Potential evidence has shown that the MSCs injection improves pain, joint functions, radiological, and arthroscopic parameters in patients with tendon disorder. Although all included studies had a small sample size, the results clearly presented MSCs dose-dependent responses regarding pain relief. To the best of our knowledge, this is the first clinical meta-analysis describing the pooled effects of MSC therapies on patients with tendon disorder.
Tendon injuries are a common health problem, which are defined as a painful condition occurring around tendons that limits the function of the affected tendons [20]. Tendons are susceptible to repeated use or degenerative condition. Injuries in those structures are rarely regenerated but repaired by scar tissue and fibrosis. This healed tissue presents inferior tensile strength and is prone to further injuries. Preclinical studies support that MSCs have a regenerative potential as those cells are able to differentiate into proper tendon cell and elicit the secretion of cytokines or growth factors [1]. Therefore, MSCs have been regarded as a possible curative treatment option for tendon degeneration.
Implanted stem cells survive in tendon defects, differentiate into the tenogenic cell lineage and secrete their own extracellular matrix to promote tendon healing [4]. Mazzocca et al. showed that bone marrow-derived stem cells differentiate into tendon-like cells [21]. Lee et al. also reported that transplanted human adipose tissue-derived stem cells survived for at least 4 weeks in the rat tendon injury model and released human-specific collagen type I and tenascin-C (TnC) [4]. The expression of TnC is known to increase rapidly during the early period of recovery after tendon injuries, and thus may be used as a marker of tenogenic differentiation [22].
In this meta-analysis, three of the four included studies examined radiological data (magnetic resonance image or ultrasonography) or arthroscopic findings after MSCs injections. These tests could confirm that the injected cells not only relieved pain and improved functions but also regenerated the damaged tissue. Noteworthy, Jo et al conducted the second-look arthroscopic examination at 6 months following MSCs injection as well as MRI follow-up [19]. They reported that the regenerated tendon tissues were identified in all subjects regardless of the location and size of the tear. The defect volumes were decreased in the groups that received mid-dose (5.0 × 107 cells) and high-dose (1.0 × 108 cells). Although this is a macroscopic observation, it may be strong supporting evidence for the regeneration effect of MSCs.
Another important biological mechanism supporting MSC therapy is paracrine effect exerted by these cells [1]. Kinnaird et al. found that growth of endothelial cells and smooth muscle cells may be promoted by the use of medium conditioned with MSCs. This phenomenon might be partly explained by the presence of VEGF and bFGF, which appeared in high levels in the MSCs conditioned medium [23]. The ability of the MSCs to produce a wide range of immunomodulatory and trophic factors has also attracted great attention [24].
There are several concerns regarding the use of MSCs as a treatment option for tendon disorder. Particularly, potential long-term adverse events from the stem cell treatment have been poorly reported in several clinical studies. In the studies included in this meta-analysis, most of the reported adverse events were not related to treatment (Table 2). The treatment-related side effects were regional swelling following allogeneic stem cell injection [9] or engrafted patch-related chronic synovitis [5]. The joint swelling spontaneously subsided, while the patch-related adverse event needed additional surgery. Considering the prognosis of the reported adverse events, these side effects might have come from the localized inflammatory response related to the treatment procedure, or to immunologic response against allogeneic cells.
The safety issues related to the MSCs have already been sufficiently assessed in clinical trials in the field of internal medicine, in which MSCs are injected systemically. The POSEIDON trial [25] was designed to investigate the safety and efficacy of autologous and allogeneic MSC therapies for ischemic cardiomyopathy. The study reported that, following trans-endocardial stem cell injection, the treated group showed improvement in structural and functional outcomes, while no serious adverse events including immunologic reactions occurred. Indeed, long-term adverse events from the stem cell treatment and its possible teratogenicity should be thoroughly considered. One animal study reported undesired cartilage formation after the injection of human MSC in eighty-one rat tendon injury models [26]. While there was no histologic evidence of tumor formation in the study, concerns for possible teratogenicity still remain.
Although there are numerous challenges to be overcome and analyzed, it is undisputable that MSC therapy is a potential treatment option to treat tendon disorder. In particular, about 17% of patients with tendon disorder are known to have no effects after undergoing conservative treatment for more than one year [27]. In some patients, the rate of re-tear is fairly high, even following surgical repair for tendon injuries [19]. Thus, the limitations of the current therapies suggest a need for more fundamental regenerative treatments and MSCs might offer the regenerating opportunity for the tendon by yielding a more robust repair tissue [28]. In order for MSCs injections to be established in tendon disorder, the aforementioned long-term safety issues should be better verified. Furthermore, well-designed clinical trials should be performed in order to support the evidence.
There are several limitations to this meta-analysis. First, we employed a limited number of studies included in our meta-analysis. Moreover, there was only one randomized controlled study available, which has not been published yet. Since MSCs have been applied for the treatment of tendon disorder for only a short period of time, the number of studies that fulfilled our criteria was limited. If a sufficient number of studies had been analyzed, more solid evidence could have been obtained. However, it is meaningful to combine the data through the meta-analysis because there are not enough studies related. Second, included studies were heterogeneous in many ways. Two studies were performed with the administration of bone marrow-derived MSCs, while the other two studies used adipose tissue-derived MSCs. The specific disease entities presented in the studies were also different, namely three studies aimed at treating the rotator cuff disease and one, lateral epicondylitis. However, in order to assure that the mechanisms and efficacy of MSC therapies in tendon disorder are clear and evident, it will be necessary to evaluate whether these treatments are suitable for not just a single specific tendinopathy but for multiple pathologies, which may involve various musculoskeletal structure.