CORR Insights®: Mesenchymal Stem Cells in Synovial Fluid Increase After Meniscus Injury

Abstract

Where Are We Now? In the era of joint preservation surgery and orthobiologic treatments, the meniscus plays a pivotal role in the management of knee disorders. This is in contrast with the early years of orthopaedic surgery when the menisci were considered as “functionless remnants of leg muscle origin” [1], and consequently, entirely excised if injured. This paradigm shift reflected the increased understanding of the meniscus function that has been gained through the years, and is now widely recognized by the orthopaedic community. However, controversy still exists regarding both the indications for surgery and the optimal reparative/regenerative treatments for meniscal tears. Briefly, lesions occurring in the vascular zone of young patients typically are repaired with one of the various suturing techniques currently available, usually with good clinical results. While many orthopaedic surgeons see benefit in restoring meniscus anatomy also in the avascular zone, it is important to recognize that spontaneous healing can occur, and therefore some meniscal lesions can be treated nonoperatively with success. An interesting rationale to these approaches is provided by the work of Matsukura et al., which demonstrates an increase in mesenchymal stem cells (MSCs), possibly derived from the synovium, in the synovial fluid after meniscus injury. This study follows a notable series of experimental studies on synovial MSCs by these authors, and is particularly valuable since it has been performed in human patients with a healthy control group. Where Do We Need To Go? In the context of meniscus regeneration, the current work by Matsukura et al. sheds light on a possible mechanism of endogenous meniscus healing that can be targeted by regenerative therapies. Particularly, the increase of synovial MSCs in the synovial fluid after meniscus injury is consistent with previous reports which described the same phenomenon after ACL injury, osteoarthritis, and rheumatoid arthritis, probably reflecting a common response to joint damage. This hypothesis is valuable, and makes the synovial MSCs an ideal and more “physiological” cell type compared to adipose tissue-derived MSCs and bone marrow-derived MSCs. This hypothesis is also ideal for developing regenerative strategies for the meniscus and articular cartilage. Moriguchi and colleagues [5] recently described a promising approach consisting of implanted scaffold-free synovial MSC aggregates in a meniscal defect. This approach followed other successful synovial MSC-based experimental animal studies and prompted for controlled clinical trials. Interestingly, in the current study, cells isolated from the synovial fluid were CD34-negative. Previous works described CD34-positive cells located in the superficial layers of the meniscus, hypothesizing a contribution of these cells to meniscus homeostasis [3]. However, there is no inconsistency between these studies since the CD34-positive population resided in the meniscal tissue, while the CD34-negative was detected in the synovial fluid. Most likely, these two cell populations reflect two different endogenous responses that are involved in the maintenance of joint homeostasis. Future work should be directed towards the development of regenerative strategies based on, and possibly combining, these endogenous regenerative mechanisms. How Do We Get There? The role of MSCs in maintaining tissue homeostasis has been shown to be much more complex than just representing a reservoir capable to differentiate into specific lineages [2]. A deeper insight into the homing mechanisms and native functions of these cells is desirable in order to develop successful regenerative strategies. As reported in the current work by Matsukura et al., future studies must emphasize the definition of strategies aimed at increasing the endogenous number of MSCs in the synovial fluid by enhancing their recruitment from the synovium. An alternative strategy is to deliver a therapeutic number of in vitro expanded MSCs, whose engraftment at tissue damage sites should be more clearly defined. An intriguing and timely vision of MSCs has been recently provided by Caplan [2] with a definition of MSCs as “Medicinal Signalling Cells,” capable of releasing a cocktail of trophic and immunomodulatory factors upon tissue damage. This dual activity meets perfectly the requirements of joint disorders, as they involve both tissue degeneration and local inflammation, and are consistent with the current work. More novel treatments like platelet rich plasma aim to establish a regenerative microenvironment, while the objective of pharmacological regulation of inflammatory signals is to prevent joint degeneration after injury [4]. However, more experimental studies, both at the bench and at the bedside, are needed to better define the activity of MSCs on joint tissues in the various clinical scenarios. If MSCs work as “injury drugstores” [2], their secretome alone can be considered as an equivalent therapeutic alternative to MSCs themselves. However, this possible alternative should be characterized in detail before any regenerative strategy can be developed. A fascinating, clinically-compliant application can be envisioned as an off-the-shelf, lyophilized, standardized MSC secretome to be used to reestablish joint homeostasis.