Geriatric fragility fractures are associated with a human skeletal stem cell defect
Geriatric fragility fractures are associated with a human skeletal stem cell defect
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DOI：
10.1111/acel.13164
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发表时间：
2020-07-01
期刊：
影响因子：
7.8
通讯作者：
Chan, Charles K. F.
中科院分区：
文献类型：
--
作者：
Ambrosi, Thomas H.;Goodnough, L. Henry;Chan, Charles K. F.
脆性骨折的再生能力有限，骨折愈合受损是老年人发病率的主要原因。最近高纯度的真人骨骼干细胞(HSSC)及其下游祖细胞的鉴定为从干细胞的角度理解年龄相关性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的hSSCs是否表现出驱动愈合受损的内在功能缺陷。应用流式细胞术对61例13~94岁患者的5个不同骨骼部位的骨痂组织中的hSSCs进行分析和分离，以进行功能和分子研究。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。然而，对分离的干细胞的功能分析显示，高龄与骨软骨形成潜能降低显著相关，但与体外克隆形成能力降低无关。与老年男性相比，女性来源的hSSCs表现出随年龄增长而加剧的功能衰退。转录比较显示，年轻的hSSCs与年长的hSSCs相比，WNT等骨骼生成途径下调，衰老相关途径上调。值得注意的是，Sirtuin1表达的缺失在hSSC功能障碍中发挥了主要作用，但反式白藜芦醇或小分子化合物重新激活在体外恢复了分化潜力。这是首次发现老年骨折中纯化的hSSCs存在与年龄相关的缺陷。我们的结果为进一步研究人类骨骼干细胞老化的机制和可逆性奠定了基础。
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.