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    • After comparing the lymph angiogenic effects of HLE and HLF

    2018-11-08

    After comparing the (lymph)angiogenic effects of HLE and HLF, UVB-induced changes in their protein expression patterns were also assessed. As shown by the protein array assessment, following UVB irradiation of HLF national prevalence  amphiregulin, uPA (a strong promoter of angiogenesis (Oh et al., 2003) the expression of which is linked with high risk for cancer metastasis via lymph-angiogenesis (Zhang et al., 2011; Jiang et al., 2012; Zhang et al., 2013)) and CXCL16 (a pro-hem and pro-lymphangiogenic factor (Wente et al., 2008; Buttler et al., 2014)) were strongly down-regulated in BHLF cells. ELISA data showed that angiogenin, IGBP-3, VEGFA and VEGF C also significantly decreased. These results suggest that the pro-angiogenic effect of HLF cells is reversed after UVB irradiation which corresponds to results for LEC proliferation, wound healing and tube formation assay and BEC tube formation assay. In the case of BHLE on the other hand, a small but significant reduction of IGFBP-3, VEGFA and VEGFC occurred in combination with the decrease of the pro-angiogenic cytokines IGFBP-1 and IGFBP-2 (Giannini et al., 2006; Kluge et al., 1997). TSP1, an inhibitor of corneal lymph and hem-angiogenesis (Cursiefen et al., 2011; Cursiefen et al., 2004b) was also increased. These data, in combination with the LEC and BEC activity assays experiments, suggest that the alterations in the protein profile of HLE cells after UVB treatment were not sufficient to induce a significant effect to these cells. While investigating the impact of UVB treatment on the angiogenic profile of HLE and HLF cells, changes in the produced inflammatory and macrophage-recruiting cytokines were also evaluated. UVB irradiation increased the pro-inflammatory cytokines TNFα and IFNγ by HLE and MCP1 by HLF. TNFα is a commonly accepted key inflammatory factor (Michalova & Lim, 2008) contributing to vasodilatation, edema, and leukocyte recruitment, which are all commonly associated with the development of cornea neovascularization (Ferrari et al., 2015). IFNγ on the other hand, has been linked with increased angiogenesis via induction of VEGF production by macrophages (Lee et al., 2014; Xiong et al., 1998). It is therefore here demonstrated that by producing these cytokines both HLE and HLF cells may contribute to the inflammatory mechanisms taking place in the cornea following UVB irradiation. Taken together, these observations put forward a double role of the limbal epithelial cells and fibroblasts subsequent to short term UVB insult. A suggested model for this response is summarized in Fig.7. On one hand limbal fibroblasts reduce their pro-angiogenic potential by down-regulating expression of key cytokines such as VEGFA and VEGFC. It is possible that the limbal cell populations put to use a defense mechanism to prevent corneal neovascularization which otherwise could occur after UVB exposure. At the same time, these cells secrete pro-inflammatory and macrophage–recruiting cytokines thus helping in tissue repair but also adding to the inflammatory conditions that propagate (lymph)angiogenesis by promoting infiltration of immune cells populations producing pro-angiogenic growth factors (Hong et al., 2005; Cursiefen et al., 2004a). This pro-inflammatory action, in combination with the decline of the putative stem cell phenotype within the limbal epithelial population may cause an indirect pro(lymph)angiogenic shift in the limbus as a result of UVB exposure (Fig.7). Via recruitment of macrophages, hem- and lymphangiogenesis can be significantly upregulated (Cursiefen et al., 2006; Bock et al., 2013). Long term UVB exposure could therefore contribute to inflammation and pathologic neovascularization both consistent with the progression and recurrence of pterygium. The long term effects of UVB are not assessed here and are the subject of a different investigation. This study highlights the changes that short term UVB treatment induces to the limbal stem cell niche phenotype as well as the functions of its cellular components in the processes indirectly leading to (lymph)angiogenesis via up-regulation of macrophage recruiting cytokines. Macrophages are well known as indirect key regulators of immune-amplification cascades and indirect amplifiers of hem- and lymphangiogenesis via producing VEGFA, C and D (Cursiefen et al., 2005; Cursiefen et al., 2004a). Our results open up new treatment avenues against pterygium recurrence by targeting macrophage recruitment-mediated prolymphangiogenesis.