Tissue repair is a complex process that requires effective communication and coordination between cells across multiple tissues and organ systems. Two of the initial intracellular signals that encode injury signals and initiate tissue repair responses are calcium and extracellular signal-regulated kinase (ERK). However, calcium and ERK signaling control a variety of cellular behaviors important for injury repair including cellular motility, contractility, and proliferation, as well as the activity of several different transcription factors, making it challenging to relate specific injury signals to their respective repair programs. This knowledge gap ultimately hinders the development of new wound healing therapies that could take advantage of native cellular signaling programs to more effectively repair tissue damage. The objective of this review is to highlight the roles of calcium and ERK signaling dynamics as mechanisms that link specific injury signals to specific cellular repair programs during epithelial and stromal injury repair. We detail how the signaling networks controlling calcium and ERK can now also be dissected using classical signal processing techniques with the advent of new biosensors and optogenetic signal controllers. Finally, we advocate the importance of recognizing calcium and ERK dynamics as key links between injury detection and injury repair programs that both organize and execute a coordinated tissue repair response between cells across different tissues and organs.

Interactions between the actin cytoskeleton and the plasma membrane are important in many eukaryotic cellular processes. During these processes, actin structures deform the cell membrane outward by applying forces parallel to the fiber's major axis (as in migration) or they deform the membrane inward by applying forces perpendicular to the fiber's major axis (as in the contractile ring during cytokinesis). Here we describe a novel actin-membrane interaction in human dermal myofibroblasts. When labeled with a cytosolic fluorophore, the myofibroblasts developed prominent fluorescent structures on the ventral side of the cell. These structures are present in the cell membrane and colocalize with ventral actin stress fibers, suggesting that the stress fibers bend the membrane to form a “cytosolic pocket” that the fluorophores diffuse into, creating the observed structures. The existence of this pocket was confirmed by transmission electron microscopy. While dissolving the stress fibers, inhibiting fiber protein binding, or inhibiting myosin II binding of actin removed the observed pockets, decreasing cellular contractility did not remove them. Taken together, our results illustrate a novel actin-membrane bending topology where the membrane is deformed outwards rather than being pinched inwards, resembling the topological inverse of the contractile ring found in cytokinesis. [Media: see text] [Media: see text]

Interactions between the actin cytoskeleton and the plasma membrane are essential for many eukaryotic cellular processes. During these processes, actin fibers deform the cell membrane outward by applying forces parallel to the fiber's major axis (as in migration) or they deform the membrane inward by applying forces perpendicular to the fiber's major axis (as during cytokinesis). Here we describe a novel actin-membrane interaction in human dermal myofibroblasts. When labeled with a cytosolic fluorophore, the myofibroblasts developed prominent fluorescent structures on the ventral side of the cell. These structures are present in the cell membrane and colocalize with ventral actin stress fibers, suggesting that the fibers bend the membrane to form a "cytosolic pocket" for the fluorophores to flow into, creating the observed structures. The existence of this pocket was confirmed by transmission electron microscopy. Dissolving the stress fibers, inhibiting fiber protein binding, or inhibiting myosin-II binding of actin removed the observed structures. However, decreasing cellular contractility did not remove the structures. Taken together, our results illustrate a novel actin-membrane bending topology where the membrane is deformed outwards rather than being pinched inwards, resembling the topological inverse of cytokinesis.