Professor Ben Simons
Ben is Professor of Theoretical Condensed Matter Physics at the Cavendish Laboratory in Cambridge and is currently a sabbatical visitor at the Gurdon Institute
Patterns of stem cell fate in adult and developing tissues
Co-workers: Teresa Krieger
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.
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 Cedric Blanpain, Hans Clevers, Philip Jones, Emma Rawlins, Shosei Yoshida, and Jochen Wittbrodt.
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 Rick Livesey and Magdalena Zernicka-Goetz (cortex), Cedric Blanpain (prostate and heart), Bill Harris and Michel Cayouette (retina), 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 Philip Jones (skin tumours), and Tony Green (leukaemia).
• 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
• Doupé 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