PMC:6141714 / 45460-49312
Annnotations
{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/6141714","sourcedb":"PMC","sourceid":"6141714","source_url":"https://www.ncbi.nlm.nih.gov/pmc/6141714","text":"Among the mechanisms proposed by the articles selected are included effects in the proliferation and differentiation of immune cells and changes in the expression pattern of growth factors, cytokines, enzymes, prostaglandins and surface receptors. A reduction in the levels of pro-inflammatory cytokines such as TNF-α (74, 75, 76), IFN-γ (75, 76, 77, 80), CCL2 (75), IL-1β (75), IL-2 (76, 77, 80), and IL-17 (75) and an increase in the expression of immunoregulatory cytokines such as IL-4 (74, 75), IL-10 (74, 75, 80), and IL-13 (74) was observed by the majority of the articles selected. In addition, in a study conducted by Wen et al. (80), the expression of the IL-2 receptor was also found to be decreased after the administration of hMSCs. In other studies, the expression of PGE2 (80) and growth factors such as TGF-β (75, 80), VEGF (80), and HGF (80) increased after hMSCs administration. Furthermore, according to Sun et al. (74), hMSCs exert an anti-apoptotic effect in pancreatic islets through the upregulation of the anti-apoptotic proteins XIAP, Bcl-xL, and Bcl-2 and the downregulation of the anti-apoptotic protein caspase 3. As a consequence, some studies reported a decrease in the amount of apoptotic cells when hMSCs were present (74, 80). Finally, a study conducted by Sun et al. (74) demonstrated that the expression of important transcription factors in islet development and differentiation such as Ngn3 and Pax6 was upregulated in pancreatic islets due to the presence of hMSCs. On the other hand, in a study by Zhang and Dou (79), hMSCs were differentiated into islet-like cells and their characteristics were compared to those of fetal pancreatic islets. This study demonstrated that the islet-like cells expressed the pancreatic islet cells-related genes pdx1, ngn3, pax4, neuroD1, nkx2.2, nkx6.1, PCSK1, insulin, glucagon, SST, and PP at levels similar to the expression profile of fetal pancreatic islets. Regarding the effects of hMSCs on the proliferation and differentiation of immune cells, some studies reported a stimulatory effect on the proliferation of CD4+CD25+Foxp3+ Treg (75, 76, 80, 164) cells while other results showed that the presence of hMSCs was found to be associated with the inhibition in the clonal expansion of CD4+IFN-γ+ Th1 (75) and CD4+IL17+ Th17 (75) cells. In addition, a study conducted by Tsai et al. (75) demonstrated that the administration of hMSCs inhibited the proliferation of CD11c+ dendritic cells in non-obese diabetic mice. Finally, a decrease in the infiltration of inflammatory T cells (77) and an increase in the proportion ofCD4+CD25+Foxp3+ Tregs (164) in the pancreatic islets were also observed. Table 2 summarizes the methodology employed and the results obtained in the studies selected in this systematic review regarding the effects of the administration of hMSCs for the treatment of type I diabetes mellitus. It is possible that the secretion of immunomodulatory cytokines and growth factors such as IL-4, IL-10, IL-13, TGF-β, PGE2, VEGF, and HGF by the hMSCs administered plays a crucial role in the inhibition in the development of the insulitis process mediated by CD4+ lymphocytes, as suggested by the inhibition in the clonal expansion of Th1 and Th17 lymphocytes after hMSCs administration. In addition, the stimulatory effect in the proliferation of Treg cells observed after hMSCs administration may exert an inhibitory effect in the proliferation and activation of dendritic cells, in clonal expansion of both T4+ and T8+ lymphocytes and in the infiltration of inflammatory T cells in pancreatic islets. Therefore, the decrease in the levels of pro-inflammatory cytokines such as TNF-α, IFN-γ, CCL2, IL-1β, IL-2, IL-17 observed by some of the studies selected can also be successfully explained by the inhibitory effects that hMSCs exert on inflammatory 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