Histopathology of human islet cell implants: Contribution to insights in their function

Onderzoeksoutput: PhD Thesis

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Samenvatting

Type 1 diabetes patients suffering from severe hypoglycemia and/or glycemic variability may qualify for intraportal islet allotransplantation. This treatment showed to be capable of correcting the metabolic state and improving quality of life for type 1 diabetes patients. However, decline of islet function occurs over time due to multiple possible causes. The intraportal location of the islets makes retrieval for analysis difficult and observations on a biopsy might not always be representative. In the present studies histopathological assessment of the transplanted islet is the main objective.

The first part of this thesis started with evaluation of intraportally transplanted islets in biopsy and autopsy samples of six type 1 diabetes patients. Amyloid deposits, derived from Islet Amyloid Polypeptide, were observed in 5-12% of the occurring beta cell containing aggregates in the liver, while almost absent (1%) in the grafts pre-transplantation. Subsequently, in a case report with intraperitoneal transplanted alginate-encapsulated islets only free floating capsules with living beta cells contained amyloid deposits. These clinical observations were extended to experimental models, both in vitro and in vivo, to examine the variables that can influence amyloid formation. In non-encapsulated implants under the kidney capsule of mice amyloid occurrence was positively associated with metabolic function. Transplantation of micro-encapsulated human implants in the peritoneal cavity of mice corrected a diabetic state, while exhibiting increased amounts of amyloid deposits. Macro-encapsulated human stem cell-derived implants in the subcutis of mice exhibited a functional beta cell mass, with substantial amyloid deposits associated to the beta cell-enriched regions within these devices. This study marks the possibility to use human stem-cell generated beta cell implants as a new study model for formation of amyloid. Amyloid deposits showed to be a marker for the occurrence of living beta cells.

To examine a functional extrahepatic transplantation site with easier accessibility, the second part of this thesis describes histopathological analysis after omental transplantation of human islets in a case series. Occurrence of endocrine cell clusters in omental biopsies was observed and these reflected the composition of the initial grafts. After omental transplantation a limited functional beta cell mass was obtained with hyperglycemic clamp 2-8% of controls. Islet transplantation within polyglactin-thrombin-fibrinogen scaffold resulted in larger endocrine cell clusters. No allo-immunity nor recurrence of auto-immunity were identified post-omental transplantation. A preceding omental implant did not impair outcome of a subsequent intraportal transplantation in this series of seven patients.

By exploring the transplanted islet and its histopathology, both in the omental site and in relation to amyloid deposits, the insights gained from the above mentioned studies can contribute to further advancement in the field of transplantation of human and stem cell-derived islets.
Originele taal-2English
KwalificatieDoctor in Medical Sciences
Toekennende instantie
  • Vrije Universiteit Brussel
Begeleider(s)/adviseur
  • Keymeulen, Bart, Promotor
  • Pipeleers, Daniel, Promotor
Datum van toekenning17 feb 2023
StatusPublished - 2023

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