Department of Orthopedic Surgery, New York University School of Medicine, New York, NY 10003.
Department of Cell Biology, New York University School of Medicine, New York, NY 10016.
Proc Natl Acad Sci U S A. 2019 Apr 2;116(14):6995-7004. doi: 10.1073/pnas.1810692116. Epub 2019 Mar 20.
Aging is associated with impaired tissue regeneration. Stem cell number and function have been identified as potential culprits. We first demonstrate a direct correlation between stem cell number and time to bone fracture union in a human patient cohort. We then devised an animal model recapitulating this age-associated decline in bone healing and identified increased cellular senescence caused by a systemic and local proinflammatory environment as the major contributor to the decline in skeletal stem/progenitor cell (SSPC) number and function. Decoupling age-associated systemic inflammation from chronological aging by using transgenic KO mice, we determined that the elevated inflammatory environment, and not chronological age, was responsible for the decrease in SSPC number and function. By using a pharmacological approach inhibiting NF-κB activation, we demonstrate a functional rejuvenation of aged SSPCs with decreased senescence, increased SSPC number, and increased osteogenic function. Unbiased, whole-genome RNA sequencing confirmed the reversal of the aging phenotype. Finally, in an ectopic model of bone healing, we demonstrate a functional restoration of regenerative potential in aged SSPCs. These data identify aging-associated inflammation as the cause of SSPC dysfunction and provide mechanistic insights into its reversal.
衰老是与组织再生受损有关。干细胞数量和功能已被确定为潜在的罪魁祸首。我们首先在人类患者队列中证明了干细胞数量与骨折愈合时间之间的直接相关性。然后，我们设计了一种动物模型，重现了与年龄相关的骨愈合下降，并确定了由全身和局部促炎环境引起的细胞衰老增加是导致骨骼干细胞/祖细胞（SSPC）数量和功能下降的主要原因。通过使用转基因 KO 小鼠将与年龄相关的系统性炎症与生理年龄脱钩，我们确定升高的炎症环境而非生理年龄是导致 SSPC 数量和功能下降的原因。通过使用抑制 NF-κB 激活的药理学方法，我们证明了衰老的 SSPC 具有较低的衰老、增加的 SSPC 数量和增加的成骨功能的功能年轻化。无偏倚的全基因组 RNA 测序证实了衰老表型的逆转。最后，在异位骨愈合模型中，我们证明了衰老 SSPC 再生潜能的功能恢复。这些数据确定了与年龄相关的炎症是 SSPC 功能障碍的原因，并为其逆转提供了机制上的见解。
