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

Tiago C. Luis (), Nikolaos Barkas, Joana Carrelha, Alice Giustacchini, Stefania Mazzi, Ruggiero Norfo, Bishan Wu, Affaf Aliouat, Jose A. Guerrero, Alba Rodriguez-Meira, Tiphaine Bouriez-Jones, Iain C. Macaulay, Maria Jasztal, Guangheng Zhu, Heyu Ni, Matthew J. Robson, Randy D. Blakely, Adam J. Mead, Claus Nerlov, Cedric Ghevaert and Sten Eirik W. Jacobsen ()
Additional contact information
Tiago C. Luis: University of Oxford
Nikolaos Barkas: University of Oxford
Joana Carrelha: University of Oxford
Alice Giustacchini: University of Oxford
Stefania Mazzi: Karolinska Institutet, Karolinska University Hospital
Ruggiero Norfo: University of Oxford
Bishan Wu: University of Oxford
Affaf Aliouat: University of Oxford
Jose A. Guerrero: University of Cambridge
Alba Rodriguez-Meira: University of Oxford
Tiphaine Bouriez-Jones: University of Oxford
Iain C. Macaulay: University of Oxford
Maria Jasztal: University of Cambridge
Guangheng Zhu: St. Michael’s Hospital
Heyu Ni: St. Michael’s Hospital
Matthew J. Robson: Florida Atlantic University
Randy D. Blakely: Florida Atlantic University
Adam J. Mead: University of Oxford
Claus Nerlov: University of Oxford
Cedric Ghevaert: University of Cambridge
Sten Eirik W. Jacobsen: University of Oxford

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-41691-y

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