Extracellular Matrix Synthesis and Remodeling by Mesenchymal Stromal Cells Is Context-Sensitive.

Janina Burk,Cornelia Kasper,Susanna Schubert,Ariane Nimptsch,Anna Sassmann

doi:10.3390/ijms23031758

Abstract

Matrix remodeling could be an important mode of action of multipotent mesenchymal stromal cells (MSC) in extracellular matrix (ECM) disease, but knowledge is limited in this respect. As MSC are well-known to adapt their behavior to their environment, we aimed to investigate if their mode of action would change in response to healthy versus pathologically altered ECM. Human MSC-derived ECM was produced under different culture conditions, including standard culture, culture on Matrigel-coated dishes, and stimulation with the pro-fibrotic transforming growth factor-β1 (TGFβ1). The MSC-ECM was decellularized, characterized by histochemistry, and used as MSC culture substrate reflecting different ECM conditions. MSC were cultured on the different ECM substrates or in control conditions for 2 days. Culture on ECM increased the presence of surface molecules with ECM receptor function in the MSC, demonstrating an interaction between MSC and ECM. In MSC cultured on Matrigel-ECM and TGFβ1-ECM, which displayed a fibrosis-like morphology, gene expression of collagens and decorin, as well as total matrix metalloproteinase (MMP) activity in the supernatant were decreased as compared with control conditions. These results demonstrated that MSC adapt to their ECM environment, which may include pathological adaptations that could compromise therapeutic efficacy.

Highlights

Multipotent mesenchymal stromal cells (MSC) have been attributed a variety of regenerative mechanisms, which are influenced and triggered by external stimuli
We showed that MSC are capable of synthesizing extracellular matrix (ECM) that reflects different culture conditions, and that MSC, when cultured on such different ECM substrates, adapt to their environment
Five different culture surfaces were used in the cell culture model to assess matrix modulatory MSC mechanisms: decellularized MSC-derived ECM grown on tissue culture plastic (TCP) (ECM), decellularized MSC-derived ECM grown on Matrigel-coated TCP (Matrigel-ECM), decellularized MSC-derived ECM grown on TCP with transforming growth factor-β1 (TGFβ1) stimulation (TGFβ1-ECM), and Matrigel-coated TCP (Matrigel) and TCP only (TCP) as controls

Summary

Introduction

Multipotent mesenchymal stromal cells (MSC) have been attributed a variety of regenerative mechanisms, which are influenced and triggered by external stimuli Their mode of action in inflammatory or immune-mediated disease is in the focus of many research activities, which have already led to successful therapeutic approaches [1,2]. The ECM turnover relies on the coordinated expression of specific ECM components as well as matrix-degrading enzymes by resident cells, such as matrix metalloproteinases (MMP) and their tissue inhibitors (TIMP) [6,7]. This enables a constant adaptation of the ECM to changing demands, e.g., during development or training and exercise

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