Focal chondral or osteochondral lesions can be painful and disabling because they have insufficient intrinsic repair potential, and constitute one of the major extrinsic risk factors for osteoarthritis (OA). Articular cartilage lesions greater than 5 mm2 do not heal spontaneously and if left untreated they lead, after a long asymptomatic interval, to full clinical OA. The major challenges in regenerative medicine for cartilage repair are restoration of a biomechanically competent extracellular matrix (ECM) and intimate integration of this newly synthesized matrix within the resident tissue. To address this specific challenge, autologous chondrocyte implantation (ACI) was developed and has paved the way for novel cell-based therapy and biomaterial-assisted cartilage engineering. However, long-term quality of the regenerated ECM is often compromised, in particular when proceeded to OA. Fragile neocartilage constructs produced by implanted or injected mesenchymal stem cells (MSCs) or chondrocytes may undergo rapid degradation when situated in inflamed or diseased joints. Therefore the underlying pathology must be brought effectively under control, because otherwise any cell-based or otherwise regenerative treatment strategy of OA is unlikely to be successful long-term. This knowledge implies that cartilage repair lacks a one-for-all therapy and research for long-term regeneration options is ongoing yet (Grässel & Lorenz, 2014).
In my talk, I would like to present the advantages of cell-free versus cell-based repair strategies in cartilage pathology from the research perspective focussing on mesenchymal stem cells (MSC) or adipose derived stem cells (ASC) and their secretome. In the past years, the musculoskeletal research field has seen an increased interest in the MSC secretome and, in particular in extracellular vesicles (EVs), due to their prognostic and therapeutic potential. EV secretion has been shown for virtually any cell type. EVs carry proteins, lipids and nucleic acids and thus are critically involved in cell-to-cell communication. EVs participate in autocrine, paracrine and systemic signalling processes and have accordingly been detected in most body fluids. There is increasing evidence for a critical role of EVs in both progression of musculoskeletal diseases as well as tissue regeneration. Therapeutic application of MSC-EVs revealed overall positive effects in various situations of musculoskeletal trauma, including repair of chondral and osteochondral lesions. EV therapy after joint trauma and concurrent cartilage injury, the main risk factor for the development of post-traumatic osteoarthritis (PTOA), can be therefore of critical importance to avoid pathogenesis of OA. There is increasing consent that MSC/ASC-EVs could protect cartilage and bone from degradation during OA pathogenesis by increasing the expression of chondrogenic markers. In that line, our group and others demonstrated that pre-treatment of MSCs with different factors, as TGFß or anti-inflammatory compounds as curcumin among others, can improve the effectiveness of EVs in cartilage regeneration. Influencing the composition of EV cargo through ex vivo pre-treatment and/or pre-activation of MSCs/ASCs with different factors thus constitute another interesting therapeutic approach to maximize pro-regenerative potential of EVs. Overall, stem cell secretomes and EVs applied intra-articularly for the treatment of cartilage pathology in knee OA had pleiotropic and mostly positive effects. Pre-clinical in vivo studies in rat, mouse and rabbit OA models resulted in positive effects on the joints and supported the effectiveness of EV intra-articular injections as a minimally invasive therapy (Grässel & Muschter, 2020).
Taken together, intra-articular EV injection might be a promising approach to prevent the development of PTOA and to improve structural damage of joint tissues in chronic OA. Moreover, EVs might enable hyaline cartilage restoration without fibrous tissue formation; thus, facilitating one of the most challenging issues in cartilage regeneration, which was not achieved so far using cell-based therapies. Considering the poor intrinsic regenerative capacity of adult human articular cartilage, it might be reasonable to apply EVs directly after a traumatic incidence to achieve an early harm reduction and reduce the risk of irreversible cartilage damage and structural tissue alteration.
However, many details of the EV biology is to be revealed yet and the biggest hurdle in EV research so far are inconsistent preparation and characterization methods. In addition, it is not fully understood how the parental cell produces EVs and incorporates the potential therapeutic effective molecules into the EVs. A detailed understanding of how the recipient cell internalizes EVs is critical to increase therapeutic effects of EVs and to develop highly efficient EVs for drug delivery and even gene therapy. This will be a requirement for the translation of EV-based procedures to clinical application.
Nevertheless, there is a big need for new therapeutic strategies in musculoskeletal diseases as incidences are increasing with an ever-growing aging population and cell-based therapies have shown limited success so far. In this light, EV-based therapies, which can circumvent many of the disadvantages related to cell therapies have a tremendous potential. EV-based therapies may also benefit from EV-engineering approaches that aim at modulating either the cargo or the targeting of EVs in order to improve their therapeutic efficiency. This includes the use of EVs as drug delivery vehicle and particularly for the delivery of lipophilic small molecules. EVs can overcome also problems arising from low solubility or bioavailability of molecules, as we and others could demonstrate for the anti-inflammatory agent curcumin. However, in common for all those features of EVs is that we still lack the full insight in underlying mechanisms and functional active components, which are responsible for the observed effects of EVs (Herrmann et al., 2021).
Grässel S. & Lorenz J.: Tissue-Engineering Strategies to Repair Chondral and Osteochondral Tissue in Osteoarthritis: Use of Mesenchymal Stem Cells. 2014, Curr. Rheumatol. Rep., Review, Doi: 10.1007/s11926-014-0452-5
Grässel S. & Muschter D.: Recent advances in the treatment of osteoarthritis. 2020, F1000Research, Review, Doi: 10.12688/f1000research.22115.1
Herrmann M., Diederichs S., Melnik S., Riegger J., Trivanovic D., Li S., Jenei-Lanzl Z., Brenner RE., Huber-Lang M., Zaucke F., Schildberg FA., Grässel S.: Extracellular vesicles in musculoskeletal pathologies and regeneration. 2021, Frontiers in Bioengineering & Biotechnology, Review, Doi: 10.3389/fbioe.2020.624096
This work was supported by a grant from the DFG (GR1301/19-1/2) and a grant from the DGOOC for establishing a German stem cell net work.