Dynamics of tissue morphogenesis

Abstract

Form fits function. Tissues and organs obtain their shapes in a complex process involving the integration of internal and external signaling and mechanical and biochemical cues. The mammary gland and other branched organs develop their characteristic tree-like geometries through the process of branching morphogenesis, a process in which the epithelium bifurcates and invades into the surrounding stroma. Controlling the pattern of branching is critical for function of these organs. In vivo, branching of the mammary gland is regulated through epithelial-stromal interactions. Adipocytes are the largest component of the surrounding stroma and yet their role is largely unknown. We used a microlithography-based approach to engineer a three-dimensional culture model that enables the determination of the effect of adipocytes on the branching morphogenesis of mammary epithelial cells. We found that adipocyte-rich stroma induces branching through paracrine signals, including hepatocyte growth factor, but does not affect the sites at which branches initiate. This tissue engineering approach can be expanded to other organs, and should enable piecemeal analysis of the cellular populations that control patterning during normal development.

Epithelial cells within three-dimensional tubules have been observed to move in a rotational pattern. To investigate the mechanisms that regulate this movement we simplified the system and examined the emergence of vortical tissue movements in bounded two-dimensional sheets. The observed rotational motion of the epithelial monolayers is dynamic and the direction of rotation switches frequently. The switches in rotational motion correlate with disturbances in the monolayer resulting from cytokinesis. We showed through simulations and experiments that cells within these small tissues behave as Vicsek-Czirók self-propelled particles, and that maintenance of the rotational motion requires neither E-cadherin-mediated cell-cell junctions nor cytoskeletal contractility. As predicted by the simulations, we found a critical role for cell density; increasing density increases correlation and reduces the effect of cytokinesis in disturbing the rotational motion. We also found that as tissue sizes became larger, cell-cell junctions play a greater role in organizing collective motion and producing global rotation. In addition, we mapped the cellular divisions in these tissues and found that the cellular division axes are oriented perpendicular to the radial direction of the tissue and this alignment is regulated by both the cellular motion and the endogenous traction stress profile. Our results suggest that the initial architecture of the tissue in which the cells reside instructs their movements with respect to each other within a collective and orient cellular division axes to guide tissue growth and establish final form.