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

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 was regulated by vascular endothelial growth factor A (VEGF-A) and platelet-derived growth factor-B (PDGF-B) derived from BM endothelial cells. 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 in orchestrating the selective activation of HSCs and progenitor cells in thrombocytopenia.