Functionally enhanced placenta-derived mesenchymal stem cells inhibit adipogenesis in orbital fibroblast with graves’ ophthalmopathy

Abstract

Background: Placenta-derived mesenchymal stem cells (PD-MSCs) have unique immunomodulatory properties, and Phosphatase of regenerating liver-1 (PRL-1) regulates 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 contents involving adipose tissue. Because the mechanism of inhibiting adipogenesis in orbital fibroblast (OF) with GO patients remains uncertain, the major objective is to investigate mechanisms alleviating adipogenesis by PRL-1 overexpressing PD-MSCs (PD-MSCsPRL-1, PRL-1+) in OF derived from GO patients. Methods: primary OFs from patients with GO were isolated from orbital adipose tissue specimens. After maturation as adipogenic differentiation, normal and GO-derived OF were cocultured with naïve and PD-MSCsPRL-1. Western blotting were conducted for evaluating molecular mechanisms for inhibiting adipogenesis in GO. Results: The characterizations of PD-MSCsPRL-1 were similar to naïve. OF with GO patients stimulated adipocyte differentiation were significantly decreased lipid accumulation by cocultivation with PD-MSCsPRL-1 comparing with naïve. The mRNA and protein expression of adipogenic markers was declined in PD-MSCsPRL-1. The expression of pPI3K/AKT/mTOR protein in OF with GO patients was downregulated by cocultivation with PD-MSCsPRL-1 secreted IGFBPs. Interestingly, IGFBP2, 4, and 7 expressions through integrin alpha 4 (ITGA4) and beta 7 (ITGB7) in PD-MSCsPRL-1 were higher than naïve and upregulated pFAK downstream factor. Conclusion: Taken together, secreted IGFBPs by PD-MSCsPRL-1 via upregulating FAK and blocking IGF inhibit adipogenesis of OF with GO patients, providing novel therapeutic approach using functionally enhanced MSCs potential for degenerative diseases.