Targeting the α-cells in diabetes

Diplôme Thèse Targeting the α-cells in diabetes eng 2026-06-04 2026-06-08 author Renaud Cédric 404443 Département de médecine génétique et développement (GEDEV) director Herrera Pedro Luis 0000-0003-0771-9504 23981 Département de médecine génétique et développement (GEDEV) director Bru Tari Eva Maria 0000-0002-0452-3867 928052 Département de médecine génétique et développement (GEDEV) 140 10.13097/archive-ouverte/unige:193906 urn:nbn:ch:unige-1939064 Sc. Méd. 67 Diabetes is characterized by an absolute or relative deficiency of insulin‐producing β‐cells. Strategies capable of restoring endogenous β‐cell mass therefore represent a major therapeutic objective. Human pancreatic α‐cells exhibit intrinsic plasticity and constitute a promising source for β‐cell replacement approaches. However, current reprogramming strategies primarily rely on viral overexpression of the β‐cell transcription factors pancreatic and duodenal homeobox 1 (Pdx1) and MAF bZIP transcription factor A (Mafa) (ectopically Pdx1‐ and Mafa‐expressing α‐cell (αPM) pseudoislets) and generate hybrid cells that retain substantial α‐cell identity. This thesis aimed to better understand and potentially promote α‐to‐β‐like reprogramming efficiency using complementary model, pharmacological, and genetic approaches. The evaluation of the αTC1.6 mouse cell line to study α‐cell conversion revealed limited plasticity compared with human α‐cells, emphasizing the importance of human models for translational studies. Pharmacological modulation of αPM pseudoislets demonstrated that efficient reprogramming requires a permissive signaling in addition to transcription factor expression. Coordinated activity of histone deacetylase (HDAC), forkhead box O (FOXO1), protein kinase C (PKC), and WNT pathways was required for sustained insulin (INS) expression. In addition, jagged 1 (JAG1), a NOTCH pathway activator, tended to enhance INS expression. These findings indicate that lineage conversion depends on integrated transcriptional and signaling regulation. The effects of ARX loss, a key regulator of α‐cell identity, were investigated using clustered regularly interspaced short palindromic repeats‐associated protein 9 (CRISPR‐Cas9)‐mediated genome editing and two complementary approaches. In purified primary α‐cells isolated by fluorescence‐activated cell sorting (FACS) transcriptional changes were assessed by bulk RNA sequencing. In parallel, ARX deletion in whole islets was examined by single‐nucleus multiome profiling to characterize transcriptional heterogeneity and associated alterations in chromatin accessibility. Deletion of ARX induced a transcriptomic shift characterized by downregulation of α‐cell identity genes and upregulation of β‐ and δ‐cell associated genes, indicating partial activation of alternative endocrine programs. Sn‐multiome analysis further revealed altered chromatin accessibility at regulatory regions associated with β‐ and δ‐cell lineages, supporting a model in which α‐cell identity is actively maintained by lineage‐restricting transcriptional and epigenetic programs. These results identify ARX as a key gatekeeper of human primary α‐cell fate and demonstrate that its disruption promotes broader endocrine plasticity. Overall, this work demonstrates that adult human α‐cells retain significant reprogramming potential and can be redirected toward β‐cell trait acquisition through coordinated modulation of transcriptional, epigenetic, and signaling networks. α‐cell Pancreas Reprogramming Dewey 576.5 135 Département de médecine génétique et développement 21D false 272 Types cellulaires pancréatiques pendant l'ontogénèse 522 1c163f94-c9c3-4930-9fbd-c721b43e772e Thesis Public CR_MDPhD_thesis_FINAL_imprematur.pdf 24345147 application/pdf MD-PhD 6acb6524e9dbcd823772ebcf4dd3d6eddbfea71ea7c6a609189bacf28131780f 5634f767-7be2-4577-8ef4-43b7f5d0642d Imprimatur Public Imprimatur.pdf 114801 application/pdf e726f3f4e39126cfcc43f3e427aef660ba3768427e2633e373e9e8ca77ad979f Vignette Public ARX_model.png 50472 image/png openAccess Faculté de médecine / Section de médecine fondamentale / Département de médecine génétique et développement

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Renaud, Cédric

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