Stress kinases negatively regulate the multipotency of mesenchymal stem/stromal cells in vitro : implications in regenerative medicine

The therapeutic efficacy of Mesenchymal stromal cells (MSCs) has been attributed to two mechanisms: one, the transdifferentiation of MSCs into tissue-specific cells and their integration into the affected tissue, and two, the reparative effects of their secretome. While the latter mechanism is now widely accepted, the ability of MSCs to transdifferentiate into non-mesodermal lineages remains highly debated. Nonetheless, several recent studies have shown that MSCs can differentiate into non-mesodermal lineages under specialized conditions. These studies are reviewed here. Notably, cultured MSCs exhibit activation of stress-kinases, and inhibition of these kinases has been shown to enhance the regenerative potential of MSCs; however, the underlying mechanisms involved in this improved potency remain poorly understood. This review also covers existing literature on the effects of stress kinase inhibition on MSC differentiation and functional potency, with an emphasis on therapeutic implications. Here, we propose a novel hypothesis that under conventional culture conditions, stress kinases negatively regulate the differentiation potency of MSCs and limit their multi-lineage potential. Inhibition of these kinases may not drive full lineage commitment that could qualify as transdifferentiation, but instead induce a quasi-differentiated or "primed" MSC state. Such primed MSCs may secrete lineage-specific reparative factors that enhance tissue repair and regeneration.