Ceramide blockade in murine hematopoietic stem cells
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ABSTRACT:
PROVIDER: PRJNA939906 | ENA |
REPOSITORIES: ENA
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Project description:Hematopoietic stem and progenitor cells (HSPCs) rely upon cellular crosstalk, including extracellular vesicles (EVs) for lifelong niche occupancy and cellular function. Vesicle secretion is tightly linked to intracellular homeostasis; however, these mechanisms are poorly understood in HSPCs, particularly at the single-cell level. In this study, we target ceramide-dependent EV secretion by pharmacologic blockade in ex vivo expanded HSPCs. We use these cells to investigate single-cell resolution of short-term and delayed transcriptional changes induced by ceramide-EV inhibition.
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Project description:Cellular crosstalk within the bone marrow niche maintains hematopoietic stem and progenitor cell (HSPC) integrity and safeguards lifelong blood and immune cell production. Deeper understanding of reciprocal niche signals governing crucial properties of HSPCs is relevant to the pathophysiology of blood disorders and improving HSPC transplantation. Extracellular vesicles (EVs) are key factors of the HSPC secretome, providing signals that regulate homeostasis and stemness. Here we demonstrate ex vivo blockade of ceramide-dependent vesicle secretion from HSPCs activates an integrated stress response (ISR), promoting downstream mTOR inhibition and metabolic quiescence. Crucially, ceramide-EV depletion leads to striking improvements in long-term transplantation. The aggregate findings link ceramide-dependent EV secretion and the ISR as a regulatory dyad guarding HSPC homeostasis and long-term fitness. Translationally, these data support exploration of ceramide inhibition during ex vivo maintenance of HSPCs for adoptive transfer.
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