Age-related intrinsic changes in human bone-marrow-derived mesenchymal stem cells and their differentiation to osteoblasts
Age-related intrinsic changes in human bone-marrow-derived mesenchymal stem cells and their differentiation to osteoblasts
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DOI：
10.1111/j.1474-9726.2008.00377.x
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发表时间：
2008-06-01
期刊：
影响因子：
7.8
通讯作者：
Glowacki, Julie
中科院分区：
文献类型：
--
作者：
Zhou, Shuanhu;Greenberger, Joel S.;Glowacki, Julie
体内和体外研究表明，人骨髓源性基质细胞（MSC，也称为间充质干细胞）的亚群具有分化成多种细胞类型的潜力，包括成骨细胞。在这项研究中，我们测试了人类MSC（17-90岁）中存在年龄内在影响的假设。我们通过碱性磷酸酶活性和成骨细胞基因表达分析，在融合单层中检测年龄对衰老相关β-半乳糖苷酶、增殖、凋亡、p53通路基因和成骨细胞分化的影响。在老年受试者的样本中，衰老相关β-半乳糖苷酶阳性的人骨间充质干细胞（hMSCs）是年轻受试者的四倍（P < 0.001; n = 17）。hMSCs的倍增时间是1.7倍长的细胞从老年人比年轻的受试者，并与年龄呈正相关（P = 0.002; n = 19）。发现了新的年龄相关变化。随着年龄的增长，更多的细胞凋亡（P = 0.016; n = 10）。此外，p53及其通路基因p21和BAX的表达与年龄相关。与其他实验一致，在STRO-1（+）细胞（P = 0.047; n = 8）和贴壁MSC（P < 0.001; n = 10）中，成骨细胞的生成均存在显著的年龄相关性减少。总之，hMSCs的增殖和成骨细胞分化呈年龄依赖性下降，衰老相关的β-半乳糖苷酶阳性细胞和凋亡增加。随着年龄的增长，p53通路的上调可能在介导hMSCs增殖和成骨细胞生成减少中起关键作用。这些发现支持了这样的观点，即随着年龄的增长，人MSC中存在内在的改变，这可能有助于人类骨骼衰老的过程。
In 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 beta-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 beta-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 beta-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.