The coordination of cell proliferation and fate specification is central to the development and maintenance of tissues. In development, systems must be tightly-regulated to ensure that precise numbers of lineage-specified cells are generated in the correct sequence whilst, in adult, a delicate balance between proliferation and differentiation is essential for homeostasis. Through a programme of interdisciplinary and collaborative research, our group is interested in establishing unifying principles of stem cell regulation in the development and maintenance of tissues, and to use them to resolve pathways leading to dysregulation in diseased states.


Theories of 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 remains fixed imposing an absolute requirement for fate asymmetry in the daughters of dividing cells, such that only half are retained. 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.


By drawing upon concepts from physics and mathematics, we have shown that strategies of stem cell self-renewal can be classified according to whether fate is specified by internal or extrinsic factors, and whether it leads to invariant asymmetric self-renewal or population asymmetry. As well as achieving a functional classification of stem cell types, this identification provides a general framework that we are using to interpret lineage tracing data. To develop this programme, we are involved in multiple collaborations, addressing different tissue types from epidermis and gut, to retina and germline. Current collaborators include Erika Bach, Cedric Blanpain, Lazaro Centanin, Hans Clevers, Sam Janes, Phil Jones, Allon Klein, Alfonso Martinez-Arias, Emma Rawlins, Wolf Reik, Hongjun Song, Doug Winton, Jochen Wittbrodt, and Shosei Yoshida.


In a related programme, we are also using lineage tracing methodologies to elucidate patterns of progenitor cell fate in the late stage development of tissues. Current collaborators include Cedric Blanpain (prostate and heart), Rick Livesey and Magdalena Goetz (cortex), Bill Harris and Michel Cayouette (retina), Kim Jensen (intestine), Anna Philpott and Jenny Nichols (pancreas and diabetes), and Fiona Watt (dermis). Finally, we are also making use of lineage tracing methods to investigate how stem and progenitor cells become subverted in tumour-initiation. Current collaborators include Hans Clevers (intestinal adenomas), Cedric Blanpain and Phil Jones (skin tumours), Tony Green (leukaemia), and Colin Watts (glioblastoma).


Plain English:
In adult, many tissues such as 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 the 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 aging.

 

Selected publications:

• He J, Zhang G, Almeida AD, Cayouette M, Simons BD, and Harris WA (2012) How variable clones build an invariant retina. Neuron 75, 786-98

• Mascre G, Dekoninck S, Drogat B, Youssef KK, Brohee S, Sotiropoulou PA, Simons BD, and Blanpain C (2012) Distinct contribution of stem and progenitor cells to epidermal maintenance. Nature 489, 257-62

• Driessens G, Beck B, Caauwe A, Simons BD, and Blanpain C (2012) Defining the mode of tumour growth by clonal analysis. Nature 488, 527-30

• Doupe DP, Alcolea MP, Roshan A, Zhang G, Klein AM, Simons BD, and Jones PH (2012) A single progenitor population switches behavior to maintain and repair esophageal epithelium. Science 337, 1091-3

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

• Snippert HJ, van der Flier LG, Sato T, van Es JH, van den Born M, Kroon-Veenboer C, Barker N, Klein AM, van Rheenen J, Simons BD and Clevers H (2010) Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 143, 134-144

• Lopez-Garcia C, Klein AM, Simons BD, and Winton DJ (2010) Intestinal stem cell replacement follows a pattern of neutral drift. Science 330, 822-825

• Klein AM, Nakagawa T, Ichikawa R,Yoshida S, and Simons BD (2010) Mouse germ line stem cells undergo rapid and stochastic turnover. Cell Stem Cell 7, 214-224

• Clayton E, Doupe DP, Klein AM, Winton D, Simons BD, and Jones PH (2007) A single type of progenitor cell maintains the epidermis. Nature 446, 185-189