Abstract
For an airway or a blood vessel to narrow, there must be a connected path that links the smooth muscle (SM) cells with each other, and transmits forces around the organ, causing it to constrict. Currently, we know very little about the mechanisms that regulate force transmission pathways in a multicellular SM ensemble. Here, we used extracellular matrix (ECM) micropatterning to study force transmission in a two-cell ensemble of SM cells. Using the two-SM cell ensemble, we demonstrate (a) that ECM stiffness acts as a switch that regulates whether SM force is transmitted through the ECM or through cell-cell connections. (b) Fluorescent imaging for adherens junctions and focal adhesions show the progressive loss of cell-cell borders and the appearance of focal adhesions with the increase in ECM stiffness (confirming our mechanical measurements). (c) At the same ECM stiffness, we show that the presence of a cell-cell border substantially decreases the overall contractility of the SM cell ensemble. Our results demonstrate that connectivity among SM cells is a critical factor to consider in the development of diseases such as asthma and hypertension.
Highlights
Asthma, Crohn’s disease, and hypertension are widespread chronic diseases that affect the airways, the gut, and blood vessels respectively
On soft substrates matching the extracellular matrix (ECM) stiffness of healthy human airways, we find that airway smooth muscle (ASM) cells exert more of their longitudinal tension on their neighboring ASM cells compared to the ECM
The length of the rectangular pattern of gelatin was specified to match the length of ASM cells plated on non-patterned NuSil gels (150 μm) and the breadth (15 μm) was set by trial and error to allow for enough space within the rectangle to fit exactly two ASM cells
Summary
Crohn’s disease, and hypertension are widespread chronic diseases that affect the airways, the gut, and blood vessels respectively. The factors that dictate the choice of force transmission pathways used by SM cells in healthy and diseased tissue are still unclear Both focal adhesions and adherens junctions are mechanosensitive structures through which cells can respond to, and probe the stiffness and ligands present in their surrounding environment. Complex/actin filament binding in adherens junctions has been shown to exhibit catch bond characteristics up to 10pN after which it transitions into a slip bond[17] Based on these data, we hypothesize that mechanical cues such as ECM stiffness can alter the nature of force transmission pathways (cell-cell vs cell-ECM) in a multicellular ensemble of human SM cells. Our results highlight the need to develop new therapies for asthma and hypertension that target extracellular matrix remodeling
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