Bone marrow microenvironment dynamics
Mammalian BM cavities contain highly dynamics tissues of unique functional and cellular complexity. Besides serving as principal hematopoietic sites during adulthood, BM tissues provide the necessary environment for the development of immune responses, and maintenance of immunological memory. The hematopoietic components of the BM are embedded within a highly complex stromal framework, which beyond lending more structural support, actively participates in the regulation of hematopoiesis. BM stromal constituents comprise dense microvascular networks, a hierarchically organized mesenchymal compartment and cells of neural origin. Our research program seeks to better dissect the cellular make-up of BM stroma, understand how stromal components assemble in unique spatial configurations and how they contribute to the regulation of BM hematopoietic and immunological function. Our goal is to ultimately how the BM structural integrity is fundamentally altered in pathological conditions, how this affects tissue organization and spezialized niche function, and the molecular and cellular mechanisms by which a fully competent/functional BM microarchitecture is regenerated post-injury.
For this purpose we employ advanced quantitative microscopy techniques that enable us to visualize, analyze and quantify the different cellular and non-cellular components found in large regions BM tissues in two and three-dimensions at subcellular resolution.
Hematopoietic Stem and Progenitor Cell niches
Hematopoietic stem and progenitor cells (HSPCs) are self-renewing, multipotent cells that sustain the continuous production of mature blood cells. HSPCs are thought to reside within the complex ecosystem of the BM in defined anatomical locations, termed niches, where they receive specific regulatory cues from neighboring cells, extracellular matriz and soluble proteins. Given the prominent role of HSPCs at the apex of the hematopoietic hierarchy, the precise description of HSPC niches in the BM is of critical importance to understand hematopoietic regulation and has major implications in regenerative medicine.
Using Laser Scanning Cytometry, we have recently provided a quantiative and comprehensive analysis of HSCP distribution in the BM and defined their interactions with both sinusoidal (venous equivalent of the BM) and arterial microvessels (Nombela-Arrieta et al, Nat Cell Biol. 2013 May; 15(5):533-43 see publications). We also employed this technology to analyze how localization in different BM regions regulated the hypoxic status of HSPCs.
One of the main goals of our research is to characterize how loss of HSPC functionality under certain pathologic conditions correlates with abnormalities in spatial distribution or loss of structural integrity of homeostatic HSPC niches.