Intracellular ERK signalling dynamics mediated epidermal stem cell fate control

ended

Understanding how stem cells maintain homeostasis in the epidermis is of great interest to regenerative medicine. Previous studies have identified the crucial role ERK signalling plays in coordinating homeostasis. Intriguingly, and somewhat paradoxically, ERK signalling has been shown to regulate divergent epidermal stem cell outputs; from maintenance, to commitment, and terminal differentiation. Uncovering how the activity of a single signalling pathway can regulate such divergent responses can not only allow us to robustly control epidermal stem cell behaviour but will also have far reaching implications for both the fields of stem cell and cancer biology. Importantly, ERK signalling manifests in a dynamic/pulsatile manner, and these dynamics have been shown to encode information in other epithelial cell lines. If ERK dynamics can encode information that regulates the divergent outputs of epidermal stem cells remains to be explored. My goal is to employ an interdisciplinary approach that combines electrical, and biomedical engineering approaches with those of stem cell biology to decipher the information encoded in the dynamics of ERK signalling that control epidermal stem cell outputs. To achieve this, I will first identify ERK activity signatures associated with the different cell states of the epidermis (stem, committed, and differentiated) using live primary human epidermal cells expressing a Förster Resonance Energy Transfer based ERK reporter. I will then decode these signatures using quantitative Fourier analysis to identify the key amplitude and frequency parameters associated with each epidermal cell state. Further, these parameters will then be tested for their ability to maintain the associated states under experimental conditions that enable control of ERK dynamics. The precise regulation afforded by these experimental conditions will also be harnessed to achieve dedifferentiation of committed cells into a stem cell state.