Senescent Cells Hinder Fracture Repair, Rather than Helping as Might Be Expected

Regeneration might be thought of as a complex and highly coordinated interaction between stem cells, somatic cells, and senescent cells. Some small fraction of cells in the injured tissue become senescent, cease replication, and secrete pro-growth, pro-inflammatory factors. They are then removed by the immune system once their task is done, to prevent long-term disruption of tissue function by those same secretions. The problem of senescent cells in aging is entirely that this signaling for growth and inflammation, beneficial in the short term, becomes very harmful and disruptive to normal tissue function when present for the long term.

It was thought that senescent cells assist in wound healing throughout the body, based on evidence gathered largely from skin injuries. Here, however, researchers present evidence to show that senescent cells actually hinder fracture healing, and thus senolytic therapies to selectively destroy senescent cells may be beneficially applied to this sort of injury. This suggests that senescent cells may actively impede regeneration in other tissues as well.

Senescent cells have detrimental effects across tissues with aging but may have beneficial effects on tissue repair, specifically on skin wound healing. However, the potential role of senescent cells in fracture healing has not been defined. Here, we performed an in silico analysis of public mRNAseq data and found that senescence and senescence-associated secretory phenotype (SASP) markers increased during fracture healing. We next directly established that the expression of senescence biomarkers increased markedly during murine fracture healing. We also identified cells in the fracture callus that displayed hallmarks of senescence, including distension of satellite heterochromatin and telomeric DNA damage; the specific identity of these cells, however, requires further characterization.

Then, using a genetic mouse model containing a Cdkn2aInk4a-driven luciferase reporter, we demonstrated transient in vivo senescent cell accumulation during callus formation. Finally, we intermittently treated young adult mice following fracture with drugs that selectively eliminate senescent cells ('senolytics', Dasatinib plus Quercetin), and showed that this regimen both decreased senescence and SASP markers in the fracture callus and significantly accelerated the time course of fracture healing. Our findings thus demonstrate that senescent cells accumulate transiently in the murine fracture callus and, in contrast to the skin, their clearance does not impair but rather improves fracture healing.



I would say that there's a spectrum of senescent cells where some are actively harmful, some are beneficial and they are not all made equal . Probably the "good" ones secrete senescence -associated factors but are not really "damaged" but rather serve as regulators. The "bad" ones are damaged goods that happen to secrete similar signals for wrong reasons.

Of course in biology everything is messier and there might be some overlap where "bad" ScC actually are performing a "good" function and vice versa.

Mammals have very poor regenerative abilities. There were some unfortunate evolutionary trade-offs which are leaving us even worse off than the birds. My gut feel tells me that senescence cells' dysfunction is one of those.

Posted by: Cuberat at October 14th, 2021 8:25 AM

Btw I have stumbled upon a very interesting article on synodic research.
Here the approach is to use antibody conjugation. Apart the novel approach the article gives a good summary about the field with published references.

Posted by: Cuberat at October 14th, 2021 9:28 PM

Cuberat above has a point. I'd add that the term 'senescent' is unhelpful as it leads to the idea that they're all 'bad'. Perhaps better would have been something like 'wound-healing cells' which, when they malfunction and hang around too long, could have been labelled senescent. But too late for that now. Senescent cells have taken the same route as cholesterol.

Posted by: Neal Asher at October 14th, 2021 10:48 PM

Senescent means pre-cancer. The only 'good' use of them is (*perverse sense of humor of evolution* sigh which 'chose' secretion created by these cells as) a signal to create skin (in embryo phase) and to start re-creating skin (after being born) in wound healing.

Posted by: SilverSeeker at October 15th, 2021 9:00 AM
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