: 2024-03-19 Last updated: 2024-03-20
In thesis
1. Transplantation of stem cell-derived islets as a treatment for type 1 diabetes
Open this publication in new window or tab >>Transplantation of stem cell-derived islets as a treatment for type 1 diabetes
2024 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Type 1 diabetes (T1D) is an autoimmune disease that leads to an immune attack on insulin-producing beta cells, necessitating lifelong insulin therapy. For individuals with brittle diabetes and poor metabolic control, the option of pancreatic human islet transplantation exists. However, the shortage of organ donors and the need for life-long immune suppressive agents pose significant challenges. Stem cell-derived islets (SC-islets) present a promising alternative for diabetes treatment. 

This thesis explores the differentiation and transplantation of SC-islets as a treatment for diabetes. In paper I, three months post-transplantation, the ingrowth of recipient blood vessels and the neural density was higher in SC-islet grafts compared to human islet grafts. Furthermore, there was a higher tendency of blood flow, whereas the oxygenation was twice as high in SC-islet grafts. Both transplanted SC-islets and human islets had formation of amyloid depositions, which can affect the long-term survival and function of transplanted cells. In paper II, a humanized mouse model transplanted with SC-islets or human islets was validated. Transplanted SC-islets or human islets were not completely rejected 11 days after injection with human peripheral blood mononuclear cells (PBMCs). In vivo imaging and flow cytometry confirmed the presence of injected human immune cells, demonstrating an effective model for studying the human immune responses of allogeneically transplanted islets or SC-islets. In paper III, positron emission tomography (PET) imaging, using the DGCR2 affibody, for monitoring transplanted beta cells revealed successful binding to SC-islets and human islets in vitro. PET imaging in vivo demonstrated successful detection of the affibody in transplanted SC-islets. Although, the affibody could be optimized since the signal vanished 30 min after administration. However, DGCR2 remains a promising marker for SC-islet imaging. In paper IV, nanofiltration with a virus clearance filter paper during SC-islet differentiation was evaluated. Filter SC-islets expressed essential markers for beta cells during differentiation in comparable amounts as the control. The filtered SC-islets demonstrated physiological insulin-releasing function similar to that of the control. Nanofiltration did not seem to affect the differentiation of SC-islets. 

In conclusion, transplantation of SC-islets is a promising future treatment for diabetes, however, long-term effects need to be evaluated. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2024. p. 55
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 2037
Keywords
Type 1 diabetes, Islet of Langerhans, Stem cell-derived islets, Islet transplantation, Humanized mouse model, Positron emission tomography, Nanofiltration
National Category
Physiology
Research subject
Physiology; Medical Cell Biology
Identifiers
urn:nbn:se:uu:diva-525235 (URN)978-91-513-2074-8 (ISBN)
Public defence
2024-05-16, B42, BMC, Husargatan 3, Uppsala, 09:15 (English)
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Supervisors
Available from: 2024-04-22 Created: 2024-03-20 Last updated: 2024-04-22

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CiteExportLink to record
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