Descrizione del progetto
Regolazione collettiva delle cellule staminali ematopoietiche
Le cellule staminali ematopoietiche (CSE) contribuiscono alla produzione delle cellule del sangue nel corso della vita e sono presenti nel midollo osseo degli adulti. Nell’età adulta, la grande maggioranza delle CSE raggiungono in modo sincrono uno stato di quiescenza e poche di loro si presentano negli stati attivi del ciclo cellulare, compensando la perdita di CSE di base a causa di differenziazione o morte cellulare. L’obiettivo del progetto IC-CCD-qHSC, finanziato dall’UE, consiste nel testare l’ipotesi per cui l’interazione molecolare tra CSE prossimali consenta loro di percepire le proprie densità locali e innescare la regolazione collettiva della funzione delle CSE per preservare l’omeostasi. Gli obiettivi sono definire le caratteristiche anatomiche e funzionali delle dipendenze spaziali tra CSE, studiare i meccanismi di quorum-sensing nell’interazione delle CSE e approfondire la possibile competizione per le risorse molecolari in siti di vicinanza delle cellule.
Obiettivo
Hematopoietic stem cells (HSCs) contribute to blood cell production throughout life and are found at rare, yet tightly regulated frequencies in adult bone marrow (BM). During embryonic and postnatal development, HSCs expand through continuous self-renewing proliferation. Upon entry into adulthood the vast majority of HSCs synchronously convert to a quiescent state. From then on, at any given moment very few HSCs are found in active stages of cell cycle, which suffices to compensate basal HSC loss due to differentiation or cell death. Since proliferation rates of individual HSCs are heterogeneous, entry and exit from cell cycle need to be coordinated at the level of the HSC pool. To date, the mechanisms that orchestrate this collective proliferative behavior and effectively control the maintenance of homeostatic HSC numbers remain unknown. In preliminary work for this project we have customized a pipeline that combines 3D microscopy, deep learning-based image analysis and spatial statistics. Using these tools, we observed that despite showing broad spatial heterogeneity, HSCs tend to cluster and accumulate in relatively large regions of the BM. We now postulate that molecular crosstalk between proximal HSCs enables them to perceive their local densities and triggers collective regulation of HSC function to preserve homeostasis. Through a multidisciplinary approach involving high-level microscopy, spatial analyses, comprehensive metabolomic profiling and single-cell transcriptomics we aim to 1) characterize the basic anatomical and functional features of spatial dependencies between HSCs 2) study the potential role of quorum-sensing mechanisms in HSC crosstalk and 3) investigate if competition for molecular resources in local neighborhoods contributes to maintenance of HSC homeostasis. Our research has the potential to unravel novel complex forms of cellular interplay and substantially advance our understanding of hematopoietic tissue organization.
Campo scientifico
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Meccanismo di finanziamento
ERC-COG - Consolidator GrantIstituzione ospitante
8006 Zurich
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