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D.W. Rickman, Y. Guo, P. Saloupis, C. De Felipe, S.P. Hunt; Substance P Regulates Multiple Ocular Progenitor Cell Populations . Invest. Ophthalmol. Vis. Sci. 2004;45(13):5385.
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Purpose: The pharmacological action of the tachykinin peptide, substance P (SP), is mediated through the neurokinin–1 (NK1) receptor. In the rodent retina, cells expressing SP and NK1 are localized primarily to populations of interneurons. SP containing sensory fibers also innervate the ciliary body and cornea, structures where numerous epithelial cells express NK1. Recently, it was shown that deletion of the NK1 gene resulted in increased neurogenesis in the adult mouse hippocampus, suggesting that SP down–regulates adult neurogenesis. In order to determine if SP is a common regulator of adult progenitor cell proliferation, we analyzed populations of ocular cells with proliferative potential in eyes from adult wildtype (NK1+/+) and NK1 null (NK1–/–) mice. These included a population of corneal epithelial cells with a perpetual turnover and cells typically devoid of adult proliferative capacity, the purported retinal progenitor cells of the pigmented ciliary epithelium. Methods: Adult NK1+/+ and NK1–/– mice received 4 injections of bromodeoxyuridine (BrdU, 50 mg/kg, i.p., q 2 hr). One day or 27 days later, animals were euthanized and perfused with 4% paraformaldehyde. Eyes were dissected, cryosectioned and processed for BrdU immunohistochemistry. Results: In the corneas of NK1+/+ mice, at Day 1, BrdU labeled nuclei were present in basal cells of the far peripheral corneal epithelium near the limbus. These labeled cells were destined for the normal renewal of the corneal epithelium. In marked contrast, in corneas from NK1–/– mice, labeled cells were present throughout the corneal epithelium, even in central regions. At Day 27, no labeled nuclei were observed in corneas from NK1+/+ or NK1–/– mice, suggesting a rapid and complete turnover of labeled cells. In the pigmented layer of the ciliary epithelium of NK1+/+ mice at Day 1 and Day 27, no labeled nuclei were observed. However, in NK1–/– mice, on both days following BrdU treatment, scattered labeled nuclei were clearly present in cells with cytoplasmic melanin granules, suggesting a low basal level of renewal of these cells. Conclusions: SP contributes to the regulation of multiple progenitor cell populations in the adult mouse through the NK1 receptor. Pharmacological manipulation of the NK1 receptor may provide a tool for enhancing adult retinal neurogenesis and facilitating endogenous retinal repair, as well as for enhancing corneal wound healing.
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