Autologous Morphogen Gradients by Subtle Interstitial Flow and Matrix Interactions

Cell response to extracellular cues is often driven by gradients of morphogenetic and chemotactic proteins, and therefore descriptions of how such gradients arise are critical to understanding and manipulating these processes. Many of these proteins are secreted in matrix-binding form to be subsequently released proteolytically, and here we explore how this feature, along with small dynamic forces that are present in all tissues, can affect pericellular protein gradients. We demonstrate that 1), pericellular gradients of cell-secreted proteins can be greatly amplified when secreted by the cell in matrix-binding form as compared to a nonmatrix-interacting form; and 2), subtle flows can drive significant asymmetry in pericellular protein concentrations and create transcellular gradients that increase in the direction of flow. This study thus demonstrates how convection and matrix-binding, both physiological characteristics, combine to allow cells to create their own autologous chemotactic gradients that may drive, for example, tumor cells and immune cells into draining lymphatic capillaries.