Differentiation and encapsulation of β-Like cells in therapy for the treatment of type 1 diabetes mellitusβββ

Abstract

Background: Type 1 Diabetes Mellitus (T1DM) is a pathology caused by the inflammatory and the autoimmune destruction of insulin-secreting β cells, resulting in endocrine perturbations and hyperglycaemia. While current treatments for T1DM regulate glycaemia through glycaemic monitoring and insulin administration, they do not cure patients, who remain drug dependent. This is why a lot of studies aim at finding a durable solution for T1DM.
Aim: This master thesis focuses on one of these new therapeutic options, in which encapsulated stem-cell-derived β-cells could be implanted/grafted into patients to restore cell-driven insulin secretion and thus, normoglycaemia.
Methods: The process involves the differentiation of human-induced pluripotent stem cells (hiPSCs) along a series of stages mimicking human β cell development and maturation, to finally obtain β-like cells, capable of glucose-stimulated insulin secretion. After this protocol, the differentiated cells will be encapsulated in an immunoprotective, implantable, and biocompatible device. This device is a semi-permeable capsule, acting as a porous barrier to protect the cells against the host immune responses, responsible for graft rejection and anti-β-cell autoimmunity.
Results: The results show the possibility to obtain human-induced stem cells to express a partly differentiated phenotype, as revealed by the expression of several specific β-cell differentiation markers, analyzed by flow cytometry and RT-qPCR. However, more experiments are required to optimize the differentiation protocol and obtain insulin-producing cells. Furthermore, in the more chemical aspect of this project, capsule-related experiments suggest alternatives for reducing the cytotoxicity of encapsulation-related elements such as Tween-20 and PFPE-PEG-PFPE surfactants, as well as for finding conditions allowing long-term survival of cells in an extracellular matrix such as the use of hydrogels including Matrigel and type 1 collagen.
Conclusion: These results suggest the importance of conducting further research for the obtention of a reliable and functional differentiation protocol for the obtention of insulin-producing cells, as well as further investigations of the in vitro properties of the biocompatible capsule, ideally followed by preclinical in vivo investigations with the cell-therapy device in preparation for its future application on T1DM patients as the ultimate goal.

Date of Award	26 Aug 2022
Original language	English
Awarding Institution	University of Namur
Supervisor	Thierry Arnould (Supervisor)