Rapamycin Treatment of Tendon Stem/Progenitor Cells Reduces Cellular Senescence by Upregulating Autophagy.

Wang Wang,James H.-C Wang,Daibang Nie,Jianying Zhang,Jiuyi Sun,Yiqin Zhou,Margherita Maioli

doi:10.1155/2021/6638249

Abstract

The elderly population is prone to tendinopathy due to aging-related tendon changes such as cellular senescence and a decreased ability to modulate inflammation. Aging can render tendon stem/progenitor cells (TSCs) into premature senescence. We investigated the effects of rapamycin, a specific mTOR inhibitor, on the senescence of TSCs. We first showed that after treatment with bleomycin in vitro, rat patellar TSCs (PTSCs) underwent senescence, characterized by morphological alterations, induction of senescence-associated β-galactosidase (SA-β-gal) activity, and an increase in p53, p21, and p62 protein expression. Senescence of PTSCs was also characterized by the elevated expression of MMP-13 and TNF-α genes, both of which are molecular hallmarks of chronic tendinopathy. We then showed that rapamycin treatment was able to reverse the above senescent phenotypes and increase autophagy in the senescent PTSCs. The activation of autophagy and senescence rescue was, at least partly, due to the translocation of HMGB1 from the nucleus to the cytosol that functions as an autophagy promoter. By reducing TSC senescence, rapamycin may be used as a therapeutic to inhibit tendinopathy development in the aging population by promoting autophagy.

Highlights

Tendinopathy is a prevalent tendon disorder that affects millions of Americans and costs billions of healthcare dollars every year
When rat patellar tendon stem/progenitor cell (TSC) (PTSCs) were treated with various concentrations of bleomycin for 5 days, they started to exhibit a typical morphology for cellular senescence, indicated by the change of cell shape into a distinct, enlarged, and flat phenotype (Figure 1(a))
When we compared the tendon tissues from young (2.5 months) and aged (18 months) rats, we found similar SA-β-gal activity to that observed from the in vitro staining of PTSCs

Summary

Introduction

Tendinopathy is a prevalent tendon disorder that affects millions of Americans and costs billions of healthcare dollars every year. Aging is thought to be one of the major risk factors for tendinopathy, which is characterized by abnormal thickening, degeneration, and calcification of tendon tissues [1, 2]. Aging decreases the ability of the tendon to maintain its structural integrity, largely due to the loss of the stem cell population within the tendon. The tendon stem/progenitor cell (TSC) population plays a major role in tendon homeostasis and repair by replacing lost mature tenocytes. TSCs are considered to contribute to the pathogenesis of tendinopathy [3]. Recent studies have demonstrated that the frequency and proliferation rates of TSCs are both reduced, and cell cycle progression is delayed in aged TSCs, which may impair tendon regeneration capacity and lead to agerelated tendinopathy [1, 4]. It is known that the potentials of TSC proliferation and differentiation decline with aging, the mechanisms regulating TSC aging are poorly understood

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