Kinetics of cell division in normal and malignant epidermis

Lead Research Organisation: University of Cambridge
Department Name: Physics

Abstract

All biological tissues, such as skin, are made from cells. Amongst the variety of different cell types, stem cells assume a very special role retaining the ability to produce identical copies of themselves when they divide, and to turn into function-specific cells, a process known as differentiation. As such, stem cells are crucial for development and are expected to play a key role in tissue maintenance and repair. Typically, each tissue is comprised of many different cell types, each having a specific function. One of the main challenges in biological sciences is to understand how stem cells and their progeny function to maintain tissue. However, studies of cellular organisation of tissue do not reveal the lineage of cells, i.e. it is often difficult to distinguish stem cells from other cell types and impossible to trace the ancestry of a given cell.

This proposal is designed to take advantage of modern genetic labelling techniques to study cell fate in the epidermis, the outer most layers of skin, and in other tissue types. By genetic modification of the DNA, a strain of mice can be developed where a fraction of skin cells can be induced to express a yellow fluorescent protein, allowing they and their progeny to be detected under the microscope as patches of yellow-stained cells. By counting the number of cells in these labelled cell clusters, known as clones, methods of statistical analysis, more familiar in the realm of physical and mathematical sciences, can be applied to reveal different cell types, cell division rates and pathways and, ultimately, to resolve the mechanism of epidermal maintenance. Intriguingly, recent studies using these techniques have revealed that the epidermis conforms to a remarkably simple random process involving only one type of dividing cell population, overturning a long-held dogma in the scientific literature.

These preliminary studies provide a platform to investigate tissue maintenance in other systems, such as humans and frogs, and to explore in detail the mechanism of early tumour growth and the effects of drug delivery.

Technical Summary

One of the main challenges in biological sciences is to understand how stem cells and their progeny function to maintain tissues in vivo. The proliferative potential of progenitor cells may be assayed in vitro and in transplantation assays in vivo, but such approaches cannot reveal how cells function within a tissue. However, recent developments in genetic labelling provide access to clonal fate data at single cell resolution in vivo over time scales long enough to address reliably the mechanism and kinetics of cell fate. Working closely with experimentalists, the aim of the present proposal is to develop a research programme using methods of non-equilibrium statistical physics to investigate the kinetics of cell division in normal and malignant tissue. Already, such methodologies have been used to reveal the mechanism of murine epidermal homeostasis. Building upon these preliminary investigations, we plan to explore the mechanism of epidermal homeostasis in human tissue, and identify the potential role of stem cells in maintenance and repair. Motivated by on-going experimental research, we further plan to explore clonal behaviour in malignant tissue with a view to understanding how such investigations may provide the means to identify early signatures of tumour growth in cancerous tissue. Finally, looking beyond the epidermal system, we plan to generalise the theoretical techniques to explore the mechanism of cell fate in development and different tissue types, with particular attention paid to the Xenopus laevis system.

Publications

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Jones P (2008) Epidermal homeostasis: do committed progenitors work while stem cells sleep? in Nature reviews. Molecular cell biology

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Klein AM (2011) Patterning as a signature of human epidermal stem cell regulation. in Journal of the Royal Society, Interface

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Klein AM (2010) Stochastic fate of p53-mutant epidermal progenitor cells is tilted toward proliferation by UV B during preneoplasia. in Proceedings of the National Academy of Sciences of the United States of America

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Klein AM (2008) Mechanism of murine epidermal maintenance: cell division and the voter model. in Physical review. E, Statistical, nonlinear, and soft matter physics

 
Description EPSRC EP/F032773/1 Cambridge Condensed Matter Theory Programme Grant
Amount £1,500,000 (GBP)
Funding ID EP/F032773/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 09/2008 
End 08/2012
 
Title Theoretical insights 
Description We have shown that scaling phenomena within clone fate data provides access to stem and progenitor cell fate. 
Type Of Material Technology assay or reagent 
Year Produced 2007 
Provided To Others? Yes  
Impact This method has now been applied successfully to several tissue types. 
 
Description Stem cell fate in epidermis and intestinal crypt 
Organisation Cancer Research UK Cambridge Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution As a theoretical physicist working in the area of biologically inspired physics, I rely heavily on the input of experiment. My collaborators have undertaken inducible genetic labeling studies to look at the homeostatic turnover of tissue. From these results, we have been able to deduce conserved patterns of stem and progenitor cell fates in adult tissues.
Collaborator Contribution Dr Doug Winton and his research group have undertaken clonal analysis in murine intestinal crypt from which we can deduce the pattern of stem cell fate. This experimental programme was inspired by, and feeds directly into, the theoretical research undertaken by my group.I have strengthened an existing collaboration with Phil Jones looking at the maintenance of mammalian epidermis. These on-going studies include investigation of normal tissue turnover using inducible genetic labeling as well as cancer models.
Impact As well as the publications already generated by these activities and further publications in preparation, this work has inspired a number of new collaborations and has led to three patent applications by MRC technology.
Start Year 2006
 
Description Stem cell fate in epidermis and intestinal crypt 
Organisation Medical Research Council (MRC)
Department MRC Cancer Cell Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution As a theoretical physicist working in the area of biologically inspired physics, I rely heavily on the input of experiment. My collaborators have undertaken inducible genetic labeling studies to look at the homeostatic turnover of tissue. From these results, we have been able to deduce conserved patterns of stem and progenitor cell fates in adult tissues.
Collaborator Contribution Dr Doug Winton and his research group have undertaken clonal analysis in murine intestinal crypt from which we can deduce the pattern of stem cell fate. This experimental programme was inspired by, and feeds directly into, the theoretical research undertaken by my group.I have strengthened an existing collaboration with Phil Jones looking at the maintenance of mammalian epidermis. These on-going studies include investigation of normal tissue turnover using inducible genetic labeling as well as cancer models.
Impact As well as the publications already generated by these activities and further publications in preparation, this work has inspired a number of new collaborations and has led to three patent applications by MRC technology.
Start Year 2006