Soluble Factors–Mediated Immunomodulatory Effects of Canine Adipose Tissue–Derived Mesenchymal Stem Cells

Abstract

Adipose tissue-derived mesenchymal stem cells (AD-MSCs), which can differentiate into several lineages, have immunomodulatory properties similar to those of bone marrow-derived MSCs. However, the specific mechanism by which the immunomodulatory effect of MSCs occurs is not clear. In this study, we isolated canine AD-MSCs (cAD-MSCs) and induced their development into adipocyte, osteocyte, and neuron-like cells. We then investigated their phenotype and cytokine expression to determine whether they were able to exert an immunomodulatory effect and what the underlying mechanisms of this effect were. cAD-MSCs expressed CD44, CD90, and MHC class I and were also partially positive for the expression of CD34; however, they did not express CD14 and CD45. In addition, they expressed the mRNA of transforming growth factor beta (TGF-beta), IL-6, IL-8, CCL2, CCL5, vascular endothelial growth factor, hepatocyte growth factor (HGF), tissue inhibitor metalloproteinase-1/2, and cyclooxygenase-2 but not that of IL-10. Further, leukocyte proliferation induced by mitogens was suppressed when they were cocultured with irradiated cAD-MSCs, as well as with culture supernatants of cAD-MSCs alone. Moreover, TNF-alpha production significantly decreased, whereas TGF-beta, IL-6, and interferon-gamma production significantly increased in cAD-MSCs that were cocultured with leukocytes. Finally, immonomodulatory factors of MSCs, such as TGF-beta, HGF, prostaglandin E2 (PGE2), and indoleamine 2, 3 dioxygenase (IDO), increased significantly in cAD-MSCs that were cocultured with leukocytes; however, the production of PGE2 and IDO showed different kinetics, and leukocyte proliferation was effectively restored by PGE2 and IDO inhibitors. Taken together, these results indicate that the immunomodulatory effects of cAD-MSCs are associated with soluble factors (TGF-beta, HGF, PGE2, and IDO). Therefore, it is suggested that cAD-MSCs have a potential therapeutic use in the treatment of immune-mediated disease.

Allogeneic and Xenogeneic Transplantation of Adipose-Derived Stem Cells in Immunocompetent Recipients Without Immunosuppressants

“…While it remains controversial whether cell-cell contact is required for ADSC's immunosuppressive effects [29][30][31], several studies have demonstrated the importance of soluble factors, among which the most frequently identified being prostaglandin E2 (PGE2) [31,[38][39][40][41]. Specifically, inhibition of PGE2 by indomethacine effectively abolished ADSC's immunosuppressive effects.…”

“…Specifically, inhibition of PGE2 by indomethacine effectively abolished ADSC's immunosuppressive effects. In addition, specific inhibition of indoleamine 2, 3 dioxygenase [39] or neutralization of leukemia inhibitory factor [42] has also been shown to abolish ADSC's immunosuppressive effects. Further, ADSC's immunosuppressive activity appears to be mediated through an interleukin-6 (IL-6)-dependent inhibition of dendritic cell differentiation and downregulation of MHC-II, CD40, and CD86 on mature dendritic cells [38].…”

Mechanisms of Immune Suppression Utilized by Canine Adipose and Bone Marrow-Derived Mesenchymal Stem Cells

“…Previously, it was reported that various different sources of canine MSC modulate immune responses in vitro [12,[50][51][52][53][54]. In the study by Lee et al, which utilized canine bone marrow MSC, PGE2 was identified as the primary MSC factor that suppressed T cell proliferation [12,54].…”

“…In the study by Lee et al, which utilized canine bone marrow MSC, PGE2 was identified as the primary MSC factor that suppressed T cell proliferation [12,54]. Kang et al identified PGE2 as an important T cell suppressive factor secreted by canine Ad-MSC, and also found that IDO production played an important role in T cell suppression [50]. Thus, the cyclooxygenase pathway appears to be a major pathway in canine MSC suppression, though relatively few other pathways have been investigated.…”

14S,21R-dihydroxy-docosahexaenoic Acid Treatment Enhances Mesenchymal Stem Cell Amelioration of Renal Ischemia/Reperfusion Injury

“…The renal reparative manifestation of MSCs involves their anti-inflammatory functions [9,15]. Studies show that MSC can suppress macrophage trans-differentiation to inflammatory phenotypes [22], inhibit DC maturation and migration, and halt inflammatory cytokine generation from leukocytes [22][23][24]. HGF is immunoregulatory and reduces inflammatory cytokine generation from DCs [25].…”