Precisely sensing and guiding cell-state transitions via the conditional genetic activation of appropriate differentiation factors is challenging. Here we show that desired cell-state transitions can be guided via genetically encoded sensors, whereby endogenous cell-state-specific miRNAs regulate the translation of a constitutively transcribed endoribonuclease, which, in turn, controls the translation of a gene of interest. We used this approach to monitor several cell-state transitions, to enrich specific cell types and to automatically guide the multistep differentiation of human induced pluripotent stem cells towards a haematopoietic lineage via endothelial cells as an intermediate state. Such conditional activation of gene expression is durable and resistant to epigenetic silencing and could facilitate the monitoring of cell-state transitions in physiological and pathological conditions and eventually the ‘rewiring’ of cell-state transitions for applications in organoid-based disease modelling, cellular therapies and regenerative medicine.

通过适当分化因子的条件遗传激活来精确感知和引导细胞状态转变具有挑战性。在这里，我们表明，所需的细胞状态转换可以通过基因编码的传感器来引导，从而内源性细胞状态特异性 miRNA 调节组成型转录的内切核糖核酸酶的翻译，而内切核糖核酸酶反过来又控制感兴趣基因的翻译。我们使用这种方法来监测几种细胞状态转变，以丰富特定的细胞类型，并自动引导人类诱导多能干细胞通过内皮细胞作为中间状态向造血谱系多步分化。这种基因表达的条件激活是持久的，并且能够抵抗表观遗传沉默，并且可以促进生理和病理条件下细胞状态转变的监测，并最终“重新布线”细胞状态转变，以应用于基于类器官的疾病建模、细胞疗法和再生医学。