Stem Cells and Tissue Homeostasis

Bardin

Allison Bardin Chef d'équipe Tel:

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.

Figure 1 : A. ISCs (red), enteroblast progenitors (gray), 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% or the time or an enteroendocrine cell 20% or the time.
Figure 1 : A. ISCs (red), enteroblast progenitors (gray), 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% or the time or an enteroendocrine cell 20% or the time.

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?

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).

Figure 2: 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).
Figure 2: 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).

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.

Key publications

Year of publication 2015

Katarzyna Siudeja, Sonya Nassari, Louis Gervais, Patricia Skorski, Sonia Lameiras, Donato Stolfa, Maria Zande, Virginie Bernard, Thomas Rio Frio, Allison J Bardin (2015 Dec 3)

Frequent Somatic Mutation in Adult Intestinal Stem Cells Drives Neoplasia and Genetic Mosaicism during Aging.

Cell stem cell : 663-74 : DOI : 10.1016/j.stem.2015.09.016
Delphine Gogendeau, Katarzyna Siudeja, Davide Gambarotto, Carole Pennetier, Allison J Bardin, Renata Basto (2015 Nov 17)

Aneuploidy causes premature differentiation of neural and intestinal stem cells.

Nature communications : 8894 : DOI : 10.1038/ncomms9894

Year of publication 2013

Juliette Mathieu, Clothilde Cauvin, Clara Moch, Sarah J Radford, Paula Sampaio, Carolina N Perdigoto, François Schweisguth, Allison J Bardin, Claudio E Sunkel, Kim McKim, Arnaud Echard, Jean-René Huynh (2013 Aug 12)

Aurora B and cyclin B have opposite effects on the timing of cytokinesis abscission in Drosophila germ cells and in vertebrate somatic cells.

Developmental cell : 250-65 : DOI : 10.1016/j.devcel.2013.07.005
Carolina N Perdigoto, Allison J Bardin (2013 Feb 4)

Sending the right signal: Notch and stem cells.

Biochimica et biophysica acta : 2307-22 : DOI : 10.1016/j.bbagen.2012.08.009
Mahéva Andriatsilavo, Louis Gervais, Clara Fons, Allison J Bardin (2013 Jan 25)

[The Drosophila midgut as a model to study adult stem cells].

Médecine sciences : M/S : 75-81 : DOI : 10.1051/medsci/2013291016

Year of publication 2012

Joaquín de Navascués, Carolina N Perdigoto, Yu Bian, Markus H Schneider, Allison J Bardin, Alfonso Martínez-Arias, Benjamin D Simons (2012 May 30)

Drosophila midgut homeostasis involves neutral competition between symmetrically dividing intestinal stem cells.

The EMBO journal : 2473-85 : DOI : 10.1038/emboj.2012.106
All publications