Developmental beta cell death orchestrates the islet’s inflammatory milieu by regulating the immune system repertoire

Mohammad Nadeem Akhtar

AutorIn

Mohammad Nadeem Akhtar

Titel

Developmental beta cell death orchestrates the islet’s inflammatory milieu by regulating the immune system repertoire

Zitierfähige Url:

https://nbn-resolving.org/urn:nbn:de:bsz:14-qucosa2-906970

Datum der Einreichung

20.07.2023

Datum der Verteidigung

23.01.2024

Abstract (EN)

Beta cell turnover is orchestrated by a balanced rate of proliferation and cell death. While beta cell proliferation has been extensively studied, less is known about beta cell death. In this thesis, we used an array of tools including genetic engineering, mathematical modelling and single cell transcriptomics to study beta cell death, its role in regulating the islet’s immune system repertoire and subsequently the islet’s inflammatory milieu. Using genetic model of caspase inhibition in beta cells, we found that blocking beta cell death during development leads to an expansion of beta cell mass specifically during the juvenile stages. Incorporating mathematical modelling to our experimental data, we discovered a previously unrecognized role of beta cell apoptosis in regulating normal islet turnover process. However, the estimated rate of beta cell apoptosis was difficult to corroborate histologically. Only upon genetic inhibition of macrophage we were able to observe the accumulation of apoptotic beta cell corpses in the islet. Next, we created a chemo genetic model of beta cell excitotoxicity which allowed us to induce beta cell death in a controllable manner. In order to study beta cell death at the molecular level, we performed single cell transcriptomics of beta cells undergoing Ca2+ excitotoxicity. The analysis revealed remarkable heterogeneity in beta cell responses to stress. While a subset of resilient beta cells survived through de-differentiation, vulnerable beta-cells progressed towards death. Dying cells were shown to activate pathways implicated in immune recognition and inflammation, suggesting that beta cell death is pro-inflammatory. Consistently, inhibition of cell death during development reduced pro-inflammatory islet macrophages and NF-kB signaling, while expanding regulatory T cells (Tregs), the deficiency of which caused islet inflammation. Overall, our study shows that beta cell death during pancreas development represents a crucial event for the communication with the immune system and thereby, it is an important player to consider in the early onset of type 1 diabetes in humans.

Freie Schlagwörter (EN)

beta cell death, mathematical model, excitotoxicity, dedifferentiation, type 1 diabetes

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