Immunomodulatory plasticity of mesenchymal stem cells: a potential key to successful solid organ transplantation

Abstract

Organ transplantation remains to be a treatment of choice for patients suffering from irreversible organ failure. Immunosuppressive (IS) drugs employed to maintain the allograft have shown excellent short-term graft survival, but, their long-term use could contribute to immunological and non-immunological risk factors, resulting in graft dysfunctionalities. Upcoming IS regimes have highlighted the use of cell-based therapies, which can eliminate the risk of drug-borne toxicities while maintaining efficacy of the treatment. Mesenchymal stem cells (MSCs) have been considered as an invaluable cell type, owing to their unique immunomodulatory properties, which makes them desirable for application in transplant settings, where hyper-activation of the immune system is evident. The immunoregulatory potential of MSCs holds true for preclinical studies while achieving it in clinical studies continues to be a challenge. Understanding the biological factors responsible for subdued responses of MSCs in vivo would allow uninhibited use of this therapy for countless conditions. In this review, we summarize the variations in the preclinical and clinical studies utilizing MSCs, discuss the factors which might be responsible for variability in outcome and propose the advancements likely to occur in future for using this as a “boutique/personalised therapy” for patient care.

Alternative Immune-Mediated-Based Methods in the Aplastic Anemia Treatment

“…Therefore, suppress T cell proliferation and activation and regulate the differentiation of Th cells and act on the humoral response by inhibiting of B cell activation and antibody production [60]. MSCs may also reduce pro-inflammatory cytokines proliferation, such TNF-α, which has an important role of the pathogenesis of autoimmune diseases and chronic inflammation (Figure 1) [14,16,61].…”

“…The mechanism of MSCs may decrease secretion of proinflammatory cytokines such as transforming growth factor (TGF), IFN-γ TNF-α, interleukin (IL)-17 and increase secretion of many soluble mediators, including anti-inflammatory cytokines stimulation that inhibit antigen-presenting cells (APCs) functions, which are capable to decrease proliferation of dendritic cells (DCs) and regulate macrophage activity by polarizing proinflammatory phenotype (M1) to anti-inflammatory phenotype (M2) [14,15]. Therefore, the decrease of B cells proliferation and antibodies production and adjustment of T cells activities as well as inhibit the proliferation of cytotoxic T cells and stimulate Treg activity [16].…”

Current Status and Future Prospects of Genome-Scale Metabolic Modeling to Optimize the Use of Mesenchymal Stem Cells in Regenerative Medicine

“…The immunomodulatory response of hMSCs is activated by inflammatory cytokines (e.g., IFN-γ, IL-1α, IL-1β, and TNFα) that are secreted by T cells and other antigen-presenting cells (Ren et al, 2008;Németh et al, 2009). In response to their activation, MSCs secrete soluble immune factors capable of affecting both the innate and adaptive immune systems by mediating the subsequent regulatory responses of target cells (Figure 4; Kaundal et al, 2018;Wang et al, 2018). The immunoregulatory effects mediated in each instance are dependent on one or more of these secreted factors.…”

“…Phase 1 expression dependent upon: TGF-β1,2 and 3 Phase 2 expression dependent upon: BMP2 IGF-I TGF-β1 Wnt/β-catenin (pro) PTHrp (anti) Mackay et al, 1998;Antonitsis et al, 2008;Li and Dong, 2016 Hepatocytes suppresses proliferation and activity of NK and T cells by its metabolic activity -converting tryptophan into kynurenine. In humans, IDO synthesis has been reported as a response of MSCs to pro-inflammatory cytokine production that suppresses the inflammatory response (Bernardo and Fibbe, 2013;Mbongue et al, 2015;Gao et al, 2016;Kaundal et al, 2018;Wang et al, 2018). Another reported soluble factor with immunoregulatory effects is the unstable oxidative molecule nitric oxide (NO), which is generated by NO synthase.…”

“…Increased secretion of NO results in modulation of both the proliferation and function of T cells. At very high concentrations, it can lead to the apoptosis of immune cells (Bernardo and Fibbe, 2013;Gao et al, 2016;Kaundal et al, 2018;Wang et al, 2018). A list of the known soluble paracrine factors secreted by hMSCs that are involved in immunoregulation is provided in Table 2, along with their related effects.…”