The Multiscale Dynamics of Tissue Development: from Nuclear Spin to Collective Migration

Abstract

Correctly building an animal from an initial, fertilized cell requires biological activity to be coordinated across multiple length scales: embryonic cells must internally generate force and interpret extracellular cues to properly move, divide, and change their shape relative to neighboring cells. Inspired by the biological self-assembly observed in vivo, this dissertation studied cell migration and division with a mechanically interacting cohort of cells. In particular, we used a combination of live-cell imaging, quantitative image analysis, and particle-based simulations to investigate coherent angular motion (CAM) and pre-mitotic nuclear spin within two-dimensional engineered epithelial tissues.

First, we investigated the dynamics of CAM within epithelial tissue. CAM, in which cells collectively rotate about a central axis in a tissue, is seen in vivo during avian gastrulation and in mammalian cell culture, though it is not clear how this motion arises and changes over time. Here, we found that cell divisions drive the robust emergence of CAM and facilitate switches in the direction of collective rotation. Furthermore, we observed that the location of a dividing cell, rather than the orientation of the division axis, facilitated the onset of this motion. These findings highlight the dynamic nature of CAM and demonstrate how regulating cell division is important for tuning emergent collective migratory behaviors.

Next, we investigated how epithelial cells spin their nuclei prior to cell division. Despite the importance of cell division in development and oncology, it remains unexplained why cells spin their nuclei prior to mitosis in vivo and in culture. Here, we quantitatively described how the tissue microenvironment and dynamic microtubules drive 3D nuclear rotation. Furthermore, we observe that the direction of nuclear spin correlated with the axis along which the cell eventually divided. Taken together, this work provides the first quantitative description of 3D nuclear spin within tissues and describes a potential link between the readily observable intracellular motion and the way in which a cell will divide.

Thus, this dissertation provides quantitative insight into multiple length scales of biological motion. While further work is needed, these results have potential applications related to basic developmental biology, oncology, tissue engineering, and regeneration.