Hematopoietic stem and progenitor cell fate decisions during acute and chronic thrombocytopenia
Final Report Abstract
Hematopoietic stem cells continuously replenish all blood cell types through a series of differentiation steps and repeated cell divisions that involve the generation of lineagecommitted progenitors. However, whether cell division in HSCs precedes differentiation is unclear. To this end, we used an HSC cell tracing approach and Ki67RFP knock-in mice, in a non-conditioned transplantation model, to assess divisional history, cell cycle progression, and differentiation of adult HSCs. Our results reveal that HSCs are able to differentiate into restricted progenitors, especially common myeloid, megakaryocyte-erythroid and premegakaryocyte progenitors, without undergoing cell division and even before entering the S phase of the cell cycle. Additionally, the phenotype of the undivided but differentiated progenitors correlated with expression of lineage-specific genes and loss of multipotency. Thus, HSC fate decisions can be uncoupled from physical cell division. These results facilitate a better understanding of the mechanisms that control fate decisions in hematopoietic cells. Although bone marrow (BM) niche cells are essential for 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.
Publications
- Hematopoietic stem cells can differentiate into restricted myeloid progenitors before cell division in mice. Nat Commun.,15;9(1):1898, 2018
Grinenko T, Eugster A, Thielecke L, Ramasz B, Krüger A, Dietz S, Glauche I, Gerbaulet A, von Bonin M, Basak O, Clevers H, Chavakis T, Wielockx B
(See online at https://doi.org/10.1038/s41467-018-04188-7) - Exercise-Induced Activated Platelets Increase Adult Hippocampal Precursor Proliferation and Promote Neuronal Differentiation. Stem Cell Reports. 2019 Apr 9;12(4):667-679
Leiter O, Seidemann S, Overall RW, Ramasz B, Rund N, Schallenberg S, Grinenko T, Wielockx B, Kempermann G, Walker TL
(See online at https://doi.org/10.1016/j.stemcr.2019.02.009) - Hematopoietic stem cell response to acute thrombocytopenia requires signaling through distinct receptor tyrosine kinases. Blood. 2019 Aug 21
Ramasz B, Krüger A, Reinhardt J, Sinha A, Gerlach M, Gerbaulet A, Reinhardt S, Dahl A, Chavakis T, Wielockx B, Grinenko T
(See online at https://doi.org/10.1182/blood.2019000721)
