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 de-differentiation and nuclear reprogramming by acting at the cell surface. We screen a lentiviral library encoding ∼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.

中文翻译：

---

用选自组合抗体文库的抗体代替重编程因子。

分化细胞重编程为诱导性多能干细胞（iPSC）通常是通过作用于细胞核的因子外源诱导转录来实现的。相反，在发育过程中，在膜上启动的信号传导途径诱导分化。这项研究的中心思想是鉴定可通过作用于细胞表面来催化细胞去分化和核重编程的抗体。我们筛选了编码约1亿种分泌型和膜结合型单链抗体的慢病毒文库，并确定了在将小鼠胚胎成纤维细胞重编程为iPSC的过程中可以替代Sox2和Myc（c-Myc）或Oct4的抗体。我们显示一种替代Sox2的抗体可拮抗膜相关蛋白Basp1，从而抑制核因子WT1，Esrrb和Lin28a（Lin28）独立于Sox2。通过操纵该途径，我们确定了三种生成iPSC的方法。我们的研究结果确定了自分泌组合抗体库的无偏选择，是发现新的生物学物质并揭示调节多能性和细胞命运的膜-核信号传导途径的可靠方法。