Sustained production of mature blood cell types relies on the continuous differentiation and self-renewal of a rare subset of hematopoietic stem and progenitor cells (HSPCs). HSPCs reside in bone marrow (BM) cavities within defined anatomical locations, also known as niches, where they receive and integrate regulatory cues that control their functional capacities to suit the changing physiological demands. BM spaces are extremely complex environments containing hematopoietic cells at different stages of differentiation, a heterogeneous stromal cell compartment of mesenchymal origin, an intricate vascular network and cells involved in bone metabolism. Not until recently have we started to gain some insight of the 3-d microanatomical organization, the population dynamics and the regulatory roles of these specialized subsets.
During the aging process, HSPCs experience a functional decline, which critically contributes to the age-related disorders of the hematopoietic system. As HSPCs undergo stringent regulation from specific niche components, age-related alterations of HSPC physiology are hypothesized to, at least partially, derive from microenvironmental, HSPC-extrinsic factors. Notably, the functional and structural transformations that BM stromal and vascular populations undergo as a result of aging, are poorly characrterized to date.
The fundamental aim of this proposal is to exploit novel imaging technologies and flow cytometric analysis to visualize, quantify and reconstruct in 3-dimensions the dynamics of the aging of BM microenvironment. Subsequently, we intend to describe how aged induced disorders of BM stroma ultimately control HSPC maintenance and perturb the homeostatic regulation of the hematopoietic system.
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