Schwayer, C.; Barbiero, S.; Brückner, D. B.; Baader, C.; Repina, N. A.; Diaz, O. E.; Meylan, L. C.; Kalck, V.; Suppinger, S.; Yang, Q.; Schnabl, J.; Kilik, U.; Camp, J. G.; Stockinger, B.; Bühler, M.; Stadler, M. B.; Hannezo, E.; Liberali, P.

Tissue regeneration relies on the ability of cells to undergo de novo patterning. While tissue patterning has been viewed as the transition from initially identical un-patterned cells to an arrangement of different cell types, recent evidence suggests that initial heterogeneities between cells modulate tissue-scale pattern formation. Yet, how such heterogeneities arise and, thereafter, regulate cell type emergence in a population of cells is poorly understood. Using in vivo and in vitro mouse regenerative systems, we identify a critical tissue density that is required to induce heterogeneous inactivation of the mechanosensor YAP1. Experimental and biophysical approaches demonstrate that YAP1 cell-to-cell heterogeneity pre-patterns the first cell fate decision, via both chromatin remodelling and a supracellular feedback between FOXA1 and Delta-Notch signalling. This feedback motif induces cell fate bistability endowing memory to the system and the maintenance of patterns during homeostasis. These findings reveal a generalisable framework in which transient cell-to-cell heterogeneity, regulated by tissue-scale properties, serves as a critical control parameter for the emergence of cell fate and stable patterning during regeneration.