Mechanisms of action of mesenchymal stromal cells in equine tendon healing: Tenogenic matrix remodeling in advanced tendon disease
Final Report Abstract
The treatment of equine tendon disease with multipotent mesenchymal stromal cells (MSC) has so far shown great promise in acute disease stages, but has been less successful in chronic stages, which are associated with substantial alterations of the tendon extracellular matrix. MSC are capable to synthesize and release matrix remodeling enzymes as well as matrix components, which could be key to restoring a healthy and functional matrix. However, knowlegde was lacking on whether the altered matrix in chronic disease impacts on MSC functional properties, thereby potentially compromising MSC matrix-modulatory potency. In this project, we established a novel cell culture model using tendon matrix scaffolds from horses with naturally occurring chronic tendon disease. We showed that while MSC tenogenic differentiation is not much affected by disease tendon matrix as compared to healthy tendon matrix, the expression of matrix remodeling enzymes and collagens is decreased in the disease environment, which could impair MSC efficacy in chronic tendon disease. Shedding light on the cross-talk between ECM- and tenogenic signaling, we showed that inhibition of the ROCK pathway reinforces TGF-b3-induced smad2/3 signaling and thereby tenogenic differentiation. Furthermore, we identified smad2/3 linker phosphorylation as a cross-talk mechanism of ECM- and TGF-b3 signaling. Last not least, first data show that ROCK inhibition and preconditioning of the MSC on collagen substrate could be a strategy to promote MSC matrix modulatory properties. The findings of the project add to our knowledge on MSC modes of action in disease environments and point towards possible therapeutic regimes for MSC-based tendon therapies for chronic tendon disease.
Publications
-
Wirkungsweisen mesenchymaler Stromazellen in der Sehne Invited presentation, Boehringer Expert Meeting, Wiesbaden, DE
Burk J.
-
Effect of rho/ROCK inhibition on early TGF-β-induced tenogenesis in mesenchymal stromal cells Poster presentation, DVG Tagung Fachgruppe Pferdekrankheiten, online, 2020 Poster prize winner (3rd)
M. Melzer, S. Schubert, B. Huber, S. Roth & J. Burk
-
Mesenchymal stromal cells: What they are and how they act Keynote presentation, DVG Tagung Fachgruppe Pferdekrankheiten, online, 2020
Burk J.
-
Characterization of native tendon scaffolds as in vitro model for chronic tendon disease Short oral presentation, TERMIS-EU, online, 2021
Doll C.U., Niebert S. & Burk J.
-
Matrix remodelling by mesenchymal stromal cells: A mode of action in chronic tendon disease? Oral presentation, DVG Tagung Fachgruppe Physiologie und Biochemie, Giessen, DE, 2021
Doll C.U., Niebert S. & Burk J.
-
Mesenchymal Stromal Cells Adapt to Chronic Tendon Disease Environment with an Initial Reduction in Matrix Remodeling. International Journal of Molecular Sciences, 22(23), 12798.
Doll, Carla U.; Niebert, Sabine & Burk, Janina
-
Rho/ROCK Inhibition Promotes TGF-β3-Induced Tenogenic Differentiation in Mesenchymal Stromal Cells. Stem Cells International, 2021, 1-11.
Melzer, Michaela; Schubert, Susanna; Müller, Simon Franz; Geyer, Joachim; Hagen, Alina; Niebert, Sabine & Burk, Janina
-
TGF-β3-induced tenogenic differentiation is improved by ROCK inhibition Oral presentation, DVG Tagung Fachgruppe Physiologie und Biochemie, Giessen, DE, 2021
Melzer M., Schubert S., Mueller S., Niebert S. & Burk J.
-
Characterization of Equine Chronic Tendon Lesions in Low- and High-Field Magnetic Resonance Imaging. Veterinary Sciences, 9(6), 297.
Doll, Carla Ulrike; von Pueckler, Kerstin; Offhaus, Julia; Berner, Dagmar & Burk, Janina
-
Effects of chronic tendon disease on multipotent mesenchymal stromal cells Poster presentation, DVG Tagung Fachgruppe Pferdekrankheiten, Berlin, DE, 2022
Doll C.U., Niebert S. & Burk J.
-
MSC in Tendon and Joint Disease: The Context-Sensitive Link Between Targets and Therapeutic Mechanisms. Frontiers in Bioengineering and Biotechnology, 10.
Roth, Susanne Pauline; Burk, Janina; Brehm, Walter & Troillet, Antonia
-
Rho/ROCK inhibition promotes TGF-β3-induced tenogenic differentiation Poster presentation, TERMIS-EU, Krakow, PL, 2022
Melzer M., Niebert S. & Burk J.
-
The mesenchymal stromal cell response to (patho)physiological tendon microenvironments Invited presentation, Final Achilles Consortium Conference, Dublin/ hybrid, IR, 2022
Burk J.
-
Influence of Rho/ROCK inhibitor Y-27632 on proliferation of equine mesenchymal stromal cells. Frontiers in Veterinary Science, 10.
Melzer, Michaela; Burk, Janina; Guest, Deborah J. & Dudhia, Jayesh
-
TGF-β3- and rho/ROCK signaling interaction in tenogenic differentiation Poster presentation, ISCT conference, Paris, FR, 2023
Melzer M., Niebert S. & Burk J.
-
Differential Smad2/3 linker phosphorylation is a crosstalk mechanism of Rho/ROCK and canonical TGF-β3 signaling in tenogenic differentiation. Scientific Reports, 14(1).
Melzer, Michaela; Niebert, Sabine; Heimann, Manuela; Ullm, Franziska; Pompe, Tilo; Scheiner-Bobis, Georgios & Burk, Janina
-
Enhancement of ultrafiltration-based depletion of extracellular vesicles from equine platelet lysate Poster presentation, DVG Tagung Fachgruppe Physiologie und Biochemie, Hannover, DE, 2024
Ramesova A., Kau-Strebinger S., Hagen A. & Burk J.
-
Optimized ultrafiltration-based depletion of extracellular vesicles from cell culture supplements increases metabolic activity and viability of equine adipose-derived mesenchymal stem cells Poster presentation, TERMIS World Congress, Seattle, US, 2024
Ramesova A., Kau-Strebinger S., Hagen A. & Burk J.
-
Preconditioning of multipotent mesenchymal stromal cells for treatment of chronic tendon lesions Oral presentation, DVG Tagung Fachgruppe Physiologie und Biochemie, Hannover, DE, 2024
Losacker C., Niebert S., Rummel C. & Burk J.
-
Ultrafiltration-based depletion of extracellular vesicles from equine platelet lysate Poster presentation, Joint Annual Meeting of ASEV and CzeSEV, Vienna, AT, 2024
Ramesova A., Kau-Strebinger S. & Burk J.
-
Modes of action of mesenchymal stromal cells are context-sensitive- How could we proceed to context-adapted therapies? Keynote presentation, TERMIS-EU, Freiburg, DE, 2025
Burk J.
