Tissue alignment enhances remodeling potential of tendon-derived cells - Lessons from a novel microtissue model of tendon scarring

Jasper Foolen,Stefania L Wunderli,Sandra Loerakker,Jess G Snedeker

doi:10.1016/j.matbio.2017.06.002

Abstract

Tendinopathy is a widespread and unresolved clinical challenge, in which associated pain and hampered mobility present a major cause for work-related disability. Tendinopathy associates with a change from a healthy tissue with aligned extracellular matrix (ECM) and highly polarized cells that are connected head-to-tail, towards a diseased tissue with a disorganized ECM and randomly distributed cells, scar-like features that are commonly attributed to poor innate regenerative capacity of the tissue. A fundamental clinical dilemma with this scarring process is whether treatment strategies should focus on healing the affected (disorganized) tissue or strengthen the remaining healthy (anisotropic) tissue. The question was thus asked whether the intrinsic remodeling capacity of tendon-derived cells depends on the organization of the 3D extracellular matrix (isotropic vs anisotropic). Progress in this field is hampered by the lack of suitable in vitro tissue platforms. We aimed at filling this critical gap by creating and exploiting a next generation tissue platform that mimics aspects of the tendon scarring process; cellular response to a gradient in tissue organization from isotropic (scarred/non-aligned) to highly anisotropic (unscarred/aligned) was studied, as was a transient change from isotropic towards highly anisotropic. Strikingly, cells residing in an ‘unscarred’ anisotropic tissue indicated superior remodeling capacity (increased gene expression levels of collagen, matrix metalloproteinases MMPs, tissue inhibitors of MMPs), when compared to their ‘scarred’ isotropic counterparts. A numerical model then supported the hypothesis that cellular remodeling capacity may correlate to cellular alignment strength. This in turn may have improved cellular communication, and could thus relate to the more pronounced connexin43 gap junctions observed in anisotropic tissues. In conclusion, increased tissue anisotropy was observed to enhance the cellular potential for functional remodeling of the matrix. This may explain the poor regenerative capacity of tenocytes in chronic tendinopathy, where the pathological process has resulted in ECM disorganization. Additionally, it lends support to treatment strategies that focus on strengthening the remaining healthy tissue, rather than regenerating scarred tissue.

Highlights

Tendon and ligament injuries account for 30% of all musculoskeletal consultations [1], presenting a high clinical demand with approximately 4 million new incidents annually [2]
Tendinopathy associates with a change from a healthy tissue with aligned extracellular matrix (ECM) and highly polarized cells that are connected head-to-tail, towards a diseased tissue with a disorganized ECM and randomly distributed cells, scar-like features that are commonly attributed to poor innate regenerative capacity of the tissue
Are cells stimulated to initiate a healing process or do they lose regenerative capacity when exposed to a disorganized environment? This work addressed the question whether the matrix remodeling capacity of tendon-derived cells depends on the organization of the 3D environment

Summary

Introduction

Tendon and ligament injuries account for 30% of all musculoskeletal consultations [1], presenting a high clinical demand with approximately 4 million new (reported worldwide) incidents annually [2] These cases are attributed to acute damage (tears or cuts) as well as fatigue damage (chronic loading) [3,4,5,6]. (2018) 65, 14–29 severe cases, lack good clinical outcome because of various drawbacks, e.g. donor site morbidity [12,13], immunological rejection [14] and poor graft integration [15,16] These drawbacks can cause re-tears in 35 to 95% of the cases [17,18]. The poor healing capacity due to limited cell numbers with low metabolism and poor blood supply [7,19,20] limits the progress made in the treatment of tendinopathy over the past decades [21]

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Conclusion