Morphogenesis and cell state transitions must be coordinated in time and space to produce a functional tissue. An excellent paradigm to understand the coupling of these processes is mammalian hair follicle development, which is initiated by the formation of an epithelial invagination—termed placode—that coincides with the emergence of a designated hair follicle stem cell population. The mechanisms directing the deformation of the epithelium, cell state transitions and physical compartmentalization of the placode are unknown. Here we identify a key role for coordinated mechanical forces stemming from contractile, proliferative and proteolytic activities across the epithelial and mesenchymal compartments in generating the placode structure. A ring of fibroblast cells gradually wraps around the placode cells to generate centripetal contractile forces, which, in collaboration with polarized epithelial myosin activity, promote elongation and local tissue thickening. These mechanical stresses further enhance compartmentalization of Sox9 expression to promote stem cell positioning. Subsequently, proteolytic remodelling locally softens the basement membrane to facilitate a release of pressure on the placode, enabling localized cell divisions, tissue fluidification and epithelial invagination into the underlying mesenchyme. Together, our experiments and modelling identify dynamic cell shape transformations and tissue-scale mechanical cooperation as key factors for orchestrating organ formation.

形态发生和细胞状态转变必须在时间和空间上协调才能产生功能组织。理解这些过程耦合的一个很好的范例是哺乳动物毛囊发育，它是由上皮内陷（称为基板）的形成启动的，这与指定毛囊干细胞群的出现同时发生。引导上皮变形、细胞状态转变和基板物理分区的机制尚不清楚。在这里，我们确定了上皮和间充质区室的收缩、增殖和蛋白水解活动产生的协调机械力在生成基板结构中的关键作用。一圈成纤维细胞逐渐包裹在基板细胞周围，产生向心收缩力，与极化上皮肌球蛋白活性配合，促进伸长和局部组织增厚。这些机械应力进一步增强了 Sox9 表达的区室化，以促进干细胞定位。随后，蛋白水解重塑局部软化基底膜，以促进基板上压力的释放，从而实现局部细胞分裂、组织流化和上皮内陷到下面的间质中。我们的实验和建模共同确定了动态细胞形状转变和组织规模的机械合作是协调器官形成的关键因素。