MECHANOBIOLOGY OF MULTICELLULAR SYSTEM: MECHANOSENSITIVE ATP RELEASE IS A KEY MECHANISM THAT ORCHESTRATES COLLECTIVE CELL BEHAVIOR
Mechanobiology Laboratory, Nagoya University Graduate School of Medicine, Japan
In organisms mechanical forces regulate tissue and organ functions in a well-organized way, as typically observed in embryogenesis, would healing or local vasoconstriction. However, the underlying mechanism how cells are orchestrated remains elusive. Here we present an example in which mechanically induced cellular ATP release acts as a key signal that can orchestrate a multicellular system. ATP has been recognized as a ubiquitous autocrine/paracrine extracellular messenger regulating spatio-temporal behavior of a variety of tissues and organs. Interestingly, cellular ATP-release is often mechanosensitive, implying its important roles in mechano-signaling in multi-cellular systems. In lactating mammary glands, secretory epithelial (SE) cells form a milk-filling alveolus, and myoepithelial (ME) cells surround the alveolus in a basket form. In response to the increased serum level of the pituitary hormone oxytocin, ME cells undergo quick and strong contraction to squeeze milk out of the alveolus. One of the remarkable features of mammary SE cells is that they release ATP in response to mechanical stimuli. Stretched SE cells in an inflated alveolus filled with milk will release ATP. Thus alveoli are surrounded by a cloud of ATP when they are filled with milk. Extracellular ATP is known to lower the threshold serum concentration of oxytocin to induce ME cell contraction from 100pM to 10pM, via stimulating the metabotropic ATP-receptor P2Y1 expressed in ME cells. When a nipple is sucked by a baby, the peak level of serum oxytocin, which is originally secreted from posterior pituitary organ in response to mechanical stimuli (e.g., nipple sucking), is approximately 50pM. Thus only the milk-filled alveoli would contract and eject milk. This is a very smart mechanism to avoid abrupt depletion of milk in mammary glands at once, enabling continual breast feeding. ATP release and subsequent signaling are emerging factors indispensable for exploring mechanobiology of multicellular systems.