Nerve-stem cell interactions during skin homeostasis and wound repair

点击翻译按钮获取中文摘要

PROJECT ABSTRACT The skin undergoes constant cycles of renewal and regeneration, depending on multiple stem cell populations for the maintenance of its function as a barrier and environmental sensor. Situated at the environmental interface, skin stem cells must be able to adapt to changes detected at the systemic level to preserve skin function. How systemic information is integrated to regulate skin stem cell behavior remains poorly understood. The sympathetic nervous system (SNS) densely innervates the skin, and forms connections with the three key stem cell populations in the skin, providing a starting point for understanding how stem cell activity is directly influenced by and integrated with systemic changes in the body. As both a local and systemic regulator, the SNS is uniquely positioned to link changes sensed at the organismal level to changes in stems cell in the periphery. The SNS is a branch of the autonomic nervous system, and is constantly active at a basal level to modulate physiological processes such as heart rate and blood pressure, but becomes highly elevated under stress to trigger fight-or flight responses. Traditionally, sympathetic neurons were thought to only directly regulate excitatory cells such as muscle; however, pioneering studies in hematopoietic and skin stem cells indicate sympathetic activity has a wider role governing physiology by directly regulating stem cells. Additionally, sympathetic neuropathy (loss of innervation) in the skin is associated with prolonged wound healing, suggesting a vital role for sympathetic activity in skin repair. The outermost layer of the skin consists of a continually renewing epidermis that depends on one of the key skin stem cells, epidermal stem cells (EpSCs), for turnover and repair. EpSC activity must be exceptionally regulated as they are extremely vulnerable to environmental carcinogens such as UV light that can lead to development of some of the most prevalent types of skin cancer. Despite its importance, how EpSCs are regulated by extrinsic signals, both at the local and systemic level, is poorly understood. Locally in the skin, sympathetic neurons innervate EpSCs, with preliminary results indicating the sympathetic neurotransmitter, norepinephrine, is able to stimulate EpSC proliferation. Given these results, I propose sympathetic activity directly regulates EpSC behavior to govern epidermal renewal and repair following injury. I will utilize pharmacological and chemogenetic tools in a mouse model that permits tracing of EpSCs and progeny to determine how the sympathetic nervous system regulates EpSCs during epidermal renewal and repair. I will also determine if this occurs directly through activation of the norepinephrine receptor, Adrb2, expressed by EpSCs and identify the molecular pathways downstream of Adrb2 signaling. This proposal will elucidate the cellular mechanisms by which the SNS regulates epidermal renewal and healing, and evaluate the therapeutic potential of harnessing Adrb2 for these processes. As many pharmacologic agents are available to modulate sympathetic activity, results from this proposal could be rapidly translated into treatments for a variety of skin diseases.