Fragility fractures have a limited capacity to regenerate, and impaired fracture healing is a leading cause of morbidity in the elderly. The recent identification of a highly purified bona fide human skeletal stem cell (hSSC) and its committed downstream progenitor cell populations provides an opportunity for understanding the mechanism of age‐related compromised fracture healing from the stem cell perspective. In this study, we tested whether hSSCs isolated from geriatric fractures demonstrate intrinsic functional defects that drive impaired healing. Using flow cytometry, we analyzed and isolated hSSCs from callus tissue of five different skeletal sites (n = 61) of patients ranging from 13 to 94 years of age for functional and molecular studies. We observed that fracture‐activated amplification of hSSC populations was comparable at all ages. However, functional analysis of isolated stem cells revealed that advanced age significantly correlated with reduced osteochondrogenic potential but was not associated with decreased in vitro clonogenicity. hSSCs derived from women displayed an exacerbated functional decline with age relative to those of aged men. Transcriptomic comparisons revealed downregulation of skeletogenic pathways such as WNT and upregulation of senescence‐related pathways in young versus older hSSCs. Strikingly, loss of Sirtuin1 expression played a major role in hSSC dysfunction but re‐activation by trans‐resveratrol or a small molecule compound restored in vitro differentiation potential. These are the first findings that characterize age‐related defects in purified hSSCs from geriatric fractures. Our results provide a foundation for future investigations into the mechanism and reversibility of skeletal stem cell aging in humans.

中文翻译：

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老年脆性骨折与人类骨骼干细胞缺陷有关。

易碎性骨折的再生能力有限，骨折愈合不良是老年人发病的主要原因。最近鉴定出的高纯度真人骨骼干细胞（hSSC）及其定型的下游祖细胞群，为从干细胞角度了解与年龄相关的受损骨折愈合的机制提供了机会。在这项研究中，我们测试了从老年骨折中分离出的hSSC是否表现出内在的功能缺陷，从而导致愈合受损。使用流式细胞仪，我们从五个不同骨骼部位（n = 61）13至94岁的功能和分子研究患者。我们观察到，hSSC群体的骨折激活扩增在所有年龄段都具有可比性。但是，对分离出的干细胞的功能分析表明，高龄与骨软骨形成能力降低显着相关，但与体外克隆形成能力降低无关。相对于老年男性，源自女性的hSSC随着年龄的增长，功能恶化加剧。转录组学比较显示年轻和较老的hSSCs的骨骼生成途径（如WNT）下调和衰老相关途径的上调。惊人地 Sirtuin1表达的丧失在hSSC功能障碍中起主要作用，但反式白藜芦醇或小分子化合物的重新激活恢复了体外分化潜能。这些是表征老年骨折中纯化的hSSC中与年龄相关的缺陷的首个发现。我们的结果为进一步研究人体骨骼干细胞衰老的机理和可逆性提供了基础。