Rejuvenation of Mesenchymal Stem Cells to Ameliorate Skeletal Aging

Abstract

Advanced age is a shared risk factor for many chronic and debilitating skeletal diseases including osteoporosis and periodontitis. Mesenchymal stem cells develop various aging phenotypes including the onset of senescence, intrinsic loss of regenerative potential and exacerbation of inflammatory microenvironment via secretory factors. This review elaborates on the emerging concepts on the molecular and epigenetic mechanisms of MSC senescence, such as the accumulation of oxidative stress, DNA damage and mitochondrial dysfunction. Senescent MSCs aggravate local inflammation, disrupt bone remodeling and bone-fat balance, thereby contributing to the progression of age-related bone diseases. Various rejuvenation strategies to target senescent MSCs could present a promising paradigm to restore skeletal aging.

Keywords: aging; bone regeneration; senescence; stem cells.

Figure 1

Schematic illustration of mechanisms leading to MSC senescence. The diagram illustrates several pathways that can induce cellular senescence, including autophagy, inhibitory ECM cues, noncoding RNAs, histone modification and mitochondria dysfunction. Both autophagy inducer and inhibitory ECM cues repress the function of focal adhesion complex, thereby inhibiting the mechanotransduction-mediated actin stabilization and downstream PI3K/AKT/mTOR signaling pathway and finally induce the expression of senescence-related genes. Noncoding RNAs and histone modifications can modulate the accessibility of senescence-related genes to alter genetic programing regulating senescence. mtDNA damage and oxidative stress of mitochondria can significantly promote the production of ROS, to induce the expression of senescence-related genes.