Multipotent stromal cells are activated to reduce apoptosis in part by upregulation and secretion of stanniocalcin-1

Abstract

Multipotent stromal cells (MSCs) have been shown to reduce apoptosis in injured cells by secretion of paracrine factors, but these factors were not fully defined. We observed that co-culture of MSCs with previously UV irradiated fibroblasts reduced apoptosis of the irradiated cells, but fresh MSC conditioned media was unable reproduce the effect. Comparative Microarray analysis of MSCs grown in the presence or absence of UV irradiated fibroblasts demonstrated that the MSCs were activated by the apoptotic cells to increase synthesis and secretion of stanniocalcin-1 (STC-1), a peptide hormone that modulates mineral metabolism and has pleiotrophic effects that have not been fully characterized. We showed that STC-1 was required but not sufficient for reduction of apoptosis of UV-irradiated fibroblasts. In contrast, we demonstrated that MSC-derived STC-1 was both required and sufficient for reduction of apoptosis of lung cancer epithelial cells made apoptotic by incubation at low pH in hypoxia. Our data demonstrate that STC-1 mediates the anti-apoptotic effects of MSCs in two distinct models of apoptosis in vitro.

Spatiotemporal proliferation of human stromal cells adjusts to nutrient availability and leads to stanniocalcin-1 expression in vitro and in vivo

“…Notably, the STC1 gene contains a hypoxiaresponsive element (HRE) motif and therefore is a hypoxia inducible factor (HIF) target gene [40]. It has been shown that STC1 has anti-apoptotic effects in MSCs [44], which would explain stable and comparable cell death in 3D vs. 2D despite steep gradients that cause nutrient limitation in 3D. Moreover, our results in vitro and in vivo suggest that the stromal cell-STC1-concentration correlation might be involved in the promotion of vessel formation in 3D through a mechanism that might be analogous to that of tumor growth via a vascular endothelial growth factor (VEGF) dependent mechanism [45].…”

Mesenchymal Stromal Cells Rescue Cortical Neurons from Apoptotic Cell Death in an In Vitro Model of Cerebral Ischemia

“…Moreover, intravenously administered MSCs reduced apoptosis and improved functional recovery after stroke in vivo (Chen et al 2003a). MSCs were found to protect irradiated fibroblasts from apoptosis (Block et al 2009). However, MSC-CM did not prevent apoptosis in this model, and MSC-mediated activation of fibroblasts by direct cell-to-cell contact was required to induce production of protective factors (Block et al 2009).…”

“…MSCs were found to protect irradiated fibroblasts from apoptosis (Block et al 2009). However, MSC-CM did not prevent apoptosis in this model, and MSC-mediated activation of fibroblasts by direct cell-to-cell contact was required to induce production of protective factors (Block et al 2009). In our OGD model, robust neuroprotection was achieved by addition of diluted MSC-CM at a concentration range of 0.25-5%.…”

Protein kinase Cα suppresses the expression of STC1 in MDA-MB-231 breast cancer cells

“…Down-regulation of PPM1D resulted in higher STC1 mRNA expression in three different breast cancer cell lines [38]. Although many studies suggest an anti-apoptotic, and consequently a tumorigenic, effect of STC1 [25,[39][40][41], there are also instances when STC1 mediates induction of cell death [42,43]. STC1 may therefore, conceivably depending on cellular context, have either pro-or anti-tumorigenic effects.…”