Inhibitory Effects of iPSC-MSCs and Their Extracellular Vesicles on the Onset of Sialadenitis in a Mouse Model of Sjögren's Syndrome.

Bo Hai,Ryang Hwa Lee,Qingguo Zhao,Fei Liu,Taeko Shigemoto-Kuroda

doi:10.1155/2018/2092315

Bo Hai, Ryang Hwa Lee + Show 3 more

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https://doi.org/10.1155/2018/2092315

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Abstract

No effective treatment for Sjögren's syndrome (SS), a chronic autoimmune disease affecting mainly salivary and lacrimal glands, is available now. Systemic infusion of allogeneic mesenchymal stem cells (MSCs) isolated from tissues such as bone marrow (BM) alleviated SS in mouse models and a small clinical trial, but further research and application of this MSC therapy were hindered by limited expandability, significant donor variations, and safety concerns of tissue-derived MSCs. To circumvent these issues, we derived MSCs from human iPSCs using an optimized protocol that can be easily scaled up to produce a huge amount of standardized MSCs. Our iPSC-MSCs inhibited the onset of lymphocyte infiltration into salivary glands in the NOD mouse model of SS in the same way as BM-MSCs. Extracellular vesicles (EVs) carry bioactive molecules in the same way as their originating cells and are more stable and considered much safer than cells for therapies. We found that EVs derived from BM-MSCs and iPSC-MSCs suppressed activation of immune cells and expression of proinflammation factors essential for SS progression in vitro and that infusion of iPSC-MSC EVs at the predisease stage decreased the lymphocyte infiltration in salivary glands and serum autoantibody levels in the same way as infusion of BM-MSCs and iPSC-MSCs. These data suggested that iPSC-MSC EVs have the potential to prevent the progression of SS before the onset of sialadenitis.

Highlights

Sjögren’s syndrome (SS) is a chronic inflammatory autoimmune disease affecting mainly salivary glands (SGs) and lacrimal glands with an incidence of about 1% in the general population and up to 3% in people above the age of 50, with women accounting for more than 90% of diagnosed cases [1]
We reported here for the first time that induced pluripotent stem cells (iPSCs)-mesenchymal stem/stromal cells (MSCs) prevented SS progression before the onset of sialadenitis in the same way as bone marrow (BM)-MSCs. iPSC-MSC Extracellular vesicles (EVs) suppressed the activation of immune cells and expression of proinflammation factors essential for SS progression in vitro in the same way as BM-MSC EVs, and infusion of iPSCMSC EVs at the predisease stage decreased the lymphocyte infiltration in SGs and serum levels of autoantibodies in the same way as infusion of MSCs
To compare the effects of these two types of MSCs on the composition and activation of lymphocytes infiltrated into SMGs, we examined the expression of various lymphocyte markers including B cell marker CD19; B/plasma cell markers CD79a, CD79b, and Ighg3; pan-T cell marker CD3e; helper T cell marker CD4; Treg marker Foxp3; T follicular helper (Tfh) marker inducible T cell costimulator (Icos) and its ligand Icosl; T helper 17 (Th17) marker IL17; panAPC marker CD11c; follicular dendritic cell (FDC) marker CD21; and activated antigenpresenting cells (APCs) marker CD40, as well as those of immune inhibitory factors including TGFβ1-3 and IL10 by qRT-PCR

Summary

Introduction

Sjögren’s syndrome (SS) is a chronic inflammatory autoimmune disease affecting mainly salivary glands (SGs) and lacrimal glands with an incidence of about 1% in the general population and up to 3% in people above the age of 50, with women accounting for more than 90% of diagnosed cases [1]. In the NOD mouse model of SS, IV infusion of soluble intracellular contents from allogeneic bone marrow-derived cells including MSCs (BM soup) before the onset of SS prevented sialadenitis and xerostomia in the same way as IV infusion of BM-MSCs [10], suggesting that cell-free products of MSCs may prevent SS progression in the same way as live MSCs. Recent studies suggest that extracellular vesicles (EVs) derived from MSCs may resolve current problems with cell-based MSC therapies. Our recent study indicated that IV-injected human BM-MSC EVs effectively prevent the onset of type 1 diabetes (T1D) and experimental autoimmune uveoretinitis (EAU) in mouse models likely by inhibiting the activation of antigenpresenting cells (APCs) and development of T helper 1 (Th1) and Th17 cells [16]. These findings suggested that iPSC-MSCs and EVs derived from them are promising to circumvent limitations of tissue-derived MSCs for preventing SS onset

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Conflicts of Interest