Replacing reprogramming factors with antibodies selected from autocrine antibody libraries

Signaling pathways initiated at the membrane establish and maintain cell fate during development and can be harnessed in the nucleus to generate induced pluripotent stem cells (iPSCs) from differentiated cells. Yet, the impact of extracellular signaling on reprogramming to pluripotency has not been systematically addressed. Here, we screen a lentiviral library encoding ~100 million secreted and membrane-bound antibodies and identify multiple antibodies that can replace Sox2/c-Myc or Oct4 during reprogramming. We show that one Sox2-replacing antibody initiates reprogramming by antagonizing the membrane-associated protein Basp1, thereby inducing nuclear factors WT1 and Esrrb/Lin28 independent of Sox2. By successively manipulating this pathway we identify three new methods to generate iPSCs. This study expands current knowledge of reprogramming methods and mechanisms and establishes unbiased selection from autocrine antibody libraries as a powerful orthogonal platform to discover new biologics and pathways regulating pluripotency and cell fate.