2024
Mech Ageing Dev. 2024 May 31:220:111951. doi: 10.1016/j.mad.2024.111951.
The age-dependent regulation of pancreatic islet landscape is fueled by a HNF1a-immune signaling loop
Mohn Research Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway. Hybrid Technology Hub-Centre of Excellence, Faculty of Medicine, University of Oslo, Norway. Institute for Surgical Research, Department of Transplant Medicine, Oslo University Hospital, Oslo, Norway. Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
Service type: Knockout mice
Abstract
Animal longevity is a function of global vital organ functionality and, consequently, a complex polygenic trait. Yet, monogenic regulators controlling overall or organ-specific ageing exist, owing their conservation to their function in growth and development. Here, by using pathway analysis combined with wet-biology methods on several dynamic timelines, we identified Hnf1a as a novel master regulator of the maturation and ageing in the adult pancreatic islet during the first year of life. Conditional transgenic mice bearing suboptimal levels of this transcription factor in the pancreatic islets displayed age-dependent changes, with a profile echoing precocious maturation. Additionally, the comparative pathway analysis revealed a link between Hnf1a age-dependent regulation and immune signaling, which was confirmed in the ageing timeline of an overly immunodeficient mouse model. Last, the global proteome analysis of human islets spanning three decades of life largely backed the age-specific regulation observed in mice. Collectively, our results suggest a novel role of Hnf1a as a monogenic regulator of the maturation and ageing process in the pancreatic islet via a direct or indirect regulatory loop with immune signaling.
Keywords: HNF1A; Immune response; Islet ageing; Pancreatic islets; Pathway analysis.
