Sensing and guiding cell-state transitions by using genetically encoded endoribonuclease-mediated microRNA sensors.

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.
Competing Interests: Competing interests: The Massachusetts Institute of Technology has filed a patent application on behalf of the inventors (R.W., D. Mishra, E. Pery, W.X. and L.W.) of the endoRNase-based miRNA sensor design described (US provisional application no. 63/164,282). The other authors declare no competing interests.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)