Abstract
Diminished regeneration or healing capacity of tendon occurs during aging. It has been well demonstrated that tendon stem/progenitor cells (TSPCs) play a vital role in tendon maintenance and repair. Here, we identified an accumulation of senescent TSPCs in tendon tissue with aging. In aged TSPCs, the activity of JAK-STAT signaling pathway was increased. Besides, genetic knockdown of JAK2 or STAT3 significantly attenuated TSPC senescence in aged TSPCs. Pharmacological inhibition of JAK-STAT signaling pathway with AG490 similarly attenuated cellular senescence and senescence-associated secretory phenotype (SASP) of aged TSPCs. In addition, inhibition of JAK-STAT signaling pathway also restored the age-related dysfunctions of TSPCs, including self-renewal, migration, actin dynamics, and stemness. Together, our findings reveal the critical role of JAK-STAT signaling pathway in the regulation of TSPC aging and suggest an ideal therapeutic target for the age-related tendon disorders.
Highlights
Tendon aging is characterized by time-dependent declines in structural, compositional, and functional properties (Zaseck et al, 2016; Marqueti et al, 2018)
We investigated the expressions of some representative senescence-associated secretory phenotype (SASP) genes, including interleukin (IL)6, matrix metalloproteinase (MMP)9, and C-X-C motif chemokine ligand 12 (CXCL12), and the results showed that these SASP gene levels were highly increased in aged tendon stem/progenitor cells (TSPCs) (Figures 1G–I)
Tendon stem/progenitor cell function declines with age
Summary
Tendon aging is characterized by time-dependent declines in structural, compositional, and functional properties (Zaseck et al, 2016; Marqueti et al, 2018). Aged tendon is more prone to tendon disorder, such as tendon tear, re-tear, and tendinopathy. Due to the limited endogenous repair capacity of aged tendon, the restoration of injured tendon is still a major clinical challenge. Stem cell-based strategies to restore the original property of injured tendon are being investigated. Tendon tissue contains terminally differentiated tenocytes and a small resident tendon stem cell population, known as tendon stem/progenitor cells (TSPCs). TSPCs showed standard mesenchymal stem cell (MSC) characteristics, including self-renewal, clonogenicity, and multilineage differentiation potential; TSPCs express classical MSC surface antigens and tendon lineage genes (Bi et al, 2007; Lui and Wong, 2019). TSPCs are essential for effective repair, regeneration, and maintenance of tendon.
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