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

Yong Bi; Xiaobin Lin; Huazheng Liang; Dehao Yang; Xiaowei Zhang; Jianming Ke; Jingjing Xiao; Zhilin Chen; Weian Chen; Xu Zhang; Shaoshi Wang; Chun-Feng Liu

doi:10.2147/CIA.S259762

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

Clin Interv Aging. 2020 Aug 13:15:1383-1391. doi: 10.2147/CIA.S259762. eCollection 2020.

Authors

Yong Bi^{1

2

3}, Xiaobin Lin⁴, Huazheng Liang², Dehao Yang⁴, Xiaowei Zhang⁴, Jianming Ke⁴, Jingjing Xiao², Zhilin Chen², Weian Chen⁴, Xu Zhang⁴, Shaoshi Wang², Chun-Feng Liu^{1

3}

Affiliations

¹ Department of Neurology and Suzhou Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, People's Republic of China.
² Department of Neurology, Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai, People's Republic of China.
³ Institute of Neuroscience, Soochow University, Suzhou, People's Republic of China.
⁴ Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China.

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 co-culture 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.

Keywords: CD4+T cell; Parkinson’s disease; T helper 17 cell; T regulatory cell; adipose-derived mesenchymal stem cells; leukemia inhibitory factor; peripheral blood mononuclear cells.

MeSH terms

Cell Differentiation / immunology*
Cells, Cultured
Humans
Interleukin-10 / metabolism
Interleukin-2 Receptor alpha Subunit / metabolism
Leukemia Inhibitory Factor / metabolism*
Leukocytes, Mononuclear / immunology
Mesenchymal Stem Cells
Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
Parkinson Disease / immunology*
Phenotype
Signal Transduction
T-Lymphocytes, Regulatory* / immunology
T-Lymphocytes, Regulatory* / metabolism
Th17 Cells* / immunology
Th17 Cells* / metabolism

Substances

IL10 protein, human
IL2RA protein, human
Interleukin-2 Receptor alpha Subunit
LIF protein, human
Leukemia Inhibitory Factor
Nuclear Receptor Subfamily 1, Group F, Member 3
Interleukin-10

Grants and funding

This study was supported by a grant from the Commission of Health and Family Planning, Hongkou District, Shanghai, awarded to Dr. Yong Bi (No. 1701-02), a grant from Zhejiang Natural Science Foundation (LY15H090019), a grant from Wenzhou Scientific Planning (Y20140684), and a grant from the State Key Open Projects of Soochow University (KJS1726).