Journal
NATURE BIOTECHNOLOGY
Volume 35, Issue 10, Pages 960-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nbt.3963
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Funding
- National Institute on Deafness and other Communication Disorders [DC012592]
- National Institute of Mental Health [MH102698]
- California Institute for Regenerative Medicine [RB3-02186]
- Baxter Family, Norris
- Las Patronas
- Dorris Neuroscience Center
- California Institute of Regenerative Medicine
- Andrea Elizabeth Vogt Memorial Award
- Del Webb Foundations
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The reprogramming of differentiated cells into induced pluripotent stem cells (iPSCs) is usually achieved by exogenous induction of transcription by factors acting in the nucleus. In contrast, during development, signaling pathways initiated at the membrane induce differentiation. The central idea of this study is to identify antibodies that can catalyze cellular dedifferentiation and nuclear reprogramming by acting at the cell surface. We screen a lentiviral library encoding similar to 100 million secreted and membrane-bound single-chain antibodies and identify antibodies that can replace either Sox2 and Myc (c-Myc) or Oct4 during reprogramming of mouse embryonic fibroblasts into iPSCs. We show that one Sox2-replacing antibody antagonizes the membrane-associated protein Basp1, thereby de-repressing nuclear factors WT1, Esrrb and Lin28a (Lin28) independent of Sox2. By manipulating this pathway, we identify three methods to generate iPSCs. Our results establish unbiased selection from autocrine combinatorial antibody libraries as a robust method to discover new biologics and uncover membrane-to-nucleus signaling pathways that regulate pluripotency and cell fate.
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