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Hematopoiesis
Thrombopoietin maintains cell numbers
of hematopoietic stem and progenitor cells with megakaryopoietic potential
Ferrata Storti Foundation
Haematologica 2021 Volume 106(7):1883-1891
Aled O’Neill,1 Desmond Chin,1 Darren Tan,1 A’Qilah Banu Bte Abdul Majeed,1 Ayako Nakamura-Ishizu1,2 and Toshio Suda1,2
1 Cancer Science Institute, National University of Singapore, Singapore and 2 International R- esearch Center for Medical Sciences, Kumamoto University, Kumamoto, Japan
ABSTRACT
Thrombopoietin has long been known to influence megakaryo- poiesis and hematopoietic stem and progenitor cells, although the exact mechanisms through which it acts are unknown. Here we show that MPL expression correlates with megakaryopoietic potential of hematopoietic stem and progenitor cells and identify a population of quiescent hematopoietic stem and progenitor cells that show limited dependence on thrombopoietin signaling. We show that thrombopoietin is primarily responsible for maintenance of hematopoietic cells with megakaryocytic differentiation potential and their subsequent megakaryocyte differentiation and maturation. The loss of megakaryo- cytes in thrombopoietin knockout mouse models results in a reduction of megakaryocyte-derived chemokine platelet factor 4 (CXCL4/PF4) in the bone marrow and administration of recombinant CXCL4/PF4 res- cues the loss of quiescence observed in these mice. CXCL4/PF4 treat- ment does not rescue reduced hematopoietic stem and progenitor cell numbers, suggesting that thrombopoietin maintains hematopoietic stem and progenitor cell numbers directly.
Introduction
Hematopoietic stem cells (HSC) are defined by their ability to not only differenti- ate into all blood cell lineages, but also to self-renew and enter the non-proliferative quiescent state.1 Maintenance of this quiescent state is thought to rely on several spatially separated niche factors2 and there are many candidates for potential ex-vivo maintenance of HSC quiescence including CXCL12 and thrombopoietin (THPO).3 It has long been known that loss of THPO signaling results in reduced HSC numbers and loss of quiescence,4,5 although the mechanisms behind this phenomenon are yet to be identified. In addition to influencing quiescence, THPO is known to drive megakaryocyte differentiation and maturation as well as platelet production.6
The THPO receptor, myeloproliferative leukemia (MPL), is expressed on HSC and it has been shown that HSC require THPO for survival in vitro.7 Cells pheno- typically similar to HSC in the hematopoietic compartment have also been shown to differentiate directly into megakaryocytes without cell division, suggesting a close relationship between the earliest megakaryocyte progenitors (MkP) and HSC.8 Determining how THPO is responsible for these seemingly different effects has been an object of much research, with several studies on mutated leukemia cell lines suggesting that the expression ratios between MPL and its downstream signal transducer JAK2 as well as extracellular THPO levels may determine whether hematopoietic stem and progenitor cells (HSPC) enter quiescent or pro- liferative pathways.9,10 Whether HSC in the bone marrow have different responses to THPO remains to be seen. We, therefore, set out to investigate the effects of THPO on various HSC both in vivo and in vitro.
Methods
Experimental mice
All experiments were performed on 8- to 12-week-old mice in the C57BL/6-NTac back-
Correspondence:
TOSHIO SUDA
sudato@keio.jp
Received: October 23, 2019. Accepted: May 28, 2020. Pre-published: June 11, 2020
https://doi.org/10.3324/haematol.2019.241406
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