Moderate and intensive mechanical loading differentially modulate the phenotype of tendon stem/progenitor cells in vivo.

Jianying Zhang,Arthur Mcdowell,Macalus V Hogan,Daibang Nie,Kelly Williamson,James H-C Wang,Gianpaolo Papaccio

doi:10.1371/journal.pone.0242640

Jianying Zhang, Arthur Mcdowell + Show 5 more

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https://doi.org/10.1371/journal.pone.0242640

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Abstract

To examine the differential mechanobiological responses of specific resident tendon cells, we developed an in vivo model of whole-body irradiation followed by injection of either tendon stem/progenitor cells (TSCs) expressing green fluorescent protein (GFP-TSCs) or mature tenocytes expressing GFP (GFP-TNCs) into the patellar tendons of wild type C57 mice. Injected mice were subjected to short term (3 weeks) treadmill running, specifically moderate treadmill running (MTR) and intensive treadmill running (ITR). In MTR mice, both GFP-TSC and GFP-TNC injected tendons maintained normal cell morphology with elevated expression of tendon related markers collagen I and tenomodulin. In ITR mice injected with GFP-TNCs, cells also maintained an elongated shape similar to the shape found in normal/untreated control mice, as well as elevated expression of tendon related markers. However, ITR mice injected with GFP-TSCs showed abnormal changes, such as cell morphology transitioning to a round shape, elevated chondrogenic differentiation, and increased gene expression of non-tenocyte related genes LPL, Runx-2, and SOX-9. Increased gene expression data was supported by immunostaining showing elevated expression of SOX-9, Runx-2, and PPARγ. This study provides evidence that while MTR maintains tendon homeostasis by promoting the differentiation of TSCs into TNCs, ITR causes the onset of tendinopathy development by inducing non-tenocyte differentiation of TSCs, which may eventually lead to the formation of non-tendinous tissues in tendon tissue after long term mechanical overloading conditions on the tendon.

Highlights

Tendons function to transmit mechanical loads from the muscle to bone, stabilizing the joint and enabling its motion
Using an in vitro model, we previously showed that one of the causes of tendinopathy development may be via the aberrant differentiation of tendon stem/progenitor cells (TSCs) into non-tenocytes when subjected to excessive mechanical loading [11]
Mechanical loading effect on tendon stem/progenitor cells cobblestone-shaped cells positively stained with the stem cell marker nucleostemin (Fig 1C, 1E and 1G)

Summary

Introduction

Tendons function to transmit mechanical loads from the muscle to bone, stabilizing the joint and enabling its motion. Using an in vitro model, we previously showed that one of the causes of tendinopathy development may be via the aberrant differentiation of TSCs into non-tenocytes when subjected to excessive mechanical loading [11]. We showed that large magnitude stretching of TSCs in vitro and ITR in mice in vivo induced aberrant differentiation of TSCs into non-tenocytes while TNCs remained unchanged [11, 13]. A novel in vivo model is necessary to study the roles of resident TSCs and TNCs in the development of tendinopathy, as well as in the maintenance of tendon homeostasis.

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