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Hematopoietic stem cell response to acute thrombocytopenia requires signaling through distinct receptor tyrosine kinases

Beáta Ramasz, Anja Krüger, Julia Reinhardt, Anupam Sinha, Michael Gerlach, Alexander Gerbaulet, Susanne Reinhardt, Andreas Dahl, Triantafyllos Chavakis, Ben Wielockx and Tatyana Grinenko

Key Points

  • A dual signal from c-Kit and VEGFR2 determines selective activation of HSCs and MPP2 in response to acute immune thrombocytopenia

  • VEGF-A and PDGF-BB from ECs re-localize SCF in megakaryocytes, triggering proliferation of HSPCs

Abstract

Although bone marrow (BM) niche cells are essential for hematopoietic stem cell (HSC) maintenance, their interaction in response to stress is not well defined. Here, we used a mouse model of acute thrombocytopenia to investigate the crosstalk between HSCs and niche cells during restoration of the thrombocyte pool. This process required membrane-localized stem cell factor (m-SCF) in megakaryocytes, which in turn was regulated by vascular endothelial growth factor A (VEGF-A) and platelet-derived growth factor-B (PDGF-B). HSCs and multipotent progenitors 2 (MPP2), but not MPP3/4 were subsequently activated by a dual receptor tyrosine kinase (RTK)-dependent signaling event, namely m-SCF/c-Kit and VEGF-A/VEGFR-2, contributing to their selective and early proliferation. Our findings describe a dynamic network of signals in response to the acute loss of a single blood cell type, and reveal the important role of three RTKs and their ligands in orchestrating the selective activation of HSCs and progenitor cells in thrombocytopenia.

  • Submitted March 21, 2019.
  • Revision received August 20, 2019.
  • Accepted August 14, 2019.