Descripción del proyecto
Regulación colectiva de células madre hematopoyéticas
Las células madre hematopoyéticas (CMH, o HSC por sus siglas en inglés) producen células sanguíneas durante toda la vida y están presentes en la médula ósea de los adultos. En la edad adulta, la gran mayoría de las CMH pasan de manera sincronizada a un estado inactivo mientras que unas pocas pasan a un ciclo celular activo para compensar la pérdida de CMH basales debido a la diferenciación o la muerte celular. El proyecto IC-CCD-qHSC, financiado con fondos europeos, se propone evaluar la hipótesis de que la interferencia molecular entre CMH proximales les permite detectar sus densidades locales y desencadena la regulación colectiva de la función de las CMH para preservar la homeostasis. Los objetivos son determinar las características anatómicas y funcionales de las dependencias espaciales entre las CMH, estudiar los mecanismos de detección de cuórum en la diafonía de las CMH e investigar la posible competencia por los recursos moleculares en los vecindarios celulares locales.
Objetivo
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.
Ámbito científico
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Programa(s)
Régimen de financiación
ERC-COG - Consolidator GrantInstitución de acogida
8006 Zurich
Suiza