Abstract
BackgroundPlacenta-derived mesenchymal stem cells (PD-MSCs) have unique immunomodulatory properties. Phosphatase of regenerating liver-1 (PRL-1) regulates the self-renewal ability of stem cells and promotes proliferation. Graves’ ophthalmopathy (GO) is an autoimmune inflammatory disease of the orbit and is characterized by increased orbital levels of adipose tissue. Here, we evaluated the therapeutic mechanism for regulation of adipogenesis by PRL-1-overexpressing PD-MSCs (PD-MSCsPRL-1, PRL-1+) in orbital fibroblast (OF) with GO patients.MethodsPD-MSCs isolated from human placenta were transfected with the PRL-1 gene using nonviral transfection method. Primary OFs were isolated from orbital adipose tissue specimens from GO patients. After maturation as adipogenic differentiation, normal and GO-derived OFs were cocultured with naïve and PD-MSCsPRL-1. We analyzed the protein levels of adipogenesis markers and their signaling pathways in OFs from GO patients.ResultsThe characteristics of PD-MSCsPRL-1 were similar to those of naïve cells. OFs from GO patients induced adipocyte differentiation and had significantly decreased a lipid accumulation after coculture with PD-MSCsPRL-1 compared to naïve cells. The mRNA and protein expression of adipogenic markers was decreased in PD-MSCsPRL-1. Insulin-like growth factor-binding proteins (IGFBPs) secreting PD-MSCsPRL-1 downregulated the phosphorylated PI3K/AKT/mTOR expression in OFs from GO patients. Interestingly, IGFBP2, − 4, − 6, and − 7 expression in PD-MSCsPRL-1, which was mediated by integrin alpha 4 (ITGA4) and beta 7 (ITGB7), was higher than that in naïve cells and upregulated phosphorylated FAK downstream factor.ConclusionIn summary, IGFBPs secreting PD-MSCPRL-1 inhibit adipogenesis in OFs from GO patients by upregulating phosphorylated FAK and downregulating PI3K/AKT/mTOR signaling pathway. The functional enhancement of PD-MSCs by nonviral gene modification provides a novel therapeutic strategy for the treatment of degenerative diseases.
Highlights
Placenta-derived mesenchymal stem cells (PD-MSCs) have unique immunomodulatory properties
Phosphatase of regenerating liver-1 (PRL-1) expression in PD-MSCs was verified by expression of the GFP reporter gene (Fig. 1b)
To confirm that the PD-MSCPRL-1-mediated increase in Insulin-like growth factorbinding proteins (IGFBPs) in orbital fibroblast (OF) from Graves’ ophthalmopathy (GO) patients contributes to regulating the adipogenic effect through the integrin signaling pathway, we investigated the expression of integrin alpha 4 (ITGA4) and ITGB7 and the integrin downstream signaling factor FAK in normal and GO-derived OFs cocultured with PD-MSCsPRL-1
Summary
Placenta-derived mesenchymal stem cells (PD-MSCs) have unique immunomodulatory properties. Graves’ ophthalmopathy (GO) is an autoimmune inflammatory disease of the orbit and is characterized by increased orbital levels of adipose tissue. We evaluated the therapeutic mechanism for regulation of adipogenesis by PRL-1-overexpressing PD-MSCs (PD-MSCsPRL-1, PRL-1+) in orbital fibroblast (OF) with GO patients. Graves’ ophthalmopathy (GO) is a thyroid-associated autoimmune disease of the eye that is potentially sightthreatening. The main symptoms of GO are proptosisassociated impairment of eye motility, lid retraction, de novo adipogenesis, and soft tissue inflammation. Inflammatory reactions of orbital fibroblasts (OFs) are responsible for these disease symptoms [1]. Corticosteroids and orbital radiotherapy continue to be used to treat patients with GO [5]. Orbital radiotherapy combined with corticosteroids protects against disease progression by reducing compressive optic neuropathy in patients with active thyroid eye disease [6]. Medical radiotherapy resulted in the development of malignancies, depending on the age and gender of patients [9]
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