Senescent Mesenchymal Stem Cells Contribute to Osteoarthritis
Cellular senescence is a significant contributing cause of osteoarthritis in old age, and senolytic therapies capable of selectively destroying senescent cells are presently undergoing clinical trials in osteoarthritic patients. Researchers here investigate a specific population of senescent cells, the supporting mesenchymal stem cells found in and around joint tissue, and establish that they are important in the progression of osteoarthritis.
Tissue accumulation of p16INK4a-positive senescent cells is associated with age-related disorders, such as osteoarthritis (OA). These cell-cycle arrested cells affect tissue function through a specific secretory phenotype. The links between OA onset and senescence remain poorly described. Using experimental OA protocol and transgenic mice, we found that the senescence-driving p16INK4a is a marker of the disease, expressed by the synovial tissue, but is also an actor: its somatic deletion partially protects against cartilage degeneration.
We test whether by becoming senescent, the mesenchymal stromal/stem cells (MSCs), found in the synovial tissue and sub-chondral bone marrow, can contribute to OA development. We established an in vitro p16INK4a-positive senescence model on human MSCs. Upon senescence induction, their intrinsic stem cell properties are altered. When co-cultured with OA chondrocytes, senescent MSC show also an impairment favoring tissue degeneration.
To evaluate in vivo the effects of p16INK4a-senescent MSC on healthy cartilage, we rely on the SAMP8 mouse model of accelerated senescence that develops spontaneous OA. MSCs isolated from these mice expressed p16INK4a. Intra-articular injection in 2-month-old C57BL/6JRj male mice of SAMP8-derived MSCs was sufficient to induce articular cartilage breakdown. Our findings reveal that senescent p16INK4a-positive MSCs contribute to joint alteration.
Does this support or contradict Unity's Senescent cell targeted Arthritis treatment?
@JohnD
It shows that Unity's approach is far from a complete solution and that senescence is driven from multiple angles
In highsight we now know that senescent cell ablation alone is not enough to heal arthritis. Apparently, there other causes of inflammation. Senolytics might postpone the arthritis in the knee but for sure don't reverse the advances stages. At least not the small molecule used by unity din't show spectacular results. Just months before the news we would have expected to have miraculous reversal. Alas, cartilage degeneration is more complicated. It is a disappointment only because our hopes were set too high of the early success we have witnessed with the senolityc studies.
Now I would imagine that the knee cartilage regenerates more-or less well in the young individuals. After all, such as mall layer is used and abused by the dynamic loads of body weight while jumping and runnig. So htere should be some constant low-grade damage that has to be repaired on regular basis. Therefore, we need something like senescent cells to mediate the regeneration. For some reason, this repair malfunctions with the age. It might requure more aggressive SC ablation combined with antibiotics and then pro-repair factors. Again, it might turn that the molecule tried removed only a small percentage of the suspect senescent cells, and another cocktail of senolytics delivered directly in the joint might have more impressive results.
@cuberat: I believe that the systemic SASP, which is unaffected by local administration of a senolytic to the knee compartment, continues to suppress the regenerative potential of stem cell niche in aged knee joints. This is to be inferred by the results (published in Nature in 2018 by Unity Bio) that their senolytic effectively eliminated senescent cells created by wounding the knees of both young and old mice, but only the young mice (who have no systemic SASP) had cartilage regeneration. Aged animals did not regenerate, even if their SnCs were eliminated.
Transthyretin deposits don't help either.
@Gary
It doesn't seem plausible that there systematic SASP would have such an effect on the localized and somehow isolated area. After all, SC can promote local inflammation which starts localized. I wrote say that SASP induced inflammation is extra burden on the repair systems. But if there repairs system is less efficient, independently of SC presence, senescence ablation would not be enough. It could be that the stem cells are depleted. Or the signaling required for regeneration is disturbed by already present damage. The good thing about your theory is that it is testable by using both localized and whole body SC ablation. High concentration in the knees, and much lower and safer for the whole body.