Potential evidence has shown that the MSCs injection improves pain, joint functions, radiological, and arthroscopic parameters in patients with tendon disorders. 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 disorders.
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 targeted tissue and replace injured resident cells [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 differentiated 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 thereby 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.
Benefits of MSCs in treating tendon disorder are not confined to their differentiation potential only. Another important biological mechanism supporting MSC therapy is that these cells release diverse cytokines, chemokines, and growth factors [1]. Several studies found that these secreted factors may stimulate their proliferation, allowing the promotion of tissue regeneration. The benefits of MSC-conditioned media proven by in vitro studies also encourages the paracrine effects of MSCs. 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]. They can recruit macrophages and endothelial cells into the injured site, allowing enhancement of the healing process.
The ability of the MSCs to produce a wide range of immunomodulatory factors has also attracted great attention [24]. Both in vitro and in vivo studies have elicited that MSCs can downregulate the excessive response of numerous immune cells, such as T cells, B cells, dendritic cells, macrophage, and natural killer cells. MSCs can also induce regulatory T cells, thereby expand and maintain long-lasting immune modulating activity, which is similar to the role of catalysts. Considering that the inflammation-derived tissue damage is one of the key process in most tendon disorders, immunomodulation induced by injected MSCs can also play an important role in promoting treating tendon diseases, in addition to their differentiation potential and paracrine effects [25].
There are several concerns regarding the use of MSCs as a treatment option for tendon disorders. 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 mild joint effusion and regional swelling following allogeneic stem cell injection [8] or engrafted patch-related foreign body reaction [11]. 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 itself, or immunologic response against allogeneic cells, but are less likely to have arisen from the MSC itself.
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 [26] 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 [27]. 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 clear that MSC therapy can be a promising treatment option to treat tendon disorders. In particular, about 17% of patients with tendon disorders are known to have no effects after undergoing conservative treatment for more than one year [28]. 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 repaired tissue [29]. In order for MSCs injections to be established in tendon disorders, 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. 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, there was heterogeneity in outcome variables among the included trials. Three studies [10, 11, 19] used the Constant score for functional assessment, while one study used the modified Mayo elbow performance index [8], and two studies added the UCLA score [10], and the Shoulder Pain and Disability Index [19], respectively. Although we used the combined pooled effect sizes to deal with this issue, the effect sizes should be cautiously interpreted from the clinical point of view. Furthermore, the heterogeneities of the MSCs origin and target tissue were also limitations of this analysis. Two studies were performed with the administration of bone marrow-derived MSCs [10, 11], while the other two studies used adipose tissue-derived MSCs [8, 19]. The specific tendon disorders 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 other tendon disorders, which may involve various musculoskeletal structure.