This therapeutic combination synergistically kills non-proliferating stem cells to enhance bone-forming capabilities in aged mice.
· Treating aged mouse bone marrow stem cells with Dasatinib and Quercetin substantially enhances their bone regeneration capacity.
· These findings provide hope for using the two therapeutic agents to rejuvenate aged tissue in humans.
Stem cells that generate and repair our tissues, such as those that reside in the marrow of our bones, drastically lose this ability as we get older. Scientists think that the capacity of stem cells to repair tissues has to do with senescence — when cells stop proliferating. Dasatinib and quercetin are two senolytics — senescent cell-killing molecules — that can increase bone volume in mice, but how these two drugs work in combination to drive bone formation is unclear.
Xu and colleagues from the UConn Center on Aging published an article in NPJ Regenerative Medicine showing that treating aged mice with Dasatinib and Quercetin enhances new bone generation in part by killing senescent bone marrow stem cells (BMSCs). In laboratory dishes, aged mouse BMSCs accumulate senescent cells, but Dasatinib (0.2 µM) and Quercetin (20 µM) restore the percentage of healthy, non-senescent cells to youthful levels. These findings carried over into aged mice, where the UConn research team showed that Dasatinib and Quercetin-treated BMSCs with restored proliferation promotes skull bone repair. These findings show that Dasatinib and Quercetin treatment is a promising strategy to improve BMSC function and bone regeneration in older people.
In tissues other than bone, researchers have touted the senolytic ability of Dasatinib and Quercetin, so Xu and colleagues sought to figure out whether they do so for BMSCs. The UConn-based research team found increased senescent cells in pools of old mouse BMSCs and that Dasatinib and Quercetin treatment reduced these senescent cell levels to those observed in young mice. These findings indicate that Dasatinib and Quercetin treatment induce aged BMSC senescent cell clearance in mice.
To better understand how Dasatinib and Quercetin treatment act as senolytics, Xu and colleagues measured gene activity for senescence-related inflammation protein markers. They found that BMSCs from older mice had higher levels for these senescence-related inflammation protein markers and that Dasatinib and Quercetin treatment reduced these levels toward those of younger mice. This suggests that Dasatinib and Quercetin diminish senescent cell levels in BMSCs by inhibiting senescence-related inflammation proteins.
So, Xu and colleagues wanted to see whether eliminating senescent BMSCs promoted the rejuvenation of non-senescent BMSCs to proliferate — a potential indicator of bone regeneration capacity. Untreated, aged BMSCs proliferated at a rate that was 15% lower than that for young mice. After Dasatinib and Quercetin treatment, the older BMSC proliferation rate improved by 10% and was only 5% less than that of younger BMSC. These findings indicate that Dasatinib and Quercetin treatment makes way for non-senescent BMSC to proliferate at higher rates, which may enhance bone regeneration capacity.
Given these findings that Dasatinib and Quercetin eliminate senescent BMSCs and promote the proliferation of non-senescent ones, Xu and colleagues wanted to know whether these senolytics influenced bone regeneration. So, the UConn research team implanted BMSCs either treated with Dasatinib and Quercetin or that went untreated into mice with missing patches of skull bone. They found that Dasatinib and Quercetin-treated BMSCs from aged mice not only facilitated better skull repair than the untreated ones but triggered bone regeneration similar to the BMSCs from young mice. These results give support to Dasatinib and Quercetin improving BMSC bone regeneration capacity in aged mice.
“We postulate that clearance of senescent cells is one of the major mechanisms by [Dasatinib and Quercetin],” said Xu and colleagues. “These agents along with other senolytic compounds hold promise for improving [bone marrow stem cell] function in aged populations.”
Aside from their capacity to eliminate senescent cells, Xu and colleagues say that Dasatinib and Quercetin could have a wide range of biological effects. They suggest that the senolytic activity of this treatment is not the primary driver for bone generation restoration in aged mice. Future studies need to evaluate how else Dasatinib and Quercetin influence bone regeneration capacity in aged mice and the long-term effects of this treatment. These findings will help guide if and how to treat deteriorating bones in older people with Dasatinib and Quercetin.