Moderate Exercise Mitigates the Detrimental Effects of Aging on Tendon Stem Cells.

Jianying Zhang,James H-C Wang

doi:10.1371/journal.pone.0130454

Abstract

Aging is known to cause tendon degeneration whereas moderate exercise imparts beneficial effects on tendons. Since stem cells play a vital role in maintaining tissue integrity, in this study we aimed to define the effects of aging and moderate exercise on tendon stem/progenitor cells (TSCs) using in vitro and in vivo models. TSCs derived from aging mice (9 and 24 months) proliferated significantly slower than TSCs obtained from young mice (2.5 and 5 months). In addition, expression of the stem cell markers Oct-4, nucleostemin (NS), Sca-1 and SSEA-1 in TSCs decreased in an age-dependent manner. Interestingly, moderate mechanical stretching (4%) of aging TSCs in vitro significantly increased the expression of the stem cell marker, NS, but 8% stretching decreased NS expression. Similarly, 4% mechanical stretching increased the expression of Nanog, another stem cell marker, and the tenocyte-related genes, collagen I and tenomodulin. However, 8% stretching increased expression of the non-tenocyte-related genes, LPL, Sox-9 and Runx-2, while 4% stretching had minimal effects on the expression of these genes. In the in vivo study, moderate treadmill running (MTR) of aging mice (9 months) resulted in the increased proliferation rate of aging TSCs in culture, decreased lipid deposition, proteoglycan accumulation and calcification, and increased the expression of NS in the patellar tendons. These findings indicate that while aging impairs the proliferative ability of TSCs and reduces their stemness, moderate exercise can mitigate the deleterious effects of aging on TSCs and therefore may be responsible for decreased aging-induced tendon degeneration.

Highlights

Tendons are fibrous connective tissue, largely made of collagens, proteoglycans, glycoproteins, water and cells
population doubling time (PDT) of tendon stem/progenitor cells (TSCs) from 24 months old mice is not shown because only a few TSCs were isolated from this group and they were insufficient to establish an in vitro culture
Semi-quantification (Fig 4G) confirmed such an increase and further revealed that the extent of Oil Red O and Safranin O staining in young TSCs were higher by ~3-fold each and that Alizarin Red S staining was higher by ~1.5 fold. These results indicate that when compared to young TSCs, aging TSCs have lower potential to differentiate into non-tenocytes in vitro suggesting a decline in the quality of TSCs in aging mice

Summary

Introduction

Tendons are fibrous connective tissue, largely made of collagens, proteoglycans, glycoproteins, water and cells. Their primary function is to transmit muscular forces to bones, thereby enabling joint movement. Effects of Aging and Exercise on Tendon Stem Cells which are resident fibroblast-like cells that maintain tendon integrity, remodeling and repair [1]. A new tendon cell type, termed tendon stem/progenitor cells (TSCs), has been identified in recent years in humans, rabbits, mice, and rats [2,3,4]. TSCs differ from tenocytes in their ability to proliferate and self-renew, as well as in their multi-differentiation potential, which allows them to differentiate into different cell types such as adipocytes, chondrocytes, and osteocytes, in addition to differentiation into tenocytes [4]

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