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

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.

Hypoxic preconditioning rejuvenates mesenchymal stem cells and enhances neuroprotection following intracerebral hemorrhage via the miR-326-mediated autophagy

“…Previous studies reviewed the relations between cellular senescence and autophagy [ 30 , 31 ] and suggested that autophagy plays a dual role in the regulation of MSC senescence. Upregulation of autophagy can decrease the apoptosis of aged MSCs in the condition of myocardial infarction [ 34 , 35 ], restore the biological properties of aged MSCs [ 76 ], rejuvenate MSCs derived from patients with idiopathic pulmonary fibrosis [ 49 ], and reduce the senescence of patellar tendon stem/progenitor cells [ 77 ]. Compared with young MSCs, aged MSCs have significantly reduced autophagic activity.…”

Autophagy Ameliorates Reactive Oxygen Species-Induced Platelet Storage Lesions

“…This discrepancy might derive from the different concentrations of rapamycin and thus the diffident regulation on autophagic flux. Rapamycin was initially found as an antifungal macrocyclic lactone, then approved for preventing allograft rejection, restenosis, and stent thrombosis [ 40 ]. It has been shown that rapamycin induces autophagy by inhibiting mTORC1 signaling, which is a master regulator in the response to nutrient availability and growth factors [ 41 ].…”

Anti-aging: senolytics or gerostatics (unconventional view)

“…As a gerostatic, rapamycin suppresses growth and senescence in yeast [71] and mammalian cells [32,[40][41][42][72][73][74][75][76][77][78][79][80][81][82]. Rapamycin slows aging, stem cell exhaustion and extends lifespan in the simplest organism: Hydra [83].…”

“…It could be due to reduction of these markers per cell, or even cell rejuvenation. In fact, rapamycin, which does not kill senescent cells, decreases expression of SA-β-gal and p16 [ 73 , 74 , 152 ]. In the organism, low doses of rapamycin decrease levels of p16 and tend to decrease SA-β-gal activity [ 153 ].…”