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Transcriptional profiles of HSCs from control and ABX-treated mice in steady-state and regenerative conditions

ABSTRACT: Hematopoietic stem cells (HSCs) are largely quiescent and metabolically inactive under steady state, but can be activated to rapidly proliferate and produce progeny in response to inflammation, hematopoietic stress and in diseases. The microbiota has recently emerged as an important regulator of hematopoiesis, with significant contributions to the production of multipotent progenitors (MPPs) and myeloid cells. However, whether the microbiota directly regulates HSC functions remain unclear. Here using antibiotics (ABX)-induced microbiota depletion model and RNA sequencing, we showed that microbiota depletion induced dramatic differences in HSC transcriptome between control and ABX-treated mice under steady state. Differences in HSC transcriptome persisted under stress condition, despite fewer pathways were clustered after 5-FU treatment.

ORGANISM(S): Mus musculus

PROVIDER: GSE153678 | GEO | 2025/06/01

REPOSITORIES: GEO

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Project description:The hematopoietic system gives rise to a heterogeneous population of terminally differentiated cells that reside in the bone marrow (BM) to fulfill their roles in immunity, blood clotting and tissue oxygenation. Hematopoietic stem and progenitor cells are at the apex of a hierarchically organized maturation cascade constantly replenishing the pool of differentiated cells to maintain blood cell homeostasis. The bone marrow microenvironment is functionally compartmentalized by heterogeneous niche cells that provide physical and soluble signals to spatio-temporally organize hematopoiesis. Megakaryocytes (MKs) are niche cells of hematopoietic origin that support hematopoietic stem cell (HSCs) homeostasis and generate circulating platelets. Platelet production involves the release of MK fragments while their cell body is entirely consumed in a process termed thrombopoiesis. Consequently, replenishment of fragmented MKs from MK progenitors (termed megakaryopoiesis) is required to ensure sufficient platelet production, but also to maintain MK homeostasis within the HSC niche. Here, we used intravital imaging of the megakaryocytic lineage to identify the spatio-temporal patterns of megakaryopoiesis during steady state and thrombocytopenia. We show that MK consumption during thrombopoiesis is compensated by immediate and local proliferation of MK progenitors. MK homeostasis is controlled by plasmacytoid dendritic cells (pDCs) that scan the BM and secrete Interferon alpha (INFa) upon detection of exhausted megakaryocytes to trigger megakaryopoiesis. We identified local pDC-derived INFa release as a physiological inflammatory stimulus of the bone marrow niche that synchronizes megakaryopoiesis and thrombopoiesis to maintain homeostasis of MKs and platelets in steady state and under stress. Viral infection with SARS-CoV-2 can manipulate pDC-driven MK proliferation leading to inappropriate megakaryopoiesis, which has been associated with thrombotic complications during COVID-19.

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Transcriptional profiles of HSCs from control and ABX-treated mice in steady-state and regenerative conditions

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