Melanocyte-secreted fibromodulin promotes an angiogenic microenvironment
Irit Adini, Kaustabh Ghosh, Avner Adini, Zai-Long Chi, Takeru Yoshimura, Ofra Benny, Kip M. Connor, Michael S. Rogers, Lauren Bazinet, Amy E. Birsner, Diane R. Bielenberg, Robert J. D’Amato
Irit Adini, Kaustabh Ghosh, Avner Adini, Zai-Long Chi, Takeru Yoshimura, Ofra Benny, Kip M. Connor, Michael S. Rogers, Lauren Bazinet, Amy E. Birsner, Diane R. Bielenberg, Robert J. D’Amato
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Research Article

Melanocyte-secreted fibromodulin promotes an angiogenic microenvironment

Abstract

Studies have established that pigmentation can provide strong, protective effects against certain human diseases. For example, angiogenesis-dependent diseases such as wet age-related macular degeneration and infantile hemangioma are more common in light-skinned individuals of mixed European descent than in African-Americans. Here we found that melanocytes from light-skinned humans and albino mice secrete high levels of fibromodulin (FMOD), which we determined to be a potent angiogenic factor. FMOD treatment stimulated angiogenesis in numerous in vivo systems, including laser-induced choroidal neovascularization, growth factor–induced corneal neovascularization, wound healing, and Matrigel plug assays. Additionally, FMOD enhanced vascular sprouting during normal retinal development. Deletion of Fmod in albino mice resulted in a marked reduction in the amount of neovascularization induced by retinal vein occlusion, corneal growth factor pellets, and Matrigel plugs. Our data implicate the melanocyte-secreted factor FMOD as a key regulator of angiogenesis and suggest an underlying mechanism for epidemiological differences between light-skinned individuals of mixed European descent and African-Americans. Furthermore, inhibition of FMOD in humans has potential as a therapeutic strategy for treating angiogenesis-dependent diseases.

Authors

Irit Adini, Kaustabh Ghosh, Avner Adini, Zai-Long Chi, Takeru Yoshimura, Ofra Benny, Kip M. Connor, Michael S. Rogers, Lauren Bazinet, Amy E. Birsner, Diane R. Bielenberg, Robert J. D’Amato

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Figure 2

FMOD expression in pigmented and nonpigmented melanocytes.

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FMOD expression in pigmented and nonpigmented melanocytes. (A) FMOD mRNA...
(A) FMOD mRNA in nonpigmented (albino) and pigmented mouse melanocytes was measured by qRT-PCR and normalized to the level of GAPDH; ***P < 0.0001. (B) Nonpigmented (albino, left) and pigmented (right) melanocytes were stained with FMOD and anti-mouse TRITC antibody and visualized by fluorescence microscopy. Nuclei were counterstained with DAPI. Scale bar: 200 μm. (C) CM from melanocytes from African-Americans and light-skinned individuals of mixed European descent were assessed by Western blot using an antibody against FMOD. (D) Retinal sections from C57-albino and (E) C57BL mice were stained for FMOD and visualized by confocal microscopy. Nuclei were counterstained with DAPI. Arrows show the choroid layer. Original magnification, ×40. (F and G) FMOD protein was examined by Western blot in choroid melanocytes (F) and iris (G) from C57BL and C57-albino mice. Each group had a minimum of 5 mice. n ≥ 10. β-Actin was used as a loading control. (H) FMOD protein from pigmented cells grown in the presence and absence of tyrosine-free medium was analyzed by Western blot. β-Actin was used as a loading control. (I) FMOD protein from nonpigmented cells treated with DHI was analyzed by Western blot. β-Actin was used as a loading control.