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‣ Stochasticity and order: studies of keratinocyte proliferation

Roshan, Amit
Fonte: University of Cambridge; Medical Research Council (Great Britain). Cancer Unit. Publicador: University of Cambridge; Medical Research Council (Great Britain). Cancer Unit.
Tipo: Thesis; doctoral; PhD
Relevância na Pesquisa
A central tenet of stem cell biology has been that proliferating tissues are maintained through a cellular hierarchy comprising of self-renewing stem cells at the apex, multiple lineage-restricted short-lived progenitor cells, and post-mitotic differentiated cells. The wide range of colony sizes in cultured human keratinocytes has been taken to support this hypothesis. Contrary to this model, researchers using genetic lineage tracing in mouse epidermis have inferred a single progenitor population for homeostasis, and a quiescent stem cell population activated upon wounding or genetic mutation. To study the proliferative behaviour of human keratinocytes, I used live imaging in vitro at single cell resolution. This shows two modes of proliferation: Type 1 cell division is stochastic with equal odds of generating dividing or non-dividing progeny, while Type 2 cell division predominantly produces two dividing daughters. These two modes are sufficient to explain the entire range of colony sizes seen after 7-12 days of culture and does not require a spectrum of proliferative ability. This insight provides a simple way to study the effects of external factors on cell fate. To exemplify this, I observed the effects of epidermal growth factor (EGF) and the Wnt agonist R-spondin on proliferation. Here I find proliferation in type 2 colonies changes by changing the proportion of cells dividing. This has implications for the limited success of EGF therapies in clinical trials following burns. To examine clonal contributions to wound repair...