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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.