It is well established that touch perception deteriorates with age and this phenomenon is accompanied by a number of structural defects in the skin including a dramatic loss of Merkel cell-neurite complexes, other tactile afferents and touch sensitivity. Deficits in touch perception are thought to contribute to the decline of postura stability and handgrip, and the resulting increase in falling frequency, which is a major factor determining quality of life and the ability to live independently for the elderly. Technical hurdle that have hindered efforts to understand the cellular and molecular basis of age-related losses in touch perception are i) the variety of somatosensory receptors and ii) the fact that mechanoreceptive end organs are scattered throughout the skin. Furthermore, information regarding putative skin progenitor populations that are responsible for maintaining the turnover of cellular mechanoreceptors that perceive light touch, such as Merkel cells, is sorely lacking. Merkel cells represent a mature neuroendocrine lineage that resides in unique structures in the epidermis of hairy skin in rodents and humans termed touch domes (TDs). Our laboratory previously identified a novel keratinocyte progenitor population localized with Merkel cells in TDs termed TD progenitor cells (TDPCs) and we demonstrated that TDPCs could give rise to the Merkel lineage both under regenerative conditions and homeostasis. To further explore the role of TDPCs in Merkel cell homeostasis, we generated a BAC transgenic mouse model in our laboratory, Krt17CreERT2 that selectively targets TDPCs in the epidermis for expression of a tamoxifen-inducible Cre recombinase while excluding mature Merkel cells. Using Krt17CreERT2 mice in combination with other Cre-inducible reporter alleles we demonstrated that i) TDPCs are permanent residents of the skin that are solely responsible for maintaining the Merkel lineage and ii) the entire pool of mature Merkel cells within the TD is turned over every two months in young adult skin. These preliminary findings establish Krt17CreERT2 mice as an excellent platform to examine how Merkel cell homeostasis may be perturbed in aged skin. The main objective of this proposal is to determine whether a decline in progenitor capacity of TDPCs underlies the age-related loss in Merkel cell-neurite complexes and diminished touch sensation. To accomplish our objective, we will employ Krt17CreERT2 mice to determine the rate of Merkel cell genesis and apoptosis in aged skin. We will also purify TDPCs from aged skin and assess their clonogenic capacity in vitro. Finally, we will transplant young adult and aged TDPCs and directly assess their ability to regenerate Merkel cells in vivo and restore tactile acuity. These studies will be critical to understanding the cellular regulation of our sense of touch, an essentil element of our ability to perceive our surroundings that is severely diminished as we age.
As we age, our skin gradually loses its sense of touch and this deficit is thought to contribute to the decline of postural stability and hand grip, and the resulting increase in falling frequency, which is a major factor determining quality of life and th ability to live independently for the elderly. However the cellular basis for this phenomenon is completely unknown. The major goal of this application is to understand how stem cells in our skin lose the ability to maintain the sensory cells that mediate light touch responses as we age.
|Palmer, Colin J; Galan-Caridad, Jose M; Weisberg, Stuart P et al. (2014) Zfx facilitates tumorigenesis caused by activation of the Hedgehog pathway. Cancer Res 74:5914-24|
|Owens, David M; Lumpkin, Ellen A (2014) Diversification and specialization of touch receptors in skin. Cold Spring Harb Perspect Med 4:|