Institute of Tendon and Bone Regeneration
Research Projects

Injured tendons often exhibit impaired healing with the formation of stiff scar tissue and altered extracellular matrix (ECM). These changes, coupled with inflammatory processes, contribute to the development of tendon disorders. Disrupted ECM has been linked to pathological metabolism in other tissues. Therefore, deregulated metabolic processes are believed to contribute to poor tendon healing. Our recent findings emphasize the significant role of the extracellular matrix protein SPARC in tendons (Wang, T., Wagner A., Gehwolf R. et al., 2021; Gehwolf R., et al., 2016).. Aging leads to a decrease in SPARC levels, resulting in a significant deterioration of tendon quality. In this major project, we map cellular and metabolic changes in degenerated tendons using single-cell RNA analysis and metabolomics in the SPARC knockout mouse model. Pilot data show that local administration of SPARC positively influences tendon healing. The effectiveness of SPARC as a therapeutic agent for enhancing tendon healing is also being investigated in this project.

Scar formation and regenerative healing are physiological responses to acute injuries in many tissues. In contrast to regenerative healing, scar formation leads to functional limitations or even complete loss of function, posing a significant burden for millions of patients. Current therapeutic gold standards for injuries do not allow modulation at the cellular level. Therefore, this project aims to investigate the role of a promising candidate in wound healing, pericytes (PC). Besides their role in vascular function, these cells also contribute to homeostasis and wound healing. Due to their transdifferentiation potential, PCs are potentially crucial for both regeneration and scar formation. Characterizing the molecular signatures of PCs contributing to non-regenerative healing versus those involved in regenerative healing may provide new therapeutic approaches to promote tissue regeneration. This interdisciplinary project will create a comprehensive molecular atlas of PC-like cells in healthy tendons, spinal cords, and optic nerves using single-cell RNA sequencing. Secondly, we aim to identify various PC subpopulations in regenerating and non-regenerating lesions of mouse tendons, spinal cords, and optic nerves to better understand the role of PCs in pathological scar formation (fibrosis).

A significant characteristic of healthy tendons is their low degree of vascularization. This means not only a reduced supply of nutrients but also a diminished oxygen supply compared to more highly vascularized tissues, such as muscles. When a tendon is pathologically over- or underloaded on a persistent basis, it leads to abnormal ingrowth of blood vessels and consequently results in fibrotic damage to the tissue, potentially leading to tendon rupture (Kortner S., et al.; 2015). The mechanisms underlying this pathological vascularization are still not fully understood, as are those that prevent excessive blood vessel ingrowth in healthy tendons despite the low oxygen availability (Tempfer H., et al.; 2019).

Our research identified a novel cell population in tendons called "Tenophages," expressing both tendon- and macrophage-associated markers (Lehner, C., et al.; 2019). These cells may play a surveillance role in tendons and, upon tissue damage, attract immune cells from the bloodstream through the release of signaling molecules (Fractalkine). Interestingly, our recent publication in the Lancet magazine "EBioMedicine" revealed that patients with allergies are more prone to tendon disorders. In a mouse model, we elucidated mechanisms: allergies elevate inflammatory levels in the body, leading to the activation of tendon cells and degradation of the tendon matrix, impairing tissue quality.

Our ongoing research aims to gain a deeper understanding of the role of Tenophages and how the Fractalkine receptor system can be activated or deactivated to reduce inflammatory processes in the tendon and enhance healing capacity. These findings may be relevant not only for allergies but also for other chronic conditions such as diabetes or obesity, contributing to an expanded understanding of tendon disorders in various patient groups.