Age‐related intrinsic changes in human bone‐marrow‐derived mesenchymal stem cells and their differentiation to osteoblasts

Abstract

SummaryIn vivo and in vitro studies indicate that a subpopulation of human marrow-derived stromal cells (MSCs, also known as mesenchymal stem cells) has potential to differentiate into multiple cell types, including osteoblasts.In this study, we tested the hypothesis that there are intrinsic effects of age in human MSCs (17-90 years). We tested the effect of age on senescence-associated β β β β -galactosidase, proliferation, apoptosis, p53 pathway genes, and osteoblast differentiation in confluent monolayers by alkaline phosphatase activity and osteoblast gene expression analysis. There were fourfold more human bone MSCs (hMSCs) positive for senescence-associated β β β β -galactosidase in samples from older than younger subjects ( P < 0.001; n = 17). Doubling time of hMSCs was 1.7-fold longer in cells from the older than the younger subjects, and was positively correlated with age ( P = 0.002; n = 19). Novel age-related changes were identified. With age, more cells were apoptotic ( P = 0.016; n = 10). Further, there were age-related increases in expression of p53 and its pathway genes, p21 and BAX . Consistent with other experiments, there was a significant age-related decrease in generation of osteoblasts both in the STRO-1 + cells ( P = 0.047; n = 8) and in adherent MSCs ( P < 0.001; n = 10). In sum, there is an age-dependent decrease in proliferation and osteoblast differentiation, and an increase in senescence-associated β β β β -galactosidase-positive cells and apoptosis in hMSCs. Up-regulation of the p53 pathway with age may have a critical role in mediating the reduction in both proliferation and osteoblastogenesis of hMSCs. These findings support the view that there are intrinsic alterations in human MSCs with aging that may contribute to the process of skeletal aging in humans.

The Lamina Propria of Adult Human Oral Mucosa Harbors a Novel Stem Cell Population

“…In contrast to reports on the negative effect of ageing on adult SC growth and functionality [18][19][20][21][22]57], the growth during the first 10 population doublings, the fraction of cells expressing Nanog and Oct4, the level of transcription of these factors, and the in vitro differentiation capacity of hOMSC were not affected by the donor age, thus, providing a biological explanation for the negligible ageing effect on wound healing in the elderly oral mucosa [25]. However, the increase in the doubling time at higher population doublings in elderly derived cultures suggests that mechanisms active in preserving telomeres length in EhOMSC is less effective than in YhOMSC.…”

Osteogenic potential and responsiveness to leptin of mesenchymal stem cells between postmenopausal women with osteoarthritis and osteoporosis

“…Although no further evidence was shown to explain the disparity in cell proliferation, we believed that the viability of MSCs from populations with different conditions might contribute to the number of differentiated osteoblasts. Zhou et al 27 found that there is an age-dependent decrease in proliferation and osteoblast differentiation in human MSCs. Also, D'Ippolito et al 28 demonstrated that decreased osteogenic potential of MSCs is partly related to aging.…”

Autophagy controls mesenchymal stem cell properties and senescence during bone aging

“…However, data suggest that beneficial functions of MSCs may become compromised with age; this is closely associated with age‐related loss of repair and regenerative capacity of different tissues (Wilson, Shehadeh, Yu, & Webster, 2010). Bone marrow‐derived mesenchymal stem cells (BMMSCs) decline in number with aging and show degenerative properties including reduced osteogenic differentiation capacity, increased adipogenic differentiation capacity and reduced proliferative ability; these are partially caused by bone aging (Wilson et al., 2010; Zhou et al., 2008). Different mechanisms of MSC senescence have been demonstrated including telomere shortening (Baxter et al., 2004), increased reactive oxygen species (ROS) (Stolzing & Scutt, 2006) and transcriptional control (Li et al., 2017).…”