胚胎干细胞来源exosomes调控BMSCs的命运防治骨质疏松的作用及机制

Osteoporosis is a major age-related disease in threatening the health condition of the elderly, thus, new therapies are urgently needed to prevent and treat this disease. Recent evidence suggests that therapeutic technique targeting senescent cells is probably a new method in treating age-related disease. Cellular aging of BMSCs is proved to play a crucial role in the occurrence and development of osteoporosis. Some striking results have been achieved in treating age-related disease with Stem cell therapy. It is now observed from some studies that stem cell-derived exosome plays a key role in reversing the process of cell aging and delaying body aging. In our previous studies, we found that embryonic stem cell-derived exosomes (ESC-exos) can impede the development of osteoporosis, which is related with the pluripotency factors ESC-exos carry. Combine with the findings of multiple and our previous researches, we speculate that ESC-exos is likely to rejuvenate aging stem cell and restore its normal function by transfer some pluripotency factors (e.g. Nanog, Oct4, Sox2), which hold back the aging progress of tissue and organs. Accordingly, our project aims to systematically evaluate the function and mechanism of ESC-exos in regulating BMSCs aging and clarify the molecular mechanism of ESC-exos transferring pluripotency factors to regulate BMSCs aging in the treatment of osteoporosis, which provides new ideas and new strategies for the use of stem cells in the treatment of aging-related diseases.

骨质疏松是严重威胁老年人群健康的衰老相关性疾病，亟待探索有效防治的新技术。研究提示针对衰老细胞治疗技术可能是有效防治衰老相关性疾病的新策略。研究表明，BMSCs衰老在年龄相关性骨质疏松发生发展过程中起着非常关键的作用。近年研究提示，干细胞来源Exosomes在逆转组织细胞衰老进程、延缓机体衰老等方面可能发挥重要作用。我们前期研究发现胚胎干细胞来源Exosomes（ESC-exos）可拮抗骨质疏松发生与发展，且提示与其运载的多能性因子有关。结合文献报道，我们推测ESC-Exos极可能通过转运Nanog、Oct4等多能性因子，使衰老干细胞重新年轻化而发挥拮抗组织器官衰老的作用。据此，本研究将系统评估ESC-Exos防治骨质疏松及对BMSCs衰老的调控作用，阐明ESC-exos通过转运干性因子调控BMSCs衰老过程防治骨质疏松的分子机制。为利用干细胞治疗衰老相关性疾病提供新思路和新策略。

衰老是引起各种老龄化疾病的主要危险因素，随着人口老龄化进程加剧，各种慢性退行性疾病的发生率逐渐升高，严重威胁中老年人群的健康，针对机体或器官衰老的机制，积极探索衰老相关疾病的防治策略具有十分重要的现实意义。骨衰老是老年性骨质疏松的主要危险因素，目前仍缺乏有效的防治措施。研究发现，干细胞移植具有显著的抗衰老作用，其中干细胞源性小细胞外囊泡（small extracellular vesicles，sEVs）是干细胞发挥生物学功能的主要媒介。多能干细胞具有无限增殖和内源性抵抗衰老的特性，其来源的sEVs在拮抗组织器官衰老、防治衰老相关疾病方面具有独特优势，显示出广阔的转化应用前景。本研究围绕胚胎干细胞来源的sEVs（ESC-sEVs）调控骨衰老防治年龄相关骨丢失的功能和机制展开研究。研究结果表明，ESC-sEVs可以有效逆转BM-MSCs衰老从而防治年龄相关骨丢失。机制研究发现，ESC-sEVs蛋白以协同、多靶点作用方式调控BM-MSCs中一种或多种衰老基因表达。同时，信号通路关联分析发现：ESC-sEVs蛋白可通过激活Wnt、AMPK、PTEN和Sirtuin信号通路调控BM-MSCs衰老基因。本研究首次证实了ESC-sEVs具有逆转BM-MSCs衰老防治年龄相关骨丢失的功能，系统阐明了ESC-sEVs逆转BM-MSCs衰老的分子调控机制。研究结果可望为有效防治骨衰老相关疾病提供多能干细胞来源sEVs的“无细胞治疗”的新策略，同时为干细胞sEVs的抗衰老研究增添了新理论。