CBX4 Upregulation Reduces Cellular Senescence and Osteoarthritis in Mice

Cellular senescence is one of the causes of aging; the inflammatory signals generated by growing numbers of senescent cells disrupt tissue maintenance and cell function, and play an important role in many age-related conditions, including osteoarthritis. The best approach to senescent cells appears to be the simple one: destroy them. They accumulate slowly, and therapies that selectively remove senescent cells have been shown in animal studies to produce significant reversal of numerous aspects of aging. Nonetheless, many research groups are more interested in preventing or modulating senescence, with the open access paper here an example of the former. To my eyes, therapies that have to be taken over decades to slow the accumulation of senescent cells are a very poor second best to methods of immediate clearance of these cells.

Stem cell senescence contributes to stem cell exhaustion, a major cause of physiological and pathological aging. Mesenchymal stem cells (MSCs) are adult multipotent cells in various mesodermal tissues that are capable of differentiating into mature cells such as osteoblasts, chondrocytes, and adipocytes. Both physiologically aged individuals and patients with premature aging syndromes exhibit functional degeneration in mesodermal tissues, along with exhaustion of MSC populations, thus characterized by atherosclerosis, osteoporosis, osteoarthritis, etc.

CBX4, a component of polycomb repressive complex 1 (PRC1), plays important roles in the maintenance of cell identity and organ development through gene silencing. However, whether CBX4 regulates human stem cell homeostasis remains unclear. In this study, we reported that CBX4 was downregulated during human MSC (hMSC) senescence and accordingly investigated the role of CBX4 in maintaining cellular homeostasis in hMSCs. Targeted CBX4 depletion in hMSCs resulted in loss of nucleolar heterochromatin, enhanced ribosome biogenesis, increased protein synthesis, and accelerated cellular aging. CBX4 overexpression alleviated senescent phenotypes in both physiologically and pathologically aged hMSCs.

More importantly, lentiviral vector-mediated CBX4 overexpression attenuated the development of osteoarthritis in mice. We demonstrate that CBX4 safeguards hMSCs against cellular senescence through the regulation of nucleolar architecture and function, suggesting a target for therapeutic interventions against aging-associated disorders.

Link: https://doi.org/10.1016/j.celrep.2019.02.088

Comments

lol your frustration with this approach is really showing through :).

Posted by: Steven Gregory at April 3rd, 2019 9:28 AM

Speaking of cellular senescence, does this impact any of the current approaches towards senolytics that are already in the works, such as Unity or Oisin?

https://www.sens.org/enhancing-innate-immune-surveillance-of-senescent-cells/

"Research Highlights:

Dr. Campisi has found that about ten percent of senescent cells are resistant to being killed, even by fresh NK cells, suggesting that these resistant cells are the ones that escape immunosurveillance and accumulate in aging tissues. Her research team and other scientists have developed preliminary data suggesting mechanisms whereby senescent cells can make themselves invisible to NK cells, thus protecting themselves from destruction.

The Buck-SRF-RC collaboration is now seeking to drill further down into these questions and test possible means to intervene in the process. The Campisi lab is looking into further elaborating the biology of one of senescent cells' two self-protective mechanisms, and also testing a potential role for another kind of immune cell (macrophages) in defending the body against senescent cell accumulation.

At the SRF-RC, we are currently perfecting the method of co-culturing NK and senescent cells and controlling the killing process, and will begin testing two potential therapeutic targets identified in the Campisi lab. The SRF-RC scientists are also working for the first time with NK cells derived directly from aged human donors (rather than long-cultured lines of NK cells, or NK cells artificially "aged" by exposure to oxidative stress or extensive replication in culture, as has been done in the past). Using these cells will allow them for the first time to observe any direct effects of aging on NK cell senolytic activity. The team is also developing an algorithm for the SRF-RC's automated microscope imaging system to rapidly analyze stained plates of cells for quantitative analysis of senescent cell-killing ability - a job hitherto done by laborious human visual microscopy."

Posted by: Ham at April 3rd, 2019 10:37 AM

@ Ham: I don't think this has much impact on any senolytic therapy approach - certainly not our approach at Oisin Bio. Current therapies ablate SCs downstream of any prior clearance by NK cells.

Posted by: Gary at April 3rd, 2019 12:54 PM

@Gary

Do you think OISIN can use CBX4 as an additional target for the senolytic therapy?

Posted by: Cuberat at April 3rd, 2019 4:52 PM

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