In the liver, ductal cells rarely proliferate during homeostasis but do so transiently after tissue injury. These cells can be expanded as organoids that recapitulate several of the cell-autonomous mechanisms of regeneration but lack the stromal interactions of the native tissue. Here, using organoid co-cultures that recapitulate the ductal-to-mesenchymal cell architecture of the portal tract, we demonstrate that a subpopulation of mouse periportal mesenchymal cells exerts dual control on proliferation of the epithelium. Ductal cell proliferation is either induced and sustained or, conversely, completely abolished, depending on the number of direct mesenchymal cell contacts, through a mechanism mediated, at least in part, by Notch signaling. Our findings expand the concept of the cellular niche in epithelial tissues, whereby not only soluble factors but also cell-cell contacts are the key regulatory cues involved in the control of cellular behaviors, suggesting a critical role for cell-cell contacts during regeneration.

在肝脏中，导管细胞在稳态期间很少增殖，但在组织损伤后会短暂增殖。这些细胞可以扩展为类器官，这些类器官概括了几种细胞自主再生机制，但缺乏天然组织的基质相互作用。在这里，我们使用类器官共培养物来概括门道的导管到间充质细胞结构，证明小鼠门静脉周围间充质细胞亚群对上皮细胞的增殖具有双重控制。根据直接间充质细胞接触的数量，通过至少部分由 Notch 信号传导介导的机制，可以诱导和维持导管细胞增殖，或者相反，完全消除导管细胞增殖。我们的发现扩展了上皮组织中细胞生态位的概念，