Stem Cells and Tissue Homeostasis

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Group leader : Allison Bardin
Stem Cells and Tissue Homeostasis

Keywords

Stem cells, Proliferation, Differentiation, Development, Somatic mutation

Plain english

We are using the stem cells in the adult intestine of Drosophila to uncover general mechanisms controlling stem cells and their differentiated daughter progeny. Our work takes advantage of the sophisticated genetic tools available in Drosophila and high-resolution confocal imaging to investigate the cell biology of the intestine. 

Allison Bardin, PhD

Stem cells and tissue homeostasis

Institut Curie / CNRS UMR3215 / INSERM U934
11-13 rue Pierre et Marie Curie
75248 Paris Cedex 05

 Tel: +33 1 56 24 65 62
Fax: +33 1 56 24 63 19

Email: allison.bardin@curie.fr

 

 

   Stem cells are essential for development and continued maintenance of tissues and organs. They are characterized by their ability to self-renew as well as to produce differentiated progeny. Understanding the dual capacity of self-renewal and differentiation is an important aim of regenerative medicine and also has implications for cancer biology. The aim of work in our group is to identify mechanisms important for these processes and ultimately to understand how they function collectively to promote homeostasis of a tissue.  To do so, we are using a simplified model system, the Drosophila intestine  which contains around 1000 multipotent intestinal stem cells (Fig. 1). The intestinal stem cells produce the two differentiated cell types required for organ function: the enterocytes and enteroendocrine cells.  The differentiated cells are replaced approximately once a week in healthy animals but can be stimulated to rapidly regenerate the intestine upon infection by pathogenic bacteria or treatment with damaging agents (DSS, paraquat). Thus, this is an excellent simple model for mammalian tissues such as the intestine, lung or skin that need to regenerate in response to environmental stimuli.  

   We are using this model system to address several important questions: How is the proliferation of the stem cell regulated? What controls the differentiation choice of the stem cell? In addition, we are using this model to understand the first steps of cancer initiation: how do somatic mutations arise?  What are their consequences on adult stem cells and tissues?

 Fig.1: The drosophila intestine: A. ISCs (red), enteroblast progenitors (grey), enterocytes (EC, blue) and enteroendocrine (ee, green) cells form the epithelia of the midgut. B. The ISC is multipotent: it divides to produce an ISC and a daughter cell, the enteroblast (EB) that will differentiate into one of two types of cells, an enterocyte cell 80% of the time or an enteroendocrine cell 20% of the time.  Fig.1: The drosophila intestine: A. ISCs (red), enteroblast progenitors (grey), enterocytes (EC, blue) and enteroendocrine (ee, green) cells form the epithelia of the midgut. B. The ISC is multipotent: it divides to produce an ISC and a daughter cell, the enteroblast (EB) that will differentiate into one of two types of cells, an enterocyte cell 80% of the time or an enteroendocrine cell 20% of the time.  

 

Fig.2: Stem cell proliferation deregulation mutants: A. A wild-type stem cell generates lineages (marked in green) containing a single stem cell (red marker) and differentiated cells. B. Upon inactivation of a chromatin-remodeling factor, stem cells overproliferate to produce rapidly growing clusters of stem cells (marked in red).Fig.2: Stem cell proliferation deregulation mutants: A. A wild-type stem cell generates lineages (marked in green) containing a single stem cell (red marker) and differentiated cells. B. Upon inactivation of a chromatin-remodeling factor, stem cells overproliferate to produce rapidly growing clusters of stem cells (marked in red).

 

     Proliferation control: In order to gain broader insight into proliferation and differentiation control of ISCs, we have conducted an EMS-based genetic screen to identify novel regulators. We are currently focusing several genes identified In this screen including regulators of chromatin remodeling that conserved in mammals, mutated in human cancers, and are essential in the fly intestine to limit stem cell proliferation (Fig. 2).

    Differentiation control:  Our past work (Bardin, AJ, 2010) has identified the achaete-scute transcription factors as being essential for stem cell differentiation into enteroendocrine cells. We have now identied additional factors controlling enteroendocrine differentiation and are studying their mechanisms of action.  This will provide insight into how an accurate balance of terminal cell fates is achieved in homeostatic adult tissues.

    Spontaneous mutation: We are using the adult fly intestine to understand the mechanisms underlying spontaneous mutation. In particular, we would like to understand the role of diet, pathogenic bacteria, and additional environmental components in promoting mutation.

 

 

 

Our lab is part of the LABEX DEEP - Development, Epigenesys, Epigenetics, Potential (2012-2020)

Key publications

  • Year of publication : 2012

  • The Drosophila adult posterior midgut has been identified as a powerful system in which to study mechanisms that control intestinal maintenance, in normal conditions as well as during injury or infection. Early work on this system has established a model of tissue turnover based on the asymmetric division of intestinal stem cells. From the quantitative analysis of clonal fate data, we show that tissue turnover involves the neutral competition of symmetrically dividing stem cells. This competition leads to stem-cell loss and replacement, resulting in neutral drift dynamics of the clonal population. As well as providing new insight into the mechanisms regulating tissue self-renewal, these findings establish intriguing parallels with the mammalian system, and confirm Drosophila as a useful model for studying adult intestinal maintenance.
  • Year of publication : 2011

  • Tight regulation of self-renewal and differentiation of adult stem cells ensures that tissues are properly maintained. In the Drosophila intestine, both commitment, i.e. exit from self-renewal, and terminal differentiation are controlled by Notch signaling. Here, we show that distinct requirements for Notch activity exist: commitment requires high Notch activity, whereas terminal differentiation can occur with lower Notch activity. We identified the gene GDP-mannose 4,6-dehydratase (Gmd), a modulator of Notch signaling, as being required for commitment but dispensable for terminal differentiation. Gmd loss resulted in aberrant, self-renewing stem cell divisions that generated extra ISC-like cells defective in Notch reporter activation, as well as wild-type-like cell divisions that produced properly terminally differentiated cells. Lowering Notch signaling using additional genetic means, we provided further evidence that commitment has a higher Notch signaling requirement than terminal differentiation. Our work suggests that a commitment requirement for high-level Notch activity safeguards the stem cells from loss through differentiation, revealing a novel role for the importance of Notch signaling levels in this system.
  • Year of publication : 2010

  • Adult stem cells maintain tissue homeostasis by controlling the proper balance of stem cell self-renewal and differentiation. The adult midgut of Drosophila contains multipotent intestinal stem cells (ISCs) that self-renew and produce differentiated progeny. Control of ISC identity and maintenance is poorly understood. Here we find that transcriptional repression of Notch target genes by a Hairless-Suppressor of Hairless complex is required for ISC maintenance, and identify genes of the Enhancer of split complex [E(spl)-C] as the major targets of this repression. In addition, we find that the bHLH transcription factor Daughterless is essential to maintain ISC identity and that bHLH binding sites promote ISC-specific enhancer activity. We propose that Daughterless-dependent bHLH activity is important for the ISC fate and that E(spl)-C factors inhibit this activity to promote differentiation.