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Ben Simons

simonsBen Simons PhD, Herchel Smith Professor at the Cavendish Laboratory in Cambridge, Associate Group Leader at the Gurdon Institute.

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Mechanisms of stem cell fate in development, homeostasis and disease

2016 SimonsHow do stem cells regulate fate behaviour to specify and maintain tissues? Stem cells are defined by their capacity to self-renew while giving rise to differentiating progeny. In development, the balance between proliferation and differentiation must be controlled to specify tissues of the correct size, patterning and composition. In the adult, stem cells must achieve a perfect balance between proliferation and differentiation to achieve homeostasis.

To address the mechanisms that regulate stem cell fate we combine genetic lineage tracing and in vivo live-imaging approaches with methods from statistical physics. Applied to epithelial tissues including epidermis, intestine and testis, our studies have shown that stem cells are not individually long-lived, but are constantly lost and replaced. Further, stem cells are not invariant, but may transit reversibly between states poised for renewal or primed for differentiation.

As well as questioning stem cell identity and the mechanisms that underpin cell heterogeneity and flexibility, these studies establish a quantitative platform to explore pathways leading to tumour initiation and progression.

Selected publications:

• Sánchez-Danés, A et al. (2016) Defining the clonal dynamics leading to mouse skin tumour initiation. Nature; 8 July 2016; DOI: 10.1038/nature19069

• Wuidart A et al. (2016) Quantitative lineage tracing strategies to resolve multipotency in tissue-specific stem cells. Genes Dev. 30(11):1261-77.

• Otani T et al. (2016) 2D and 3D Stem Cell Models of Primate Cortical Development Identify Species-Specific Differences in Progenitor Behavior Contributing to Brain Size. Cell Stem Cell 18(4): 467-80.

• Chabab S et al. (2016) Uncovering the Number and Clonal Dynamics of Mesp1 Progenitors during Heart Morphogenesis. Cell Reports 14(1): 1–10.

• Roshan A et al. (2016) Human keratinocytes have two interconvertible modes of proliferation. Nat Cell Biol. 18(2):145-56. 

• Kolahgar G et al. (2015) Cell competition modifies adult stem cell and tissue population dynamics in a JAK-STAT dependent manner. Developmental Cell 34(3):297-309. Featured Article 

• Watson JK et al. (2015) Clonal Dynamics Reveal Two Distinct Populations of Basal Cells in Slow Turnover Airway Epithelium. Cell Reports 12:1-12

 • Mascre G et al. (2012) Distinct contribution of stem and progenitor cells to epidermal maintenance. Nature, 489, 257-62

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

groupSimons2015

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 represents 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. Using 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.

Co-workers

Philip Greulich • Seungmin Han • Edouard Hannezo • David Jorg • Steffen Rulands