Abstract
Cleft formation during submandibular salivary gland branching morphogenesis is the critical step initiating the growth and development of the complex adult organ. Previous experimental studies indicated requirements for several epithelial cellular processes, such as proliferation, migration, cell-cell adhesion, cell-extracellular matrix (matrix) adhesion, and cellular contraction in cleft formation; however, the relative contribution of each of these processes is not fully understood since it is not possible to experimentally manipulate each factor independently. We present here a comprehensive analysis of several cellular parameters regulating cleft progression during branching morphogenesis in the epithelial tissue of an early embryonic salivary gland at a local scale using an on lattice Monte-Carlo simulation model, the Glazier-Graner-Hogeweg model. We utilized measurements from time-lapse images of mouse submandibular gland organ explants to construct a temporally and spatially relevant cell-based 2D model. Our model simulates the effect of cellular proliferation, actomyosin contractility, cell-cell and cell-matrix adhesions on cleft progression, and it was used to test specific hypotheses regarding the function of these parameters in branching morphogenesis. We use innovative features capturing several aspects of cleft morphology and quantitatively analyze clefts formed during functional modification of the cellular parameters. Our simulations predict that a low epithelial mitosis rate and moderate level of actomyosin contractility in the cleft cells promote cleft progression. Raising or lowering levels of contractility and mitosis rate resulted in non-progressive clefts. We also show that lowered cell-cell adhesion in the cleft region and increased cleft cell-matrix adhesions are required for cleft progression. Using a classifier-based analysis, the relative importance of these four contributing cellular factors for effective cleft progression was determined as follows: cleft cell contractility, cleft region cell-cell adhesion strength, epithelial cell mitosis rate, and cell-matrix adhesion strength.
Highlights
Branching morphogenesis is a specific type of tissue morphogenesis that is a crucial developmental process occurring in several organs, such as the mammary glands, lungs, kidney, and salivary glands to maximize epithelial surface area for secretion or absorption of fluids and gases [1]
Branching morphogenesis is a complex and dynamic embryonic process that creates the structure of many adult organs, including the salivary gland
Many cellular changes occur in the epithelial cells, including changes in cell-cell adhesions, cell-extracellular matrix adhesions, cell proliferation, and cellular contraction, resulting in formation of clefts in the epithelial cells of the organ
Summary
Branching morphogenesis is a specific type of tissue morphogenesis that is a crucial developmental process occurring in several organs, such as the mammary glands, lungs, kidney, and salivary glands to maximize epithelial surface area for secretion or absorption of fluids and gases [1]. The process of branching morphogenesis is complex and dynamic, requiring reciprocal interactions between the epithelium and the mesenchymal cell types [2,3]. Since many organs develop by branching morphogenesis, one strategy for a regenerative medicine-based restoration of diseased or damaged branched organs would be to reactivate the cellular and molecular mechanisms that produce these organs during development. The gland starts to develop at embryonic day 11 (E11) when the epithelium protrudes into the neural crest-derived mesenchyme. Cleft progression is associated with proliferation of the epithelial cells causing tissue outgrowth [2]. Since the salivary glandular structure is presumably important to facilitate its function, the question of how this ramified epithelial structure is established has been the subject of many biological studies and some recent computational modeling studies
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
