Slow-releasing hydrogen sulfide donors: innovative tools for stem cell based tissue repair and regeneration

Gasotransmitters is a family of membrane-permeable gaseous signaling molecules able to trigger specific physiological changes in the cells. Among the members of this family, which include the widely studied gaseous molecules CO and NO, H2S is the most recently discovered and one of the most promising for tissue regeneration and tissue engineering purposes. Its production in mammalian cells is strictly regulated and occurs through enzymatic and non-enzymatic pathways. H2S can also be administered exogenously to the cells via molecular donors; in particular, H2S-slow releasing donors are of significant interest for their ability to exert cytoprotective effects. In fact, H2S targets many cellular components involved in the anti-hypoxic, anti-oxidant and anti-apoptotic response, such as Cytochrome C oxidase, the Nrf2/ARE-regulated genes and the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. In addition, H2S can also directly scavenge free radicals, thus further increasing its therapeutic potential. The effects of H2S administration on stem cells are yet to be fully investigated, but preliminary data show that H2S pretreatment can enhance mesenchymal stem cells survival after implantation at the site of injury. Here, commercially available H2S-slow releasing donors Na2S and GYY4137 and new donors obtained from the conjugation of glutathione (GSH) with water-soluble garlic extract (GSGaWS) were used to investigate the effects of exogenous H2S on human cardiac Mesenchymal Stem Cells (cMSC). In vitro cell viability, GSGaWS-mediated resistance to H2O2 induced damage and multipotency of the cells were evaluated by WST-1 assay, immunofluorescence microscopy and western-blot analysis. Moreover, the oil soluble fraction, named GSGaOS, obtained during the production of GSGaWS, was used to functionalize polylactic acid (PLA) fibers, which were able to protect the cells from H2O2 induced damage. These preliminary data confirm the high therapeutic potential of H2S, suggesting its possible application in association with synthetic biocompatible scaffolds for tissue regeneration and tissue engineering.