This meta-analysis of 13 studies and 20 treatment arms provided evidence of therapeutic benefit of MSCs on preclinical Sjögren's syndrome models. To our knowledge, this is the first meta-analysis providing a comprehensive summary of the MSCs effect in SS, involving different donor species, tissues and treatment protocols. Furthermore, this work makes it possible to explain potential mechanisms of therapy by pooling large data samples. Our meta-analysis may provide important clues for the future clinical translation of MSCs in the treatment of patients with Sjögren's syndrome.
Overall, MSCs therapy shows definite improvements in histological score, SFR and lacrimal gland secretion function. Specific effect size varies depending on the MSCs donor species, tissues of origins, transplant types, administration routes or injection frequency. The three main outcome indicators that had similar results suggest that multiple injections are significantly better than single injection, and the IV route is superior to IP. Considering tissue origins, AD-MSCs have shown more favorable histology scores and lacrimal gland function, compared to the UC derived MSCs, while BM-MSCs provided weaker effects than these two. Of note, in all studies that are included in the analysis, AD-MSCs are from rabbits, UC-MSCs came from human and BM-MSCs are from murine tissue. In order to distinguish whether tissue source or donor species play a dominate role in the observed differences, it would be prudent to explore the optimal combination of derived species and tissues. In addition, other data have drawn different conclusions in other diseases: UC-MSCs and G-MSCs (gingival tissue-derived MSCs) were more suitable sources for the RA treatment than other options [12, 45, 46]; IP injection of AD-MSC achieved more effective outcome on EAE than IV administration . Therefore, the best MSCs treatment strategy may vary in different autoimmune diseases.
Notably, although derived from homologous organ tissues, local injection of SHEDs did not show significant effects compared with other tissue-derived MSCs or by other administration routes. Of the administration routes. This observation may imply that although tissue homology and local injection may enhance the targeting of MSCs, it could not achieve better regulation of systemic immunity. Most superior performances of targeted therapies are preferentially reported in tissue regeneration studies [48, 49].
We summarized the comprehensive analysis of autoantibodies, immune cells and cytokines. Although only 5 of the 13 studies were included for this portion of the analysis, the results of autoantibodies showed a consistent decrease with active treatments. Indeed, targeting autoantibody has been associated with favorable outcome in the treatment of autoimmune diseases [50, 51]. In terms of immune cells, Th17 reduction accompanied by Treg increase appeared in peripheral immune organs, but not uniformly in salivary or lacrimal glands. In contrast, inflammatory cytokines analysis presented significant difference in the local milieu (increased level of IL-10 and decreased trend of IL-6) after MSCs injection, while heterogeneity in serum was high. Our meta-analysis indicates that MSCs might control the local inflammatory response in lesions by regulating immune cell differentiation in peripheral immune organs but not by acting directly in the exocrine glands. Several reports have mentioned that MSCs will preferentially reach the lungs, liver, and spleen after infusion in vivo[52, 53], whereas some researchers illustrated that viable MSCs could not pass through the lung. There is no consistent report of MSCs targeting glandular lesions in our included literature [29, 30], which further suggests that the mechanism involves indirect regulation of MSCs in exocrine glands. Overall, biodistribution of different MSCs in autoimmune disease models should be taken into account in the future, which may explain the similarities and differences in therapeutic mechanisms.
TNF-α plays an important inflammatory role in SS pathogenic process [55, 56]. TNF-α neutralizing antibodies induce a remission of the SS clinical phenotype in animal models, but TNF-α inhibitors have not been shown to be effective in human studies [58, 59]. It is likely that TNF-α exerts its differential effects based on the specific type of TNF-α receptor engaged [44, 60, 61]. In addition, TNF-α also promotes the functional capacity of MSCs . In our meta-analysis, MSCs treatment was associated with reduced TNF-α production in both glands and in serum. Considering that MSCs may regulate inflammatory and immunity more upstream, they would be a better choice for clinical application. Different from Graft-versus-Host Disease (GVHD) and rheumatoid arthritis (RA), our analysis did not suggest robust and consistent trend for changes in levels of TGFβ. As TGFβ abnormalities are clearly recognized as involved in the pathogenesis of SS, the results were more likely due to the heterogeneous effect of different treatment strategies [65-67].
Sjögren's syndrome is a relatively common autoimmune disease that mainly affects the exocrine glands. It is often secondary to another autoimmune diseases, such as RA or systemic lupus erythematosus (SLE); which results in significant heterogeneity. Although traditional and biological DMARDs are used empirically for Sjogren's symptoms, their efficacy is limited in modulating the systemic process. Over the past few decades, cell therapy has emerged as a promising therapeutic strategy for treatment of autoimmune and other diseases. Optimization of the parameters in this therapeutic approach, such as the origin of MSCs, easiness of cell preparation, cost, functional stability, treatment protocol, as well as the disease clinical stage, merits further efforts to explore clinical applications in the future [69-71].
Quality assessment of studies was performed in this meta-analysis to investigate their credibility. Even though most of the studies were regarded as good quality with low or unclear risks of bias, few of them attempted to elaborate their strategies to prevent the potential performance bias or detection bias. Therefore, the results from this meta-analysis should be interpreted with caution. Moreover, the MSCs-based Sjögren's syndrome treatment would benefit from design modifications in the future. In addition, the number of included trials was small, with several types of MSCs, different injection methods and unequal therapeutic doses involved. Although, we performed subgroup and sensitivity analyses, the above factors may weaken the reliability of the observations. Finally, there was a potential for the incomplete reports of identified research studies, which could have introduced publication bias.