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.
The molecular events that drive multipotent progenitors along the lymphoid pathway of differentiation are still poorly understood. Aging is one of the major challenges in Western societies that saw the life expectancy of the population increase by 20 years in the last half century. Aging is accompanied by major alterations of the hematopoietic system with increased numbers of phenotypically defined HSC that have lower self-renewal capacity and can no longer produce lymphocytes. As a result aging individuals have fewer naïve lymphocytes and increased numbers of memory cells resulting in impaired responses to new antigenic encounters and reduced efficacy of vaccination protocols. Moreover, myelopoiesis although kept to its normal levels is affected in aging and telomere dysfunction in common myeloid progenitors can result in myelodysplasia. To be able to devise new strategies to complement the hematopoietic system of the aging population we need to understand the cellular and molecular mechanisms underlying hematopoietic aging. Progeroid syndromes recapitulate molecular, cellular and organismal aspects of aging. This implies that, from the study of the physiopathological paths of progerias, one can extrapolate significant information on the molecular bases of physiologic aging.
This project will set the basis for a rigorous analysis the hematopoietic and the surrounding stromal compartments. Progeroid syndromes implicate crucial biological pathways including DNA replication, DNA damage, and nuclear architecture and are therefore a matter of general scientific interest. The use of pathophysiological cellular and animal models to analyze these processes will help unraveling the interplay between the different factors involved, and how single molecular determinants as well as the overall nuclear structure act, in the cell, and in the organism, contributing to understanding the biological complexity underlying not only progeria, but also aging. Particularly relevant in the future years will be to understand how the molecular alterations of aged cells/organisms contribute to stem cell exhaustion and cancer development.
References of the entire project
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