Tenogenic Properties of Mesenchymal Progenitor Cells Are Compromised in an Inflammatory Environment

Luisa Brandt,Susanna Schubert,Janina Burk,Patrick Scheibe,Jan Franzen,Claudia Gross,Walter Brehm

doi:10.3390/ijms19092549

Abstract

Transplantation of multipotent mesenchymal progenitor cells is a valuable option for treating tendon disease. Tenogenic differentiation leading to cell replacement and subsequent matrix modulation may contribute to the regenerative effects of these cells, but it is unclear whether this occurs in the inflammatory environment of acute tendon disease. Equine adipose-derived stromal cells (ASC) were cultured as monolayers or on decellularized tendon scaffolds in static or dynamic conditions, the latter represented by cyclic stretching. The impact of different inflammatory conditions, as represented by supplementation with interleukin-1β and/or tumor necrosis factor-α or by co-culture with allogeneic peripheral blood leukocytes, on ASC functional properties was investigated. High cytokine concentrations increased ASC proliferation and osteogenic differentiation, but decreased chondrogenic differentiation and ASC viability in scaffold culture, as well as tendon scaffold repopulation, and strongly influenced musculoskeletal gene expression. Effects regarding the latter differed between the monolayer and scaffold cultures. Leukocytes rather decreased ASC proliferation, but had similar effects on viability and musculoskeletal gene expression. This included decreased expression of the tenogenic transcription factor scleraxis by an inflammatory environment throughout culture conditions. The data demonstrate that ASC tenogenic properties are compromised in an inflammatory environment, with relevance to their possible mechanisms of action in acute tendon disease.

Highlights

Mesenchymal progenitor cells, referred to as multipotent mesenchymal stromal cells (MSC), are considered as potent therapeutic tools to promote musculoskeletal regeneration
Tenogenic differentiation could be induced by naturally occurring stimuli such as tendon extracellular matrix and cyclic loading, as demonstrated by our own [22] and others’ [23,24] previous work, in which progenitor cell-seeded decellularized tendon matrices were subjected to dynamic culture in customized cyclic strain bioreactors. These findings demonstrate that the tenogenic differentiation of mesenchymal progenitor cells, potentially followed by matrix-modulating activities [25], could contribute to their regenerative mechanisms in tendon healing
adipose-derived stromal cells (ASC) proliferation in monolayer culture was enhanced in the presence of the pro-inflammatory cytokines IL-1β and tumor necrosis factor-α (TNF-α), alone as well as when combined

Summary

Introduction

Mesenchymal progenitor cells, referred to as multipotent mesenchymal stromal cells (MSC), are considered as potent therapeutic tools to promote musculoskeletal regeneration. Direct progenitor cell transplantation to the site of injury is currently the most promising approach to treat conditions involving large load-bearing tendons such as the human Achilles tendon. This concept is already in clinical use in equine veterinary medicine for more than a decade [5], which is of particular interest for human medicine, as the horse represents the only available model animal for naturally occurring large tendon disease [6], and because human and equine mesenchymal progenitor cells have been shown to display a high degree of similarity [7]. Were set to a default value, and the automatic adjustment for the camera was turned off.

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