期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：23
页码：7195-7200
DOI：10.1073/pnas.1504177112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceThe role of nerves in regulating stem cells is largely unknown. Here, we use the touch dome epithelium in skin as a model to study neural regulation of adult stem cells. We find that sensory nerves trophically maintain the touch dome epithelium by signaling with Sonic hedgehog (Shh) to lineage-specific stem cells. This novel aspect of touch dome innervation demonstrates retrograde paracrine signaling to sensory epithelium progenitors by afferent sensory neurons. Indeed, neural Shh is a key regulatory factor in the perineural niche required for long-term renewal of touch dome stem cells. We further demonstrate that Hedgehog upregulation alone is not sufficient to drive malignant expansion of mouse Merkel cells, despite reports of active Hedgehog signaling in Merkel cell carcinoma. The touch dome is a highly patterned mechanosensory structure in the epidermis composed of specialized keratinocytes in juxtaposition with innervated Merkel cells. The touch dome epithelium is maintained by tissue-specific stem cells, but the signals that regulate the touch dome are not known. We identify touch dome stem cells that are unique among epidermal cells in their activated Hedgehog signaling and ability to maintain the touch dome as a distinct lineage compartment. Skin denervation reveals that renewal of touch dome stem cells requires a perineural microenvironment, and deleting Sonic hedgehog (Shh) in neurons or Smoothened in the epidermis demonstrates that Shh is an essential niche factor that maintains touch dome stem cells. Up-regulation of Hedgehog signaling results in neoplastic expansion of touch dome keratinocytes but no Merkel cell neoplasia. These findings demonstrate that nerve-derived Shh is a critical regulator of lineage-specific stem cells that maintain specialized sensory compartments in the epidermis.
