Abstract
BackgroundMacrophage migration inhibitory factor (MIF) is a multifunctional cytokine that regulates inflammatory reactions and the pathophysiology of many inflammatory diseases. Intervertebral disc (IVD) degeneration is characterized by an inflammatory reaction, but the potential role of MIF in IVD degeneration has not been determined. Recent studies have shown that MIF and its receptor, CD74, are involved in regulating the migration of human mesenchymal stem cells (MSCs); Thus, MIF might impair the ability of mesenchymal stem cells (MSCs) to home to injured tissues. Our previous studies indicated that cartilage endplate (CEP)-derived stem cells (CESCs) as a type of MSCs exist in human degenerate IVDs. Here, we investigate the role of MIF in regulating the migration of CESCs.Methods and FindingsCESCs were isolated and identified. We have shown that MIF was distributed in human degenerate IVD tissues and was subject to regulation by the pro-inflammatory cytokine TNF-α. Furthermore, in vitro cell migration assays revealed that nucleus pulposus (NP) cells inhibited the migration of CESCs in a number-dependent manner, and ELISA assays revealed that the amount of MIF in conditioned medium (CM) was significantly increased as a function of increasing cell number. Additionally, recombinant human MIF (r-MIF) inhibited the migration of CESCs in a dose-dependent manner. CESCs migration was restored when an antagonist of MIF, (S, R)-3(4-hydroxyphenyl)-4, 5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1), was added. Finally, a CD74 activating antibody (CD74Ab) was used to examine the effect of CD74 on CESCs motility and inhibited the migration of CESCs in a dose-dependent manner.ConclusionsWe have identified and characterized a novel regulatory mechanism governing cell migration during IVD degeneration. The results will benefit understanding of another possible mechanism for IVD degeneration, and might provide a new method to repair degenerate IVD by enhancing CESCs migration to degenerated NP tissues to exert their regenerative effects.
Highlights
Macrophage migration inhibitory factor (MIF) was first described as a soluble factor that is released by activated Tlymphocytes in 1966
cartilage endplate-derived stem cells (CESCs) were immunophenotyped via flow cytometry in accordance with the immunophenotypic criteria of the International Society for Cellular Therapy [31]
The multipotency of CESCs was evaluated via differentiation into osteogenic (Figure 2 A1, A2), adipogenic (Figure 2 B1, B2) and chondrogenic (Figure 2 C1, C2) lineages over a period of 21 days, which indicated that CESCs were capable of differentiating into osteoblasts, adipocytes and chondroblasts under differentiating conditions in vitro tissue culture
Summary
Macrophage migration inhibitory factor (MIF) was first described as a soluble factor that is released by activated Tlymphocytes in 1966. As an important proinflammatory cytokine, MIF might counter-regulate glucocorticoid effects by activating immune/inflammatory cells and promoting the expression of matrix metalloproteinases, nitric oxide and prostaglandin E2 release [1,2,3], or the release of proinflammatory and inflammatory cytokines [4], such as TNF-a, IL- 1b, IL-2, IL-6, IL-8, IFN-c. Each of those proinflammatory and inflammatory cytokines are involved in the pathogenesis of intervertebral disc (IVD) degeneration [5,6,7,8,9]. We investigate the role of MIF in regulating the migration of CESCs
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