<p>Human Adipose Tissue-Derived Mesenchymal Stem Cells in Parkinson’s Disease: Inhibition of T Helper 17 Cell Differentiation and Regulation of Immune Balance Towards a Regulatory T Cell Phenotype</p>

Abstract

Background: Parkinson's disease (PD) is a neurodegenerative disorder displaying a typical neuroinflammation pathology that may result from an imbalance between regulatory T cells (Treg) and T helper 17 (Th17) cells. Human adipose tissue-derived mesenchymal stem cells (Ad-MSCs) exert immunomodulatory effects by inhibiting effector T cell responses and have been used to treat diverse immune disorders. We aimed to investigate the modulating effect of human Ad-MSCs on peripheral blood mononuclear cells (PBMCs) of patients with PD, focusing on differentiation into Th17 and Treg cells. Methods: We isolated human peripheral blood CD4 + T cells and co-cultured them with Ad-MSCs at a ratio of 4:1 under either Th17 or Treg cell polarizing conditions for 4 days to detect the proportions of IL-17-producing CD4 + T (Th17) and CD4 + CD25 + Foxp3 + regulatory T (Treg) cells by flow cytometry. We also determined the mRNA expression levels of the retinoid-related orphan nuclear receptor (RORγt) transcription factor and those of interleukin-6 receptor (IL-6R), interleukin-23 receptor (IL-23R), leukemia inhibitory factor (LIF), and LIF receptor (LIFR) by quantitative reverse transcription PCR. We detected levels of cytokines in the supernatant (including LIF, IL-6, IL-23, IL-10, and TGF-β) using ELISA. Results: Our results showed that Ad-MSCs specifically inhibited the differentiation of PBMCs of patients with PD into IL-17-producing CD4 + T cells by decreasing expressions of IL-6R, IL-23R, and RORγt (the key transcription factor for Th17 cells). Moreover, Ad-MSCs induced a functional CD4 + CD25 + Foxp3 + T regulatory cell phenotype as evidenced by the secretion of IL-10. The levels of IL-6, IL-23, and TGF-β remained constant after coculture under either the Th17 or the Treg cell polarizing condition. In addition, levels of LIF protein and its receptor mRNA were significantly increased under both polarizing conditions. Conclusion: The present in vitro study found that Ad-MSCs from healthy participants were able to correct the imbalance between Th17 and Treg found in PBMCs of PD patients, which were correlated with an increase in LIF secretion and a decrease in expression of IL-6R, IL-23R, and RORγt. These findings should be confirmed by in vivo experiments.

Human Adipose Tissue-Derived Mesenchymal Stromal Cells Inhibit CD4+ T Cell Proliferation and Induce Regulatory T Cells as Well as CD127 Expression on CD4+CD25+ T Cells

“…In fact, MSC have been reported to influence Th subset differentiation [ 11 ]. For instance, MSC were documented to promote the induction of anti-inflammatory and regulatory Th subsets in vitro [ 41 , 42 , 43 ] while inhibiting pro-inflammatory Th1 cells [ 1 ]. Measurement of Th cytokines in the conditioned media of cocultures allows the detection of a possible shift in the Th1/Th2 subpopulations [ 11 , 13 ].…”

Human Amniotic Fluid Stem Cells Ameliorate Thioglycollate-Induced Peritonitis by Increasing Tregs in Mice

“…The proposed mechanisms include the secretion of soluble mediators by MSCs, cell-to-cell contact, and the regulation of antigen-presenting cells [ 6 , 42 , 43 ]. In vivo and in vitro studies have shown that MSC therapy increases the number of Tregs in the host [ 44 , 45 , 46 ]. Unfortunately, there is limited evidence on the effect of hAFSCs on Tregs.…”

Modulatory Impact of Adipose-Derived Mesenchymal Stem Cells of Ankylosing Spondylitis Patients on T Helper Cell Differentiation

“…Dysregulated expression of IL-17A and IL-17F is associated with AS and dual inhibition of these cytokines gives promising results [ 30 ]. Mesenchymal stem cells of various origins are known to support Treg cells and normalize the function of other Th subsets [ 14 , 25 , 31 , 32 ]. However, it is unknown whether AS/ASCs possess such capabilities.…”

“…Data concerning the effects of MSCs on TGFβ and IL-10 production are inconsistent. Neither MSCs nor MSCs conditioned medium were found to change TGFβ in target cells [ 31 , 55 ], but modulation of this cytokine in T cells was demonstrated [ 49 ]. As for IL-10, unchanged level [ 43 ], increased [ 46 , 47 , 48 , 50 , 55 ], or reduced [ 44 , 49 ] production of this cytokine in MSCs-PBMCs/T cells co-cultures were found.…”