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Transplantation of stem cell-derived islets as a treatment for type 1 diabetes
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
2024 (English)Doctoral thesis, comprehensive summary (Other academic)
Description
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 [en]
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: urn:nbn:se:uu:diva-525235ISBN: 978-91-513-2074-8 (print)OAI: oai:DiVA.org:uu-525235DiVA, id: diva2:1845794
Public defence
2024-05-16, B42, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2024-04-22 Created: 2024-03-20 Last updated: 2024-04-22
List of papers
1. Efficient vascular and neural engraftment of stem cell-derived islets
Open this publication in new window or tab >>Efficient vascular and neural engraftment of stem cell-derived islets
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(English)Manuscript (preprint) (Other academic)
National Category
Physiology
Identifiers
urn:nbn:se:uu:diva-525230 (URN)
Available from: 2024-03-19 Created: 2024-03-19 Last updated: 2024-03-20
2. An in vivo experimental model to study human immune responses towards transplanted human pluripotent stem cell-derived islets or primary human islets
Open this publication in new window or tab >>An in vivo experimental model to study human immune responses towards transplanted human pluripotent stem cell-derived islets or primary human islets
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(English)Manuscript (preprint) (Other academic)
National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-525229 (URN)
Available from: 2024-03-19 Created: 2024-03-19 Last updated: 2024-03-20
3. Preclinical evaluation of Affibody molecule for PET imaging of human pancreatic islets derived from stem cells.
Open this publication in new window or tab >>Preclinical evaluation of Affibody molecule for PET imaging of human pancreatic islets derived from stem cells.
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2023 (English)In: EJNMMI Research, E-ISSN 2191-219X, EJNMMI research, ISSN 2191-219X, Vol. 13, no 1, p. 107-, article id 107Article in journal (Refereed) Published
Abstract [en]

BackgroundBeta-cell replacement methods such as transplantation of isolated donor islets have been proposed as a curative treatment of type 1 diabetes, but widespread application is challenging due to shortages of donor tissue and the need for continuous immunosuppressive treatments. Stem-cell-derived islets have been suggested as an alternative source of beta cells, but face transplantation protocols optimization difficulties, mainly due to a lack of available methods and markers to directly monitor grafts survival, as well as their localization and function. Molecular imaging techniques and particularly positron emission tomography has been suggested as a tool for monitoring the fate of islets after clinical transplantation. The integral membrane protein DGCR2 has been demonstrated to be a potential pancreatic islet biomarker, with specific expression on insulin-positive human embryonic stem-cell-derived pancreatic progenitor cells. The candidate Affibody molecule ZDGCR2:AM106 was radiolabeled with fluorine-18 using a novel click chemistry-based approach. The resulting positron emission tomography tracer [18F]ZDGCR2:AM106 was evaluated for binding to recombinant human DGCR2 and cryosections of stem-cell-derived islets, as well as in vivo using an immune-deficient mouse model transplanted with stem-cell-derived islets. Biodistribution of the [18F]ZDGCR2:AM106 was also assessed in healthy rats and pigs.

Results[18F]ZDGCR2:AM106 was successfully synthesized with high radiochemical purity and yield via a pretargeting approach. [18F]ZDGCR2:AM106 retained binding to recombinant human DCGR2 as well as to cryosectioned stem-cell-derived islets, but in vivo binding to native pancreatic tissue in both rat and pig was low. However, in vivo uptake of [18F]ZDGCR2:AM106 in stem-cell-derived islets transplanted in the immunodeficient mice was observed, albeit only within the early imaging frames after injection of the radiotracer.

ConclusionTargeting of DGCR2 is a promising approach for in vivo detection of stem-cell-derived islets grafts by molecular imaging. The synthesis of [18F]ZDGCR2:AM106 was successfully performed via a pretargeting method to label a site-specific covalently bonded fluorine-18 to the Affibody molecule. However, the rapid washout of [18F]ZDGCR2:AM106 from the stem-cell-derived islets graft indicates that dissociation kinetics can be improved. Further studies using alternative binders of similar classes with improved binding potential are warranted.

Place, publisher, year, edition, pages
Springer, 2023
Keywords
Affibody molecule, DGCR2, Diabetes, Fluorine-18 chemistry, PET, Stem cells
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-518407 (URN)10.1186/s13550-023-01057-3 (DOI)001125115500001 ()38100042 (PubMedID)
Available from: 2023-12-19 Created: 2023-12-19 Last updated: 2024-03-20Bibliographically approved
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