Deletion of RFX6 impairs iPSC‑derived islet organoid development and survival, with no impact on PDX1+/NKX6.1+progenitors – published online 30/07/2024

Noura Aldous, Ahmed K. Elsayed, Bushra Memon, Sadaf Ijaz, Sikander Hayat, Essam M. Abdelalim

Mutations in the RFX6 gene (which encodes regulatory factor X6; RFX6) lead to monogenic diabetes with a hypoplastic pancreas. In this issue, Aldous et al (https://doi.org/10.1007/s00125-024-06232-2) investigate the mechanisms behind the impairment of pancreatic islet development caused by RFX6 loss-of-function mutations. The authors utilise human embryonic stem cells and a gene-edited induced pluripotent stem cell model to investigate the role of RFX6 during differentiation into human pancreatic islets. The authors show that while RFX6 is present in the early stages of pancreatic development, its absence does not prevent the formation of pancreatic progenitors. Instead, its absence has two significant effects: downregulation of genes crucial for endocrine specification and the formation of smaller islet organoids due to an increased rate of cellular apoptosis (linked to reduced expression of the antioxidant enzyme catalase). These findings suggest that RFX6 mutations primarily disrupt islet cell formation through increased cell death and suppression of essential pancreatic endocrine genes. The authors conclude that these insights may pave the way for potential therapeutic strategies, such as enhancing catalase levels, to mitigate diabetes related to RFX6 defects.