PhD PROPOSAL FOR THE PASTEUR-PARIS UNIVERSITY INTERNATIONAL PROGRAM

 

Deadline for full application: December 15th, 2013

 

Interviews: March, 2014

Start of the Ph.D.: October 1st, 2014

 

 

 

Department:  Immunology

Title of the PhD project: The signals that regulate homeostasis of hematopoietic stem cells

Name of the lab: Lymphopoiesis

Head of the lab: Ana Cumano

PhD advisor: Ana Cumano

Email address: ana.cumano@pasteur.fr

Web site address of the lab:

Doctoral school affiliation and University: Paris VII

B2ME

 

 

Presentation of the laboratory and its research topics:

 

The main objectives of the laboratory are the identification of the mechanisms underlying the establishment of the hematopoietic system and more specifically of the immune system

 

 

 

Description of the project:

(1 page, Arial font size 11 : 600 words in total with at least 50% dedicated specifically to the proposed PhD project(s))

 

The signals that regulate homeostasis of hematopoietic stem cells

 

The establishment of a functional hematopoietic system takes place in the fetal liver (FL). Hematopoietic progenitors, generated in the dorsal aorta, home to the FL where they differentiate to give mature blood cells. They also expand, from a few hundred cells by E11, to reach 5000-10000 hematopoietic stem cells (HSC), at E15. However, in the bone marrow (BM), they reach a homeostatic equilibrium and are unable to expand, in steady-sate conditions. At 4 weeks of age, more than 70% of HSC are in G0 phase of the cell cycle. In response to particular stimuli, from which the most common is infection, BM HCS can massively proliferate. Our project has four objectives:

1. Identifying the stromal compartment, in FL.

The non-hematopoietic cells (stroma) that provide, in FL, the signals controlling HSC expansion and differentiation, remain poorly characterized. We have identified a novel stromal subset, in FL. We will use a set of mutant mouse strains, where this newly defined stromal population has been targeted: 1. to visualize hematopoietic/stromal interactions and their specific function. 2. to define, in vivo, the implication of this stromal subset in HSC expansion and differentiation.

2. Characterizing the signals from FL stroma, inducing HSC expansion.

To identify FL stromal signals responsible of HSC expansion, we will perform differential microarray analyses of stromal cells from normal and mutant mice with a defective stroma. Microarray comparisons will also be applied to fetal endothelial cell subset and adult hepatocytes.

3. Probing the HSC compartment, in mice devoid of bacterial stimulation.

To test if stimulation through molecules released by commensal bacteria is implicated in HSC homeostasis, we will characterize BM HSC isolated from conventional, SPF, germ-free mice, as well as from NOD1/NOD2 and MyD88/Trif double mutants, that do not sense bacterial molecular products.

 

References:

 

 

12-03 A. Kieusseian, P. Brunet de la Grande, O. Burlen-Defranoux, I. Godin & A. Cumano.

Immature hematopoietic stem cells undergo maturation to HSC in the fetal liver. 2012.

Development 139 : 3521-3530

 

11-03 C. Possot, S. Schmutz, S. Chea, L. Boucontet, A. Louise, A. Cumano & R. Golub.

Notch signaling is necessary for adult, but not fetal, development of RORgt+ innate lymphoid cells. 2011.

Nature Immunol. 12 : 949-959

 

13-03. Delphine Guy-Grand, Pierre Vassalli, Gerard Eberl, Pablo Pereira, Odile Burlen-Defranoux, Fabrice Lemaitre, James P. Di Santo, Antonio A. Freitas, Ana Cumano, and Antonio Bandeira

Origin, trafficking, and intraepithelial fate of gut-tropic T cells. 2013

J. Exp. Med. 210:1839-1854

 

13-04. Marie Le Bouteiller,1,2 Céline Souilhol,1,2 Sarah Beck-Cormier,1,2
Aline Stedman,1,2 Odile Burlen-Defranoux,3 SandrineVandormael-Pournin,1,2 Florence Bernex,4 Ana Cumano,3 and Michel Cohen-Tannoudji

Notchless-dependent ribosome synthesis is required for the maintenance of adult hematopoietic stem cells. 2013

J. Exp. Med. In press

 

 

Keywords: hematopoiesis, stem cells, fetal liver

 

 

 

 

Expected profile of the candidate (optional):

 

 

 

 

 

Contact: ana.cumano@pasteur.fr

 

 

Mis à jour le 16/09/2013