Lowell, Sally Elizabeth; (2000) Delta and the fate of stem cells in human epidermis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Human epidermis is renewed throughout life from a population of stem cells, which are located in evenly spaced patches within the basal cell layer. Those daughters of stem cells that are destined to differentiate are called transit amplifying cells, and these are located in the remaining regions of the basal layer that surround the stem cell patches. Cell movement and cell differentiation must be tightly coordinated in order to maintain the organisation of the tissue. In this thesis I describe a stably heritable lineage marking technique based on Green Fluorescent Protein (GFP) which I have used to follow the clonal progeny of single cells within a cell culture model of human epidermis. Using this technique, I found that stem cell progeny tend to remain in cohesive clusters whilst transit cell progeny move more freely amongst their unlabelled neighbours. Signals from surrounding keratinocytes influence the differentiation of epidermal stem cells, but the nature of the signals is unknown. I found that the transmembrane signalling protein Delta is expressed in stem cells. I overexpressed Delta in primary human keratinocytes by retroviral infection and used GFP as a lineage marker to follow the effect of Delta on the fate of neighbouring cells within a reconstituted epidermis. The results of these experiments suggest that Delta signalling promotes differentiation at the boundary of stem cell clusters. I also obtained evidence that Delta promotes cohesiveness between groups of keratinocytes. This function of Delta requires the intact cytoplasmic domain of the protein and appears to be independent of effect s on stem cell differentiation. Thus, Delta may have a dual role in the epidermis: regulating stem cell differentiation and location.

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