Department of Orthopedics, National Taiwan University Hospital, Hsin-Chu Branch, Taiwan, Republic of China.
Inflammation Research and Drug Development Center, Changhua Christian Hospital, Taiwan, Republic of China.
Aging (Albany NY). 2020 Nov 26;13(1):578-597. doi: 10.18632/aging.202166.
Aging impairs the IGF-I signaling of bone marrow mesenchymal stem cells (bmMSCs), but the mechanism is unclear. Here, we found that the ability to auto-phosphorylate IGF-I receptor (IGF-IR) in response to IGF-I was decreased in the bmMSCs of aged donors. Conversely, data showed that decorin (DCN) expression was prominently increased in aged bmMSCs, and that under IGF-I treatment, DCN knockdown in serum-starved aged bmMSCs potentiated their mitogenic activity and IGF-IR auto-phosphorylation, whereas DCN overexpression in serum-starved adult bmMSCs decreased both activities. Co-immunoprecipitation assays suggested that IGF-I and DCN bound to IGF-IR in a competitive manner. Online MethPrimer predicted 4 CpG islands (CGIs) in the introns of gene. RT-qPCR and bisulfite sequencing showed that dimethyloxalylglycine, an inhibitor of DNA demethylation, increased mRNA expression and CGI-I methylation in adult bmMSCs, whereas 5-aza-2'-deoxycytidine, a DNA methylation inhibitor, decreased mRNA expression and CGI-I methylation in aged bmMSCs, and ultimately enhanced the proliferation of serum-starved aged bmMSCs under IGF-I stimulation. Thus, IGF-IR could be the prime target of aging in down-regulating the IGF-I signaling of bmMSCs, where DCN could be a critical mediator.
衰老大幅削弱骨髓间充质干细胞（bmMSCs）的 IGF-I 信号，但具体机制尚不清楚。我们发现，衰老供体 bmMSCs 对 IGF-I 产生 IGF-IR 自身磷酸化的能力降低。相反，数据显示，衰老 bmMSCs 中 decorin（DCN）表达显著增加，IGF-I 处理时，血清饥饿衰老 bmMSCs 中的 DCN 敲低可增强其有丝分裂活性和 IGF-IR 自身磷酸化，而血清饥饿成年 bmMSCs 中的 DCN 过表达则降低了这两种活性。免疫共沉淀实验表明，IGF-I 和 DCN 以竞争性方式与 IGF-IR 结合。在线 MethPrimer 预测基因的内含子中有 4 个 CpG 岛（CGIs）。RT-qPCR 和亚硫酸氢盐测序显示，DNA 去甲基化抑制剂二甲氧乙醯基甘氨酸增加了成年 bmMSCs 中的 mRNA 表达和 CGI-I 甲基化，而 DNA 甲基化抑制剂 5-氮杂-2'-脱氧胞苷则降低了衰老 bmMSCs 中的 mRNA 表达和 CGI-I 甲基化，并最终增强了 IGF-I 刺激下血清饥饿衰老 bmMSCs 的增殖。因此，IGF-IR 可能是衰老下调 bmMSCs 的 IGF-I 信号的主要靶点，而 DCN 可能是关键的介质。
