ECM-modulated cellular dynamics as a driving force for tissue morphogenesis

Abstract

The extracellular matrix (ECM) plays diverse regulatory roles throughout development. Coordinate interactions between cells within a tissue and the ECM result in the dynamic remodeling of ECM structure. Both chemical signals and physical forces that result from such microenvironmental remodeling regulate cell behavior that sculpts tissue structure. Here, we review recent discoveries illustrating different ways in which ECM remodeling promotes dynamic cell behavior during tissue morphogenesis. We focus first on new insights that identify localized ECM signaling as a regulator of cell migration, shape, and adhesion during branching morphogenesis. We also review mechanisms by which the ECM and basement membrane can both sculpt and stabilize epithelial tissue structure, using as examples Drosophila egg chamber development and cleft formation in epithelial organs. Finally, we end with an overview of the dynamic mechanisms by which the ECM can regulate stem cell differentiation to contribute to proper tissue morphogenesis.

Figure 1. Focal ECM deposition regulates dynamic cell behavior during branching morphogenesis

Fibronectin (FN) is focally assembled to promote cleft progression during epithelial morphogenesis. FN induces Btbd7 at the base of an initiated cleft, which in turn up-regulates Snail2 and down-regulates E-cadherin. This increases local cell dynamics at the cleft base (black wavy arrows) and opens up transient intercellular gaps (between dark gray cells) to advance the cleft (yellow arrow). The FN assembly requires intracellular Rho kinase (ROCK)-mediated actomyosin contraction and focal adhesion kinase (FAK) activation to unfold dimeric globular FN for fibril assembly (left panel).

Figure 2. Directional cell migration orients ECM to drive tissue shape change during egg chamber morphogenesis

The Drosophila egg chamber is an initially rounded structure that elongates along the anterior/posterior axis to produce an oval-shaped egg. This requires the complete 360° rotation of the entire egg chamber (red arrows), which polarizes the alignment of basement membrane fibrils (green dashed lines) to act as a molecular corset restricting the direction of tissue expansion. At the cellular level, the mechanism of this ECM alignment involves the directional rotational migration (gray arrows) of individual follicular epithelial cells.

Figure 3. Differential regional accumulation of ECM proteins stabilizes tissue structure during branching morphogenesis

ECM is deposited heterogeneously in the basement membrane and stroma surrounding epithelial branched organs. This produces regional force anisotropies that either stabilize or guide the direction of epithelial tissue expansion. For example, thick accumulations of basement membrane (heavy green lines) are present around bud flanks and ducts, and in cleft regions. In contrast, ECM is thinner at end bud tips where epithelia expand (thin green lines).

Figure 4. ECM regulates stem cell retention within the niche and determines lineage commitment

Binding to ECM and basement membrane components is required for both stem and niche cell localization within the niche (1). Niche-associated ECM and soluble factors secreted by cells present within the niche help regulate the decision between stem cell self-renewal and differentiation (2). ECM mechanical properties also determine mesenchymal stem cell lineage commitment along osteogenic, myogenic, and neurogenic differentiation pathways (3).