Abstract
The unique immunomodulation and immunosuppressive potential of Wharton’s jelly-derived mesenchymal stromal cells (WJ-MSCs) make them a promising therapeutic approach for autoimmune diseases including type 1 diabetes (T1D). The immunomodulatory effect of MSCs is exerted either by cell-cell contact or by secretome secretion. Cell-cell contact is a critical mechanism by which MSCs regulate immune-responses and generate immune regulatory cells such as tolerogenic dendritic cells (tolDCs) and regulatory T cell (Tregs). In this study, we primed WJ-MSCs with TNF-α and IFN-γ and investigated the immunomodulatory properties of primed WJ-MSCs on mature dendritic cells (mDCs) and activated T cells differentiated from mononuclear cells (MNCs) of T1D patient’s. Our findings revealed that primed WJ-MSCs impaired the antigen-mediated immunity, upregulated immune-tolerance genes and downregulated immune-response genes. We also found an increase in the production of anti-inflammatory cytokines and suppression of the production of pro-inflammatory cytokines. Significant upregulation of FOXP3, IL10 and TGFB1 augmented an immunosuppressive effect on adaptive T cell immunity which represented a strong evidence in support of the formation of Tregs. Furthermore, upregulation of many critical genes involved in the immune-tolerance mechanism (IDO1 and PTGES2/PTGS) was detected. Interestingly, upregulation of ENTPD1/NT5E genes express a strong evidence to switch immunostimulatory response toward immunoregulatory response. We conclude that WJ-MSCs primed by TNF-α and IFN-γ may represent a promising tool to treat the autoimmune disorders and can provide a new evidence to consider MSCs- based therapeutic approach for the treatment of TID.
Highlights
Type 1 diabetes (T1D) is a T-cell mediated autoimmune disorder in which insulin-secreting b-cells of the pancreas are selectively destroyed
Type 1 diabetes is a well-known autoimmune disease characterized by specific adaptive immunity against b-cell antigens
The results showed that high differentiation potential and unique morphological features were obtained when Wharton’s jellyderived mesenchymal stromal cells (WJ-mesenchymal stromal cells (MSCs)) were primed with both IFN-g and TNFa
Summary
Type 1 diabetes (T1D) is a T-cell mediated autoimmune disorder in which insulin-secreting b-cells of the pancreas are selectively destroyed. The mechanisms involved in the b-cell destruction are still not understood. Tyrosine kinase, islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP), insulinoma-associated protein 2 (IA-2), zinc transporter (ZnT), and glutamic acid decarboxylase 65 (GAD65) are all considered to be involved in the b-cell specific autoimmune process [1, 2]. Mature dendritic cells (mDCs) and T cells are implicated in the pathogenesis of T1D. Mature dendritic cells play a key role in all stages of b-cells destruction due to their immunostimulatory effect on naïve T cells [4]. MDCs trigger two important functions in controlling T-cell immunity; T-cell activation by the expression of T-cell antigen and secretion of specific cytokines which determine the nature of T-cell responses [5]
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