Highlights: 

  • Treating aged tendon stem cells with POG reduces cellular senescence – a dysfunctional state where cells cease to grow and divide – and boosts their function (stemness). 
  • Orally supplementing injured aged (18-month-old) rats with POG enhances tendon regeneration and reduces markers of senescence and inflammation. 

Our ability to bounce back from tendon injuries falters with age, and this happens, in part, due to stem cell exhaustion – a condition in which stem cells lose their ability to regenerate and repair damaged tissues. Notably, ongoing efforts to recover the regenerative potential of aged stem cells have focused on the identification of compounds capable of reversing cellular senescence, a primary driver of stem cell decline. 

Now, in a new study published in the journal Bone Research, Wang and colleagues from Peking University in China utilized machine learning to identify the compound prim-O-glucosylcimifugin (POG), a compound found in saposhnikova root, as a top candidate to ameliorate stem cell senescence and potentially reignite tendon healing capabilities in aged rats. Researchers found that treating aged tendon stem cells with POG  mitigated cellular senescence, enhanced stem cell growth, and boosted stemness – the fundamental properties of stem cells that optimize growth, cell differentiation, and tissue repair. Moreover, the investigators demonstrated that the oral administration of POG rejuvenated tendon regeneration and repair in aged rats. 

POG Reverses Stem Cell Senescence and Enhances Stemness

Cellular senescence poses a major threat to the function of stem cells, as this harmful state diminishes their ability to grow and differentiate into different cell types, both of which are essential for tissue regeneration. With this in mind, the investigators explored whether POG could rejuvenate tendon stem cell function by reversing cellular senescence. 

In a lab dish (in vitro), Wang and colleagues found that aged rat stem cells treated with POG had significantly fewer senescent cells than untreated stem cells, confirming POG’s ability to quench senescence. Additionally, the investigators showed that POG treatment enhanced stem cell growth, with treated cells displaying larger cell colonies than untreated controls. Uniquely, POG treatment also boosted the activity of several markers indicative of stemness, further demonstrating that POG restores stem cell function. Taken together, the findings suggest that POG revitalizes the stemness of tendon stem cells by reversing cellular senescence.

(Wang et al., 2023 | Bone Research) POG decreases senescence and increases stem cell growth. Aged stem cells treated with POG (18M+POG) had fewer senescent cells (SAβ-gal positive cells, left) and formed more colonies called colony-forming units (CFUs, right, purple dots) than untreated controls (18M+DMSO), demonstrating increased proliferation. These cells also display higher levels of Oct4, indicating increased stemness. 

POG Enhances Tendon Regeneration 

After establishing POG’s ability to ameliorate cellular senescence and preserve stem cell function, Wang and colleagues wanted to see if these findings translated to improved tendon healing in injured aged rats. First, the investigators orally supplemented aged rats with POG for two months. Subsequently, the rats were given an injury by partially slicing the achilles tendon. Wound healing was monitored for four weeks afterward.

Following four weeks of observation, the POG-treated rats presented with more complete and ordered collagen fibers, known to heavily influence the structural integrity, stability, and strength of tendons after recovering from injury. Notably, tissue analysis revealed that the injured tendons treated with POG also had reduced levels of senescent and inflammatory markers. Collectively, these findings demonstrate that POG rejuvenates tendon regeneration by reversing cellular senescence in aged stem cells. 

(Wang et al., 2023 | Bone Research) POG improves tendon healing. (Left) Schematic outlining the timeline of the experiment. (Right) 4 weeks after receiving treatment with POG, injured rats displayed more complete and ordered collagen fibers (18M+POG) than untreated rats (18M+Vehicle), as shown by hematoxylin and eosin (HE) staining.   

Targeting Senescence to Thwart Aging

Although the study’s investigators targeted cellular senescence to revitalize stem cells and improve tendon healing, other leading research institutions have targeted senescence to positively influence a myriad of age-related diseases. In fact, the removal of senescent cells with compounds known as senolytics has been shown to ameliorate cardiac dysfunction, improve muscle regeneration, alleviate cognitive impairment and brain inflammation, and extend the lifespan of mice. 

The success of these preclinical studies has sparked excitement among aging science researchers, as senolytics offer a multi-faceted approach to mitigate one of the primary hallmarks of aging – senescence. Whether these findings translate to humans is still unclear, but the available data strongly suggests that limiting senescence can help optimize healthy aging.