BEST4/CA7 ⁺ and goblet cells are interdependent regulators of intestinal mucus homeostasis

The intestinal mucus layer is essential for the integrity of the intestinal barrier. It is produced by goblet cells, whose depletion is common in colonic inflammation but remains poorly understood. Here, we show that goblet cell survival relies on a reciprocal dependence with newly discovered BEST4/CA7 ⁺ cells. We developed a method to follow BEST4/CA7 ⁺ and goblet cells in time from birth to death in human colon organoids. Notably, goblet cells induce BEST4/CA7 ⁺ fates in sister cells and other neighbors, using DLL1-mediated lateral activation of Notch-signaling. BEST4/CA7 ⁺ cells in turn promote goblet survival, with the latter depleting rapidly after differentiation in absence of BEST4/CA7 ⁺ cells. This apoptosis inhibition does not require direct cell-cell contact and instead depends on their shared lumen. Such differentiation and survival interdependencies may be relevant beyond the maintenance of mucosal homeostasis.