SIRT1 is required for long-term growth of human mesenchymal stem cells

Abstract

Human mesenchymal stem cells (MSCs) have therapeutic potential because of their ability to self-renew and differentiate into multiple tissues. However, senescence often occurs in MSCs when they are cultured in vitro and the molecular mechanisms underlying this effect remain unclear. In this study, we found that NAD-dependent protein deacetylase SIRT1 is differentially expressed in both human bone marrow-derived MSCs (B-MSCs) and adipose tissue-derived MSCs after increasing passages of cell culture. Using lentiviral shRNA we demonstrated that selective knockdown of SIRT1 in human MSCs at early passage slows down cell growth and accelerates cellular senescence. Conversely, overexpression of SIRT1 delays senescence in B-MSCs that have undergone prolonged in vitro culturing and the cells do not lose adipogenic and osteogenic potential. In addition, we found that the delayed accumulation of the protein p16 is involved in the effect of SIRT1. However, resveratrol, which has been used as an activator of SIRT1 deacetylase activity, only transiently promotes proliferation of B-MSCs. Our findings will help us understand the role of SIRT1 in the aging of normal diploid cells and may contribute to the prevention of human MSCs senescence thus benefiting MSCs-based tissue engineering and therapies.

Aging of Stem and Progenitor Cells: Mechanisms, Impact on Therapeutic Potential, and Rejuvenation

“…Enzymes with histone deacetylase (HDAC) activity, also, have a role in aging. Among them, the most important are sirtuins [25][26][27][28][29]. Histone acetylation controls chromatin structure and thus affects the regulation of gene expression ( Figure 1).…”

Protective Effects of Ellagic Acid against UVA-induced Oxidative Stress in Human Dermal Papilla

“…Though SIRT1 acts as a growth suppressor gene of telomerase-immortalized cells, the expression of SIRT1 was gradually decreased with the serial cell passage [24]. In the knockdown of SIRT1 of MSCs, cellular senescence was accelerated with the accumulation of the protein p16, whereas the overexpression of SIRT1 delayed senescence [25]. The relationship between SIRT1 and ROS has been demonstrated regarding the aspect of mitochondrial biogenesis in that a cause of aging is the oxidation of macromolecules through the generation of the ROS of mitochondria [26].…”

Adipose TSHB in Humans and Serum TSH in Hypothyroid Rats Inform About Cellular Senescence

“…SIRT1, which is another important mediator of mitochondrial biogenesis and energy expenditure in AT [27][28][29], is widely known as a negative regulator of cellular senescence [30,31]. In humans, increased AT SIRT1 mRNA levels and activity associates with mitochondrial function [28,29] and with reduced markers of cellular senescence [32,33]. Furthermore, DBC1 interacts and inhibits the activity of Sirt1 [34], a crucial component for the prevention of cellular senescence [35,36].…”