The crosstalk between hematopoietic progenitors and the stromal environment, composed of endothelial and mesenchymal cells, modulates bone marrow hematopoiesis. Aging is accompanied by increased numbers of hematopoietic progenitors that have lower self-renewal capacity and can no longer produce lymphocytes. Aging individuals have fewer naïve lymphocytes and impaired responses to new antigenic stimuli and to vaccination protocols, and telomere dysfunction can result in myelodysplasia. These hematopoietic defects have been attributed to accumulated abnormalities in both hematopoietic progenitors and stroma, although the nature of the contribution of each compartment to the physiopathology of aging is unclear.
Progeroid syndromes, as the Hutchinson-Gilford Progeria Syndrome (HGPS) are characterized by premature aging with stem cell dysfunction that recapitulates some molecular, cellular and organismal aspects of physiologic aging. We described a telomeric protein (Ft1 in mouse) involved in progeria and generated a hypomorphic Ft1 mouse model that displays a progeroid phenotype. Recently we obtained a constitutive knock out model and a tissue specific (SM-22) knock out model, targeting stromal progenitors, that shows specific signs tissue specific developmental defects and progeroid traits. Our objective is to determine the extent to which hematopoietic abnormalities in physiologic aging relate to those in progeroid syndromes and establish the implication of the stromal compartment. We will conduct a cellular, functional and molecular characterization of hematopoietic cells and stroma in the bone marrow of mice deficient in Ft1 (hypomorphic and constitutive and SM-22 knock out models) and compare them to those in progerin knock-in (model for HGPS) and normal aged mice.
The proposed study will address the molecular basis of hematopoietic aging creating the conceptual basis to devise new strategies to complement the hematopoietic system of the aging population.
