Small Molecule Induction of Stem Cell Behavior Applied to Tendon Aging
While reprogramming usually refers to the production of pluripotent stem cells from somatic cells, is is becoming more broadly used to describe a range of manipulations in which the characteristics of cells in aged tissues are rejuvenated in some way. For example, finding small molecule drug candidates that can restore the potency of aging stem cell populations is the topic of today's open access paper. Since the regulation of adult stem cell and progenitor cell state is complex, there are likely many ways in which it can be manipulated, and those ways probably differ by stem cell type.
Researchers here describe the production of a system for evaluation of stem cell state and discovery of new small molecules to alter that state. They applied this system to aging tendon stem cells, and came up with a drug candidate that restores the regenerative capacity of tendons in old animals. One can make the case for this to be a form of reprogramming because of the way in which tendon stem cells lose their stemness with age; in other stem cell populations, loss of capacity with age may occur for different reasons, such as greater quiescence, or reduced population size, and different solutions will be needed.
Like most tissue regenerative processes, the regenerative capacity of tendons decreases with aging or even fails and is often accompanied by stem cell exhaustion and cellular senescence. The regenerative capacity of adult tendons depends on the status of stem/progenitor cells (TSPCs), which can activate and expand to form new tendon collagen fibers or self-renew to restore the TSPC pool in response to tissue damage. At later stages in life, TSPCs present a marked impairment of stemness and regenerative capacity, resulting in inefficient tendon self-repair. In previous research, we found that the difference in TSPC stemness between the neonatal and adult stages influenced multiple biological functions of TSPCs and the adult tendon regenerative process.
In this context, a reasonable stemness-modulating method is a prospective strategy for remedying aged TSPCs. Traditionally, the dampened stemness can only be reversed by inducing Yamanaka factors genetically. However, an efficient strategy to identify stemness-promoting small molecules is currently lacking. In recent years, deep learning approaches have been widely applied in target-based drug design and for the development of various therapeutic strategies. However, these methods cannot be used when the target is unknown; for instance, with regard to stemness promotion, only four transcription factors are known. In this study, we employed the newly developed system, DLEPS, which is an efficacy prediction system using transcriptional profiles with deep learning, to identify potential drugs to stimulate stemness.
In our study, we found that the top-ranked candidate compound prim-O-glucosylcimifugin (POG) could efficiently inhibit TSPC senescence and promote their tenogenic differentiation potential in an in vitro serial passaging cell senescence model. We also found that the top-ranked POG potently rejuvenated the proliferation and tenogenic potential of TSPCs from both aged rats and middle-aged humans by maintaining stemness and suppressing senescence.
Generally, the results from multiple senescent cell models provide solid and convincing evidence that POG is indeed a potent antisenescent drug for TSPCs. Moreover, the systemic administration of POG and the local delivery of POG encapsulated in nanoparticles were found to promote aged tendon self-repair in small-sized, partial transection tendon injuries. The combination of POG administration and the transplantation of scaffolds significantly enhanced the aged endogenous regenerative capacity in large-sized, full-cut tendon window defects in aged rats. These findings provide multiple alternative strategies for endogenous tendon repair and regeneration in aging according to different injury conditions.