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Geriatric fragility fractures are associated with a human skeletal stem cell defect.

老年脆性骨折与人类骨骼干细胞缺损有关。

  • 影响因子:7.42
  • DOI:10.1111/acel.13164
  • 作者列表:"Ambrosi TH","Goodnough LH","Steininger HM","Hoover MY","Kim E","Koepke LS","Marecic O","Zhao L","Seita J","Bishop JA","Gardner MJ","Chan CKF
  • 发表时间:2020-06-14
Abstract

: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.

摘要

: 脆性骨折的再生能力有限,骨折愈合障碍是老年人发病的主要原因。一种高度纯化的真正的人类骨骼干细胞 (hSSC) 的最新鉴定其承诺的下游祖细胞群为从干细胞角度理解年龄相关的骨折愈合障碍的机制提供了机会。在本研究中,我们检测了从老年骨折中分离的 hSSCs 是否表现出驱动愈合受损的内在功能缺陷。使用流式细胞术,我们分析并分离了 13 ~ 94 岁患者 5 个不同骨骼部位 (n = 61) 愈伤组织的 hSSCs,进行功能和分子研究。我们观察到 hSSC 人群的骨折激活扩增在所有年龄都具有可比性。然而,分离干细胞的功能分析发现,高龄与骨软骨病潜能降低显著相关,但与体外克隆形成能力降低无关。相对于老年男性,来源于女性的 hSSCs 显示出随年龄增长而加剧的功能下降。转录组学比较揭示了年轻与老年 hSSCs 中 WNT 等骨骼生成途径的下调和衰老相关途径的上调。引人注目的是,Sirtuin1 表达缺失在 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再激活恢复了体外分化潜能。这些是首次发现老年骨折纯化 hSSCs 中年龄相关缺陷的特征。我们的结果为将来研究人类骨骼干细胞衰老的机制和可逆性提供了基础。

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