Inhibition of phosphatidylcholine‐specific phospholipase C prevents bone marrow stromal cell senescence in vitro

Abstract

Bone marrow stromal cells (BMSCs) can proliferate in vitro and can be transplanted for treating many kinds of diseases. However, BMSCs become senescent with long-term culture, which inhibits their application. To understand the mechanism underlying the senescence, we investigated the activity of phosphatidylcholine-specific phospholipase C (PC-PLC) and levels of integrin beta4, caveolin-1 and ROS with BMSC senescence. The activity of PC-PLC and levels of integrin beta4, caveolin-1 and ROS increased greatly during cell senescence. Selective inhibition of increased PC-PLC activity with D609 significantly decreased the number of senescence-associated beta galactosidase positive cells in BMSCs. Furthermore, D609 restored proliferation of BMSCs and their differentiation into adipocytes. Moreover, D609 suppressed the elevated levels of integrin beta4, caveolin-1 and ROS. The data suggest that PC-PLC is involved in senescence of BMSCs, and its function is associated with integrin beta4, caveolin-1 and ROS.

Caveolin-1, cellular senescence and age-related diseases

“…The importance of caveolin-1 in replicative senescence was also supported by studies showing that old human diploid fibroblasts express higher levels of caveolin-1 compared to younger cells (Park et al, 2000; Wheaton et al, 2001) and that caveolin-1 expression is increased in replicative senescent mesenchymal stem cells (Park et al, 2005) and bone marrow stromal cells (Sun et al, 2009). In addition, upregulation of caveolin-1 positively correlates with shortening of chondrocyte replicative lifespan after treatment with interleukin (IL)-1β (Yudoh et al, 2009).…”

“…The activity of PC-PLC is dramatically increased and caveolin-1 expression is upregulated during replicative senescence of bone marrow stromal cells (BMSCs) (Sun et al, 2009). Inhibition of PC-PLC activity by the specific inhibitor D609 reduces the upregulation of caveolin-1 expression and the number of replicative senescent BMSCs, suggesting that PC-PLC mediates senescence of BMSCs possibly with a mechanism involving caveolin-1-dependent signaling (Sun et al, 2009).…”

“…Inhibition of PC-PLC activity by the specific inhibitor D609 reduces the upregulation of caveolin-1 expression and the number of replicative senescent BMSCs, suggesting that PC-PLC mediates senescence of BMSCs possibly with a mechanism involving caveolin-1-dependent signaling (Sun et al, 2009). Since senescence of BMSCs greatly limits their use in transplants for the treatment of a variety of diseases, manipulation of caveolin-1 expression in BMSCs may represent an alternative approach to improve the therapeutic use of these cells.…”

The Role of Caveolin 1 in HIV Infection and Pathogenesis

“…Several studies have shown that oxidative stress enhances the expression of Cav-1 [131]. p38 MAPK, Sp1, and NF-κB, cyclooxygenase 2 (COX2), and phosphatidycholine-specific phospholipase activates cav-1 gene promoter during oxidative stress resulting in enhanced Cav-1 expression [172,188,189,190,191]. The HIV proteins Tat, Nef, Vpr, and Gp120 have been shown to independently increase reactive oxygen species (ROS) while decreasing antioxidants, establishing HIV-mediated oxidative stress [192].…”

Soy Protein Isolate Inhibits High-Fat Diet-Induced Senescence Pathways in Osteoblasts to Maintain Bone Acquisition in Male Rats

“…This evidence suggests that caveolin-1 is at least involved in mediating one of the categories of cellular senescence. Indeed, we and others have previously shown that caveolin-1 expression is increased in replicative senescent mesenchymal stem cells (22,44) and bone marrow stromal cells (45). In addition, old human diploid fibroblasts express higher levels of caveolin-1 than younger cells (46,47), further supporting the important role of caveolin-1 in cellular senescence.…”