Adult mesenchymal stem cells and the NO pathways

Adult marrow-derived mesenchymal stem cells (MSCs) were named by me in the late 1980s, and data were published in the 1990s by our group and others (1, 2) to indicate that these cells were capable of differentiating into a number of mesenchymal phenotypes in culture. At that time, it was the dogma that only one adult stem cell could be found, the hematopoietic stem cell. We now know that there are a number of tissue- or organ-specific progenitors, including neural, cardiac, liver, epidermis, and gastrointestinal stem cells, to name the most obvious. Moreover, we now appreciate that MSCs originate in many tissues as perivascular or mural cells (pericytes) (3). Importantly, these pericytes, when detached from their blood vessel nest, become activated MSCs that secrete large amounts and a substantial array of bioactive molecules. These MSC injury site-secreted molecules have profound effects on the host’s immune system and trophic effects that serve to establish a regenerative microenvironment (4). Indeed, in searching ClinicalTrials.gov, more than 285 MSC trials were listed for a vast array of clinical symptoms and diseases. For this reason, I have suggested that the stem cell activity of these cells was relatively minor, and that MSCs should be short for “medicinal signaling cells” (5). In this context, the paper by Gomes et al. (6) documents that signaling by S-nitrosoglutathione reductase (GSNOR), an enzyme that metabolizes S-nitrosothiols (SNOs) to regulate protein nitrosylation (7), contributes to MSC-mediated vasculogenesis. Although the authors state that MSCs can differentiate into endothelial cells that form vessels, this differentiation capacity is far from certain (it is certainly not shown in this publication). To the authors’ credit, the results of their experimentation on increasing or decreasing SNO bioactivity are explained by the MSC-mediated effects on vasculogenesis. Indeed, as …