SIRT1 Inhibition Affects Angiogenic Properties of Human MSCs

Abstract

Humanmesenchymal stem cells (hMSCs) are attractive for clinical and experimental purposes due to their capability of self-renewal and of differentiating into several cell types. Autologous hMSCs transplantation has been proven to induce therapeutic angiogenesis in ischemic disorders. However, themolecular mechanisms underlying these effects remain unclear. A recent report has connected MSCsmultipotency to sirtuin families, showing that SIRT1 can regulate MSCs function. Furthermore, SIRT1 is a criticalmodulator of endothelial angiogenic functions. Here, we described the generation of an immortalized human mesenchymal bone marrowderived cell line and we investigated the angiogenic phenotype of our cellular model by inhibiting SIRT1 by both the genetic and pharmacological level. We first assessed the expression of SIRT1 in hMSCs under basal and hypoxic conditions at both RNA and protein level. Inhibition of SIRT1 by sirtinol, a cell-permeable inhibitor, or by specific sh-RNA resulted in an increase of prematuresenescence phenotype, a reduction of proliferation rate with increased apoptosis. Furthermore, we observed a consistent reduction of tubule-like formation and migration and we found that SIRT1 inhibition reduced the hypoxia induced accumulation of HIF-1 protein and its transcriptional activity in hMSCs. Our findings identify SIRT1 as regulator of hypoxia-induced response in hMSCs andmay contribute to the development of new therapeutic strategies to improve regenerative properties ofmesenchymal stem cells in ischemic disorders through SIRT1 modulation.