DS0402 - Décryptage des fonctions biologiques élémentaires et de leur intégration

IDENTIFYING THE DRIVERS OF LUNG RESIDENT VASCULAR PROGENITORS RECRUITMENT CONTRIBUTING TO PULMONARY ARTERIAL HYPERTENSION DEVELOPMENT – PAHVAP

Submission summary

Pulmonary arterial hypertension (PAH) is a rare and life-limiting cardiovascular disorder with no curative options, characterized by an occlusive remodeling of the distal pulmonary vasculature that ultimately leads to right heart failure. Recent studies suggest that vascular resident progenitor cells could be involved in the pulmonary vascular remodeling during PAH. Our results show that smooth muscle cells (VSMC) of small pulmonary vessels differentiate from lung progenitor cells expressing a marker recently identified by a collaborating team. We have used an original transgenic mouse tool which allows us an easy detection, quantification and isolation (for in vitro culture) of progenitor cells and of cells recently derived from these progenitors. We have shown that the lung progenitor cells identified by this marker are perivascular (both in mouse and human lung), that they express other progenitor markers and that they can differentiate in VSMCs in vitro and in vivo. We also observed that their number and the number of VSMCs derived from these progenitors are increased at an early stage in a mouse PAH experimental model induced by chronic hypoxia. Preliminary results suggest that these progenitors are also induced during human PAH. These results show that we have identified a pulmonary progenitor that participate in small vessel muscularization during PAH development.
Our project seeks to better understand the role and the regulation of these pulmonary vascular progenitors involved in the vascular wall hyperplasia during pulmonary arterial hypertension and to develop therapeutic tools targeting these progenitors
Our aims are to answer these 3 complementary questions:
1. What is the importance of these cells in pulmonary vascular remodeling during mouse and human PAH?
- We will identify, in vitro and in vivo, the progenitor subpopulations that differentiate into vascular cells during chronic hypoxia-induced vascular remodeling and determine the hierarchical link between the different populations of progenitor cells.
- We will isolate and culture the human pulmonary progenitors, confirm their recruitment during human PAH and compare their function with progenitors from control patients
2. What are the mechanisms involved in the recruitment of progenitors during PAH?
3. We will determine, in vitro and in vivo, the role of key pathways for PAH development and progenitors function: FGF-2, IL-6 and PDGF-PDGFR?. Can we inhibit the recruitment of progenitors and thereby prevent PAH development?
- We will modify the hypoxia-induced vascular remodeling by inactivating the marker gene and determine the effects on the progenitors function in vitro and in vivo
- We will test existing tyrosine kinase receptor inhibitors to target in vitro the proliferation and differentiation of these progenitors
Our transgenic mouse model combined with other transgenic models constitutes an original, specific and innovative tool, which allows us to study the early regulation of progenitor cells participation in the development of the disease and place this project in a unique competitive position to achieve these goals. The expected outcome of this research project is a better understanding of the molecular mechanisms driving human and mouse progenitors proliferation, differentiation and participation to the occlusive remodeling of the distal pulmonary vasculature. This project also allows us to develop tools (i.e. cultured human and rodent progenitors) to study in the future the functional pathways regulated in progenitors during PAH (through transcriptomic and proteomic studies) and to test the effect of therapeutic molecules on their function. This project could hence allow the development of new therapeutic tools.

Project coordination

Sophie NADAUD (Institut de recherche sur les maladies cardiovasculaires, du métabolisme et de la nutrition. UMR_S 1166)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

UPMC Institut de recherche sur les maladies cardiovasculaires, du métabolisme et de la nutrition. UMR_S 1166
INSERM INSERM UMR_S 999 - Hypertension artérielle pulmonaire, pathophysiologie et innovation thérapeutique

Help of the ANR 430,639 euros
Beginning and duration of the scientific project: September 2015 - 48 Months

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