Abstract
AbstractAge-related bone loss and disease strongly affect the quality of life of the elderly population. Cellular circadian rhythms have been reported to regulate bone aging, and micro RNAs (miRNAs) play crucial posttranscriptional regulatory roles in the peripheral clock network. Proliferation capability, osteogenic lineage commitment, senescence-associated secreted phenotype (SASP) and circadian oscillation of clock genes under osteogenic condition were assessed in bone marrow mesenchymal stromal cells (BMSCs) from young adult and aged adult mice. miRNAs targeting the core clock gene brain and muscle arntl-like protein 1 (Bmal1) were screened and verified in young and old BMSCs with RT-qPCR and Western Blot analysis. ChIP-seq and RNA-seq datasets were mined to define the downstream mechanism and gain- and loss-of-function genetic experiments were performed to confirm the hypothesis. To compare the therapeutic effect of these clock-engineered BMSCs, SASP and osteogenic capability of Bmal1-overexpressing and miR-142-3p-inhibited BMSCs were investigated in vitro and transplanted into bone defects and femur cavities of aged mice. Aged BMSCs displayed an abolished circadian rhythm, impaired self-renewal capability and decreased osteoblast differentiation. miR-142-3p was elevated with aging, which downregulated Bmal1 and diminished the osteogenic potential of BMSCs. In addition, Bmal1 inhibited YAP expression to promote BMSCs osteogenesis, which was independent from the activation of Hippo signaling pathway. Overexpression of Bmal1 or inhibition of miR-142-3p rescued the molecular temporal rhythm and osteoblast differentiation ex vivo. Cell-based circadian therapy showed improved bone formation and higher turnover levels in vivo. This study demonstrates that transcriptional and post-transcriptional level clock-modified BMSCs rescued circadian oscillation and age-related bone loss via miR-142-3p/Bmal1/YAP signaling axis. These data provide promising clinical prospects of circadian-mediated stromal cell-based therapy and bone tissue regeneration.
Funder
National Science Foundation of China | Major Research Plan
National Natural Science Foundation of China
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Cell Biology,Cellular and Molecular Neuroscience,Immunology
Cited by
6 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献