The current understanding of cell biology suggests that cells receive cues or signals from their ‘microenvironment’ (cells and proteins in their immediate surroundings), which are transduced internally, resulting in a cellular response. This is referred to as the ‘cue-signal-response’ paradigm. Cells in different parts of an organism behave differently; for instance, cells in the eye behave differently from those in the liver. The cue-signal-response paradigm would suggest that given the cells in different organs reside is different microenvironments, they receive different signals which activate different pathways internally thereby generating different responses. However, recent data showed a curious observation in the cells that reside in the human skin. Skin cells that reside in the same microenvironment appear to activate the same signalling pathway (called ‘ERK’) – which is not too surprising. However, they can give rise to sharply divergent cellular responses. For instance, some cells maintain stemness, whereas some differentiate – and both these cell types appear to respond to the external cues via the ERK signalling pathway. This led to the question of how the cells in the skin could identify the ERK signal that was intended to guide the cells to differentiate from the one that was aimed to maintain stemness. Recent data has suggested that ERK signalling in skin cells manifests in a dynamic manner – i.e. it appears in pulses, and different skin cell subpopulations may have different signatures of these dynamics. Some pulses have high ERK levels, others have low levels. Some have a high frequency of pulses; the others have low frequencies of ERK pulses. The central hypothesis of the action ‘Intracellular ERK signalling dynamics mediated epidermal stem cell fate control’ was that skin cells were able to decipher and decode information directly from these ERK pulses to make decisions on whether they would maintain stemness or differentiate. This would allow them to utilize the same signalling pathway but make different cellular decisions.
A deeper understanding of the question mentioned above has long reaching consequences. Not only would it uncover complex aspects of cellular decision making which would dramatically improve our understanding of basic biology, but it would also allow scientists to develop strategies that enable fine tune control over cellular behaviour and improve the current technologies related to the field of regenerative medicine. These strategies could significantly improve the outlook for patients that struggle with debilitating medical conditions.
The objectives of the project were to disentangle the signalling profiles associated with the various subpopulations in the human skin and identify the profiles attributed to each subpopulation. To achieve this, the fellow needed to establish strategies to identify different cellular subtypes in living human skin cells. This required the transfer of a novel technology that the fellow had developed to micropattern adherent cells for use in human epidermal cell types. The final goal was to develop tools that would permit the testing of the central hypothesis for this action by exogenously controlling the ERK signalling dynamics in the skin cells and query if the cell states were able to be controlled by controlling the dynamic profiles of ERK signalling activity.
