Silencing the G-protein coupled receptor 3-salt inducible kinase 2 pathway promotes human β cell proliferation.
Caterina IorioJillian L RourkeLisa WellsJun-Ichi SakamakiEmily MoonQueenie HuTatsuya KinRobert A ScreatonPublished in: Communications biology (2021)
Loss of pancreatic β cells is the hallmark of type 1 diabetes, for which provision of insulin is the standard of care. While regenerative and stem cell therapies hold the promise of generating single-source or host-matched tissue to obviate immune-mediated complications, these will still require surgical intervention and immunosuppression. Here we report the development of a high-throughput RNAi screening approach to identify upstream pathways that regulate adult human β cell quiescence and demonstrate in a screen of the GPCRome that silencing G-protein coupled receptor 3 (GPR3) leads to human pancreatic β cell proliferation. Loss of GPR3 leads to activation of Salt Inducible Kinase 2 (SIK2), which is necessary and sufficient to drive cell cycle entry, increase β cell mass, and enhance insulin secretion in mice. Taken together, our data show that targeting the GPR3-SIK2 pathway is a potential strategy to stimulate the regeneration of β cells.
Keyphrases
- cell cycle
- cell proliferation
- stem cells
- endothelial cells
- high throughput
- induced apoptosis
- single cell
- cell therapy
- pluripotent stem cells
- induced pluripotent stem cells
- cell cycle arrest
- randomized controlled trial
- mesenchymal stem cells
- metabolic syndrome
- bone marrow
- healthcare
- fatty acid
- cancer therapy
- signaling pathway
- tyrosine kinase
- cell death
- electronic health record
- risk factors
- insulin resistance
- pain management
- data analysis
- machine learning