Mesenchymal Stromal Cells Inhibit Inflammatory Lymphangiogenesis in the Cornea by Suppressing Macrophage in a TSG-6-Dependent Manner

Abstract

The cornea is a transparent tissue devoid of blood and lymphatic vessels. However, various inflammatory conditions can cause hemangiogenesis and lymphangiogenesis in the cornea, compromising transparency and visual acuity. Mesenchymal stem/stromal cells (MSCs) have therapeutic potentials in a variety of diseases because of anti-inflammatory properties. Herein, we investigated the effects of MSCs on corneal angiogenesis using a model of suture-induced inflammatory corneal neovascularization. Data demonstrated that an intravenous administration of MSCs suppressed corneal inflammation and neovascularization, inhibiting both hemangiogenesis and lymphangiogenesis. MSCs reduced the levels of vascular endothelial growth factor (VEGF)-C, VEGF-D, Tek, MRC1, and MRC2 in the cornea, which are expressed by pro-angiogenic macrophages. Moreover, the number of CD11b monocytes/macrophages in the cornea, spleen, peripheral blood, and draining lymph nodes was decreased by MSCs. Depletion of circulating CD11b monocytes by blocking antibodies replicated the effects of MSCs. Importantly, knockdown of tumor necrosis factor alpha (TNF-α)-stimulated gene/protein 6 (TSG-6) in MSCs abrogated the effects of MSCs in inhibiting corneal hemangiogenesis and lymphangiogenesis and monocyte/macrophage infiltration. Together, the results suggest that MSCs inhibit inflammatory neovascularization in the cornea by suppressing pro-angiogenic monocyte/macrophage recruitment in a TSG-6-dependent manner.

UV light crosslinking regresses mature corneal blood and lymphatic vessels and promotes subsequent high-risk corneal transplant survival

“…Interestingly, macrophages decreased in inflammatory corneas after CXL, which should contribute to the regression of pathologic BVs and LVs in corneas, as macrophages play a key role in the induction of angiogenesis44, 45 and lymphangiogenesis46, 47, 48, 49 under pathological conditions in the cornea and in the maintenance of LVs 50. Furthermore, we also observed significant reduction in CD45 + leukocytes in suture‐induced inflammation in corneas after CXL treatment using riboflavin and UVA.…”

Anti-inflammatory protein TSG-6 secreted by bone marrow mesenchymal stem cells attenuates neuropathic pain by inhibiting the TLR2/MyD88/NF-κB signaling pathway in spinal microglia

“…TSG-6 is a pleiotropic immunomodulatory molecule activated rapidly in response to stimulation by several pro-inflammatory cytokines and functions at an early phase of the inflammatory process [38,57,58]. Several lines of evidence suggest that TSG-6 secreted by MSCs can produce anti-inflammatory effects in a wide variety of diseases, such as bronchopulmonary dysplasia [59], diabetic retinopathy [60], corneal injury [44], inflammatory bowel disease [39], renal fibrosis [45], severe acute pancreatitis [61], and other inflammation-associated diseases. In the present study, we showed that intrathecal injection of BMSCs reduced the expression of IL-1β, IL-6, and TNF-α in the ipsilateral spinal cord dorsal horn; meanwhile, BMSCs administration alleviated CCI-induced allodynia and hyperalgesia.…”

“…We reasoned that BMSCs exert this analgesic effect by secreting some anti-inflammatory factors. Previous studies have proven that BMSCs can exert a beneficial effect in corneal neovascularization and renal fibrosis by secreting the anti-inflammatory protein TSG-6 [44,45]. Thus, we investigated whether BMSCs exert their therapeutic effect on CCI-induced neuropathic pain by releasing TSG-6.…”

Emerging Roles of Tumor Necrosis Factor-Stimulated Gene-6 in the Pathophysiology and Treatment of Atherosclerosis

“…Co-incubation of human adipose tissue-derived MSCs suppresses LPS-induced IL-1β secretion from THP-1 monocytes via increasing TSG-6 expression [ 38 ]. Knocking down TSG-6 in MSCs abrogates the inhibitory effects of MSCs on inflammatory neovascularization and monocyte/macrophage infiltration [ 39 ]. The intraarticular injection of MSCs increases TSG-6 expression in joint cartilage and inhibits monoiodoacetate-induced arthritis in rats [ 40 ].…”