| Residing in a host of tissues, including skin, muscle, liver, heart, and even hair follicles, non-embryonic stem cells, which are gaining a popularity rivaling that of their embryonic precursors, are capable of combating a number of pathological disorders. Owing to their ability to regenerate specialized tissues associated with each of the three germ layers and being derived from the marrow of human bone, adult mesenchymal stem cells (hMSCs) have been viewed with increased promise, and have been suggested as putative therapeutics for an array of pathologies including Parkinson's disease, cardiovascular disease, arthritis, and even diabetes. However, hMSC cytotherapy has been limited due to inconsistencies observed between their in vitro and in vivo behaviors that include alterations to self-renewal properties and varying propensities to differentiate, necessitating the elucidation of the mechanisms controlling their overall growth and fate. Despite promiscuous expression profiles, the presence of various extracellular protein products, proteolytic enzymes, and adhesion molecules has clearly implicated potential roles for matrix remodeling pathways and associated interactions---features leading to the involvement of a family of enzymes known as matrix metalloproteinases (MMPs). As the primary enzymes responsible for extracellular matrix maintenance, MMPs are also essential in numerous fundamental cellular processes such as proliferation, differentiation, and apoptosis. Combined with evidences indicating their expression in hMSCs, MMPs were studied for their potential control in the proliferation and differentiation of hMSCs. Facilitating this assessment was a subset of small, synthetic mercaptosulfonamide matrix metalloproteinase inhibitors (MMPIs), which, employing a thiol zinc-binding group, reversibly coordinate the catalytic Zn2+ in the active site of MMPs to block their proteolytic activities. Characterized for their inhibitory potential and biological compatibility in the first two parts of this discussion, the mercaptosulfonamide MMPIs were primarily utilized as 'tools' to delineate any potential MMP involvement in hMSC behavior. Although the use of these compounds led to the finding that MMP activity was not an integral component of hMSC behavior, several mercaptosulfonamides and their non-inhibitory complements were unexpectedly shown to enhance the adipocytic differentiation of these cells, ultimately suggesting a novel role for these compounds---potential modulators of stem cell differentiation. |
