A prioritized medium-throughput screen on human stem cell derived insulin secreting beta cells identifies FGF4, FGF5, FGF8F, FGF19 and FGF21 as protective factors
AbstractStem cell-derived {beta}-like cells (SC{beta} cells) are a potential alternative to cadaveric {beta} cells for replacement therapy in type 1 diabetes. However, SC{beta} cells face a multitude of stresses that must be overcome. Both {beta} cells and SC{beta} cells reside in complex microtissues and can therefore be modulated by hundreds of autocrine/paracrine signals within these islets or spheroids. Here, we leveraged multi-omics data from late-stage SC{beta} cells and human islets to map ligand-receptor pairs and generate a prioritized list of ligands for high-content SC{beta} cell survival screening. Our medium-throughput screen tracked cell number, cell death, and INS production over several days using automated, high-content imaging. Members of the fibroblast growth factor (FGF) family significantly prevented cytokine-induced cell death, with the top validated hits being FGF4, FGF5, FGF19, FGF21, and FGF8F. With these results, there is the potential to improve SC{beta} cell survival in vitro via readily targetable pathways and to produce a more robust product for translation to the clinic.