Les cellules de la moelle osseuse: Une cible reelle des estrogenes dans la protection cardiovasculaire?

摘要

It is generally well accepted that endothelial progenitor cells derived from the bone marrow exert an important regulatory role in the maintenance of cardiovascular homeostasis. Recently, the discovery of the implication of endothelial progenitor cells in estrogens-induced cardiac repair has generated a great interest. Still, it remains unknown if estrogens naturally modulate level of circulating endothelial progenitor cells in women. Such regulation could partially explain the lower prevalence of cardiovascular events in women at middle age compared to men. In addition, even if in several models, estrogens were able to act directly on endothelial progenitor cells to increase their mobilisation and their functionality; it remains unclear if estrogens modulate only endothelial progenitor cells or whether they can act more broadly to protect the cardiovascular system by regulating processes involved in the functional organization of the stem cell niche.;Our results suggest a physiological regulation of the availability and the maturity of endothelial progenitor cell subpopulations in premenopausal women throughout menstrual cycle. This regulation occurs in parallel with 17beta-estradiol blood level which, based on a comprehensive analysis of 17beta-estradiol action, suggests an active role for this molecule on the mobilization of endothelial progenitor cells in women. In addition, greater mean global number of several endothelial progenitor cell subpopulations was found in women compared to men. This particularity helped us identifying 17beta-estradiol as a predictive factor for the gender differences perceived.;It appears that 17beta-estradiol treatment alters the genome expression pattern in both stem cells and stromal cells of the bone marrow. Among the genes modulated, we were able to identify key factors involved in signalling processes and cellular interactions by which 17beta-estradiol regulates the functional organisation of the bone marrow stem cell niche. It is now evident that 17beta-estradiol, by direct actions on stem cells and indirect actions via stromal cells, influences biological processes involved in mediating and balancing the quiescence, self-renewal, commitment, proliferation and mobilisation of stem cells certainly contributing to its reparative benefits on the cardiovascular system.;Our work thus proposes a direct action of estrogens on endothelial progenitor cells and the functional organisation of the bone marrow. This action will certainly be beneficial to the development of novel therapeutics in the prevention and treatment of cardiovascular diseases.;This project was thus designed to (I) evaluate, in vivo, if menstrual cycle influences circulating levels and maturity of endothelial progenitor cells in normally menstruating women and if this could underline gender differences and (II) determine, in vitro, the influence of 17beta-estradiol on biological processes involved in the functional organization of the stem cell niche.;Keywords. estrogens, endothelial progenitor cells, stem cell niche, bone marrow and cardiovascular system.