Identification and characterization of Stanniocalcin-1 as a potential therapeutic protein secreted by injury-activated multipotent stromal cells
Description
Multipotent Stromal Cells (MSCs) hold great promise for future cell-based therapeutics. By understanding the mechanisms by which MSCs contribute to tissue repair, not only can insight be gained as to their potential applications, but novel therapeutic candidates can be identified as well. We determined that MSCs were activated by apoptotic cells to upregulate and secrete Stanniocalcin-1 (STC1), a highly evolutionarily-conserved mineral-regulating protein hypothesized to be stress-responsive in mammals. We determined that STC1 was required for the MSCs to elicit an anti-apoptotic effect on injured cells in two in vitro models of apoptosis. In the first model, STC1 was required but not sufficient to reduce apoptosis of fibroblasts that had been UV-irradiated. In the second model, STC1 was both required and sufficient to reduce apoptosis of ischemic lung epithelial cells. We then tested the stress-responsive nature of STC1 more directly by adopting a model of injury that allowed us to visualize calcium dynamics immediately following insult. We demonstrated that STC1 dramatically enhanced calcium wave propagation following mechanical stimulation of an epithelial monolayer. We showed that the propagation of the calcium wave was dependent on extracellular nucleotides, and that STC1 enhanced the calcium response downstream of extracellular ATP. Blocking STC1 inhibited the propagation of the calcium wave as well as the ATP-induced calcium response indicating that STC1 was required for ATP signaling. These novel data provide mechanistic grounds for the pleiotropic nature of STC1 and may have profound implications on the application of STC1 as a therapeutic target considering the ubiquity of ATP signaling in various biological processes