A prioritized medium-throughput screen identifies fibroblast growth factors as protective for human stem cell derived insulin secreting beta cells

Abstract

Stem cell-derived {beta}-like cells (SC{beta} cells) are an alternative to cadaveric {beta} cells for replacement therapy in type 1 diabetes. However, SC{beta} cells face a multitude of stresses. Both {beta} cells and SC{beta} cells reside in complex microtissues and are modulated by hundreds of autocrine/paracrine signals. 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, 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.