Dexamethasone-boosted mesenchymal stem cell secretome: insight into hepatic protection.

Abstract

As the independent anti-inflammatory effects of mesenchymal stem cells (MSCs) and glucocorticoids are well documented, it is hypothesized that the conditioned media derived from dexamethasone (DEXA)-treated MSCs may exhibit a potent therapeutic effect. To explore this, bone marrow-derived MSCs were transiently maintained in DEXA-containing media, where cell viability, phenotype, and osteogenic differentiation were assessed. Furthermore, the MSC-conditioned media (MSC-CN) was utilized to inhibit the proliferation of hepatoma cells and treat drug-induced acute liver failure (ALF) in mice. We found that low doses of DEXA (≤100 nM) maintained MSC viability and their typical mesenchymal phenotype. Conversely, 1000 nM decreased the expression of the mesenchymal markers (CD105 and CD90), triggered osteogenic differentiation as evidenced by the modulation of osteogenesis-related genes (alkaline phosphatase, osteopontin, and Runt-related transcription factor 2), and increased the intracellular calcium, assessed by Alizarin Red S staining. Moreover, MSC-DEXA-S restricted colony formation, cell migration, and glucose consumption in hepatoma cells. In parallel, MSC-DEXA-S protected mice against acetaminophen-induced ALF, where both liver functions, oxidative stress (Nrf-2, SOD1, GSH, and MDA), angiogenic (VEGF), and inflammatory (TNF-α) markers were improved. Also, MSC-DEXA-S resolved liver necrosis one week after transfusion. These data suggest that pretreatment of MSCs with low doses of dexamethasone maintains their stemness and enhances their paracrine therapeutic effect against hepatic diseases.