Published August 25, 2023 | Version 1
Journal article Open

Perivascular niche cells sense thrombocytopenia and activate hematopoietic stem cells in an IL-1 dependent manner

Authors/Creators

  • 1. Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, W12 0NN London, UK
  • 2. Haematopoietic Stem Cell Biology Laboratory and MRC Molecular Haematology Unit; MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, OX3 9DS Oxford, UK.
  • 3. Human Technopole, Viale Rita Levi-Montalcini 1, 20157 Milan, Italy
  • 4. Center for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, SE-141 86 Stockholm, Sweden.
  • 5. Department of Haematology, University of Cambridge and, National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge, UK.
  • 6. Earlham Institute, Norwich Research Park, NR4 7UZ Norwich, UK.
  • 7. Toronto Platelet Immunobiology Group and Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON, Canada M5B 1W8.
  • 8. Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH 45267, USA
  • 9. Department of Biomedical Science, Charles E. Schmidt College of Medicine and Stiles-Nicholson Brain Institute, Florida Atlantic University, Jupiter FL 33458, USA.
  • 10. MRC Molecular Haematology Unit; MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, OX3 9DS Oxford, UK.

Description

Hematopoietic stem cells (HSCs) residing in specialized niches in the bone marrow are responsible for the balanced output of multiple short-lived blood cell lineages in steady-state and in response to different challenges. However, feedback mechanisms by which HSCs, through their niches, sense acute losses of specific blood cell lineages remain to be established. While all HSCs replenish platelets, previous studies have shown that a large fraction of HSCs are molecularly primed for the megakaryocyte-platelet lineage and are rapidly recruited into proliferation upon platelet depletion. Platelets normally turnover in an activation-dependent manner, herein mimicked by antibodies inducing platelet activation and depletion. Antibody-mediated platelet activation upregulates expression of Interleukin-1 (IL-1) in platelets, and in bone marrow extracellular fluid in vivo. Genetic experiments demonstrate that rather than IL-1 directly activating HSCs, activation of bone marrow Lepr+ perivascular niche cells expressing IL-1 receptor is critical for the optimal activation of quiescent HSCs upon platelet activation and depletion. These findings identify a feedback mechanism by which activation-induced depletion of a mature blood cell lineage leads to a niche-dependent activation of HSCs to reinstate its homeostasis.

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Additional details

Funding

UK Research and Innovation
Identification, characterisation and therapeutic targeting of leukaemic stem/propagating cells in Acute Myeloid Leukaemia MC_UU_12009/11
Wellcome Trust
Role of the haematopoietic stem cell niche in pre-leukemic clonal haematopoiesis and myelodysplatic syndromes 210424