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Ahdeah Pajoohesh-Ganji, Sonali Ghosh, Gauri Tadvalkar, Mary Ann Stepp; Activation of the Hedgehog pathway is involved in the expansion of compound niches after corneal injury. Invest. Ophthalmol. Vis. Sci. 2013;54(15):987.
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The hedgehog (Hh) signaling pathway has been suggested to regulate corneal homeostasis and is up-regulated during corneal re-epithelialization. Sonic Hh interacts with its receptor Patched-1 on cell surfaces to mediate the movement of Gli1/2 to the nucleus and the activation of genes involved in cell proliferation and differentiation. The corneal epithelium is maintained by stem cells which are found at the limbus in higher numbers. We recently showed that progenitor cells for both corneal epithelial and goblet cells are found within compound niches (CNs) present at the limbal region of the healthy BALB/c mouse cornea. CNs proliferate upon wounding, and give rise to both corneal epithelial and goblet cells. If wounds get close to the limbus, goblet cells that arise from the CN are found on the central cornea, creating an unsuitable corneal surface and preventing the appropriate passage of light. These studies were initiated to investigate the role played by the Hh signaling pathway in proliferation of CNs and generation of corneal goblet cells during corneal homeostasis and in response to injury.
Adult BALB/c mice were wounded using a 2.5mm trephine and a dulled blade. Mice were allowed to heal for different time points after wounding: 1, 7, 14, 21, 28 days. Unwounded corneas were used as control. After sacrifice, corneas were processed for whole mount immunofluorescence to localize sonic hedgehog (Shh) and Patched-1 as well as Muc5ac+ CNs. A minimum of 3 corneas were used for each time point and antibody combination evaluated.
Patched -1 is present in the cells that make up the CN in unwounded corneas but Shh, the Patched-1 ligand, is absent. However, 1 and 7 days after wounding, Patched-1 and Shh co-localize in CNs both at the limbus and on the central cornea in cells that arise from the disaggregation of CNs. While many of these Patched-1+Shh+ cell clusters are Muc5ac+, few are Muc5ac-.
These experiments indicate that activation of the Hh signaling pathway is involved in the expansion and/or migration of CNs that takes place after wounding. Hh signaling may regulate the differentiation of CNs into goblet cells. If so, manipulating this pathway may reduce the numbers of the goblet cell clusters formed after wounding in the central cornea.
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