Mechanisms of action of mesenchymal stromal cells in equine tendon healing: Tenogenic matrix remodeling in advanced tendon disease

• Applicant: Professorin Dr. Janina Burk
• Subject Area: Veterinary Medical Science
• Term: since 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 265078493

Tendon disease occurs frequently in equine and human athletes and aged patients. It is accompanied by successive alterations of the tendon extracellular matrix (ECM), which result from failed repair of microlesions, triggering an imbalance of matrix remodelling processes. This often leads to a chronic condition with inferior biomechanical tissue properties, which predisposes the patients for acute injury. Due to the complex interplay of inflammation and degeneration, tendon disease is difficult to treat and conventional therapies fail to yield satisfactory results. The local injection of multipotent mesenchymal stromal cells (MSC) is considered as a promising regenerative approach to treat tendon disease. In horses with naturally occurring tendon disease or experimental tendon lesions, several studies suggested beneficial effects of MSC-based therapy. Furthermore, locally injected MSC persisted at the injury site, providing the basis for long-term regenerative effects. However, there is a substantial lack of knowledge regarding the MSC mechanisms of action in different stages of tendon disease, hampering a targeted use of MSC therapies. In this context, it is crucial to acknowledge that MSC fate and modulatory activities are directed by their local environment. For acute inflammatory tendon disease, previous data indicate that tenogenic differentiation is impaired but immunomodulatory mechanisms are activated. However, in advanced tendon disease, other mechanisms, such as remodeling of the pathologically altered ECM, are anticipated to be activated. It is known that MSC actively synthesize ECM components as well as express and activate ECM degrading enzymes (e.g. MMP) and their endogenous inhibitors (TIMP). However, the clinical potential of their matrix-modulatory activity is only beginning to be explored. The aim of the proposed project is to understand the interplay of MSC and ECM in the context of tendon disease, focusing on the tenogenic matrix-modulatory activities of MSC, and to use this novel understanding for the development of targeted treatment strategies. First, the adaptations of MSC matrix-modulatory mechanisms in different ECM environments are investigated, regarding active enzymatic ECM degradation as well as selective ECM component protection and de novo synthesis. For that purpose, biomimetic nanofiber matrices and decellularized tendon matrices are used, reflecting healthy as well as lesion and scar tendon ECM. Next, the intracellular signaling cross-talk mechanisms underlying the anticipated adaptations of MSC matrix-modulatory activity to the different ECM-environments are addressed. Here, we focus on the impact of ECM-induced intracellular signaling cascades on canonical TGF-β/smad signaling. Finally, we will test strategies for MSC-based matrix-modulatory therapies using targeted MSC-preconditioning and cell-free approaches, providing the basis for future therapies in advanced tendon disease.

• DFG Programme: Research Grants
• International Connection: Austria