Enhanced Therapeutic Potential of Preactivated Mesenchymal Stromal Cells and Their Secretory Factor Stanniocalcin-1 in Models for Acute Injuries and Inflammation

Abstract

There has been significant interest in the therapeutic potential of the adult stem/progenitor cells from bone marrow called multipotent mesenchymal stromal cells (MSCs). Signals from injured tissues activate MSCs to secrete beneficial factors and contribute to immune/inflammatory modulation and tissue healing. In order to enhance the therapeutic potential of MSCs hanging drop culture method was used to preactivate the cells in vitro and eliminate the lag period required for their activation in vivo. Stanniocalcin-1 (STC-1) is a potent anti-inflammatory and anti-apoptotic protein secreted from activated MSCs and has been considered as a substitute for MSCs in several disease conditions; therefore, the effects of STC-1 were studied on monocyte fate in vitro and in a mouse model of ischemic myocardial injury.

Aggregated MSCs in hanging drops were self-activated to produce several therapeutic factors such as anti-inflammatory protein STC-1 and TNFα stimulated gene/protein 6 (TSG-6). MSCs dissociated from spheroids were also smaller than MSCs from standard 2 dimensional cultures, and as a result, larger numbers of them trafficked through the lung of mice after intravenous administration. Notably, spheroid MSCs were more effective than MSCs from standard cultures in suppressing inflammatory responses in a co-culture system with activated macrophages and in a mouse model of peritonitis. The data suggest enhanced therapeutic potential of spheroid MSCs for diseases caused by unresolved inflammation. Treatment with STC-1 reduced expression of CD14, a coreceptor for toll-like receptors, in differentiating monocytes/macrophages and suppressed the inflammatory responses of the cells to endotoxin. Administration of STC-1 also reduced CD14 expression in monocytes stimulated with various danger signals and in hearts of mice after myocardial infarction. These findings may explain the observed decreases in cardiac inflammation following myocardial infarction, and the improvements in ejection fraction and infarct size. The results suggest that STC-1 is a promising therapy to protect the heart and other tissues from ischemic injury.