The coordination of cell proliferation and fate specification is central to specification and maintenance of tissues. In development, systems must be tightly-regulated to ensure that cells are generated in the correct number, sequence and composition whilst, in adult, a delicate balance between proliferation and differentiation is essential to ensure homeostasis. Through a programme of multidisciplinary and collaborative research, we target unifying principles of stem and progenitor cell regulation in the development and maintenance of tissues, and factors leading to their dysregulation in the transition to diseased states.

Theories of adult tissue maintenance place stem cells at the apex of proliferative hierarchies, possessing the lifetime property of self-renewal. In homeostasis the number of stem cells must remain fixed imposing an absolute requirement for fate asymmetry in the daughters of dividing cells such that only half are retained. Such fate asymmetry can be achieved either by being the invariant result of every division or by being orchestrated from the whole population, where cell fate following stem cell division is specified only up to some probability. These alternative models suggest different mechanisms of fate regulation, yet their identification in most tissues has remained elusive.

To study stem cell fate behaviour, emphasis has been placed on genetic labelling using transgenic animal models. In this approach, the activation of a fluorescent reporter gene can be used to mark a targeted cell population and their differentiating progeny. By adapting methods based on non-equilibrium statistical mechanics and population dynamics, the quantitative analysis of lineage-labelled cells -termed clones- allows the hierarchy and fate behaviour of stem and progenitor cells to be recovered. By defining the functional fate behaviour of cell populations, we are targeting the molecular mechanisms that regulate cell fate choice.

To develop this programme, we expanding our own experimental activities at the Cambridge Stem Cell Institute, while maintaining multiple collaborations with partner experimental labs, studying stem cell self-renewal in blood, brain, intestine, skin epidermis, stomach and testis. Our approach draws heavily on cell lineage tracing strategies, from in vivo live-imaging and genetic labeling of animal models to naturally occuring genomic and mitochondrial DNA mutations in human tissues. Current collaborators include Laure Bally-Cuif (zebrafish brain), Cedric Blanpain (skin development and maintenance), Hans Clevers (intestine and brain), Rakesh Heer (human prostate), Bon-Kyoung Koo (intestine and stomach), Jacco van Rheenen (intestinal maintenance and mammary gland development) and Shosei Yoshida (spermatogenesis).

Alongside research into the maintenance of adult tissues, we are interested in understanding how cells regulate the late-stage development, repair and regeneration of adult tissues. Current collaborators include Cedric Blanpain (prostate and heart), Kim Jensen (intestine and sebacious gland), Anna Philpott (pancreas) and Songhai Shi (neocortex).

We are also making use of in vivo lineage tracing methods and culture studies to investigate how stem and progenitor cells become subverted in the initiation and progression of tumours. Together with our own experimental work, current collaborators include Cedric Blanpain (skin and mammary tumours) and Peter Dirks (medulloblastoma and glioblastoma).

Alongside strategies of stem cell self-renewal, the group has a growing interest in understanding how single-cell approaches can provide insights into the molecular mechanisms that regulate cell fate choice. To embark on this programme, we are participating in an exciting programme with colleagues at the Sanger Institute-EBI Single-Cell Genomics Centre, the Babraham Institute and the University, supported by a Wellcome Trust Strategic Award, with the goal to study cell fate decision-making of the post-implantation mouse embryo.

Plain English:
In adult, many tissues such as the skin epidermis, blood and gut undergo routine and constant turnover. The maintenance and repair of such tissues relies upon stem cells. As with embryonic stem cells, tissue stem cells are defined by their capacity to self-renew and to differentiate into more specialised cell types. However, in contrast to embryonic stem cells, tissue stem cells must achieve a perfect balance between proliferation and differentiation. Resolving the mechanisms of balance represent one of the defining questions of stem cell biology. To address this question, most studies focus on the identification of molecular regulatory factors. However, such factors are rare and often unspecific. By exploiting methods of population dynamics and statistical physics, we have shown that, in homeostasis, stem cells must follow simple and restricted patterns of fate, which impart characteristic signatures in the size distribution of surviving clones. We are using this general methodology to explore the pattern of tissue maintenance in normal adult tissues, and to address the mechanisms of dysregulation in disease, cancer and ageing.


Selected publications:

• Hannezo E, et al. (2017) A unifying theory of branching morphogenesis. Cell 171, 242-255

• Lan X, et al. (2017) Fate mapping of human glioblastoma reveals an invariant stem cell hierarchy. Nature 549 227-232

• Scheele CL, et al. (2017) Identity and dynamics of mammary stem cells during branching morphogenesis. Nature 542 313-317

• Sánchez-Danés A, et al. (2016) Defining the clonal dynamics leading to mouse skin tumour initiation. Nature 536 298-303

• Driessens G, et al. (2012) Defining the mode of tumour growth by clonal analysis. Nature 488, 527-30

• Simons BD and Clevers H (2011) Strategies for homeostatic stem cell self-renewal in adult tissues. Cell 145, 851-62

• Lopez-Garcia C, et al. (2010) Intestinal stem cell replacement follows a pattern of neutral drift. Science 330, 822-825

• Clayton E, et al. (2007) A single type of progenitor cell maintains the epidermis. Nature 446, 185-189