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Hematopoiesis
Granulocyte colony-stimulating factor directly acts on mouse lymphoid-biased but not myeloid-biased hematopoietic stem cells
Ferrata Storti Foundation
Haematologica 2021 Volume 106(6):1647-1658
Miner Xie,1 Shanshan Zhang,1 Fang Dong,1 Qingyun Zhang,1 Jinhong Wang,1 Chenchen Wang,1 Caiying Zhu,1 Sen Zhang,1 Bingqing Luo,1 Peng Wu1 and Hideo Ema1,2,3
1State Key Laboratory of Experimental Hematology; 2National Clinical Research Center for Hematological Disorders and 3Department of Regenerative Medicine, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
ABSTRACT
Granulocyte colony-stimulating factor (G-CSF) is widely used in clin- ical settings to mobilize hematopoietic stem cells (HSC) into the cir- culation for HSC harvesting and transplantation. However, whether G-CSF directly stimulates HSC to change their cell cycle state and fate is controversial. HSC are a heterogeneous population consisting of different types of HSC, such as myeloid-biased HSC and lymphoid-biased HSC. We hypothesized that G-CSF has different effects on different types of HSC. To verify this, we performed serum-free single-cell culture and competitive repopulation with cultured cells. Single highly purified HSC and hematopoietic progenitor cells (HPC) were cultured with stem cell factor (SCF), SCF + G-CSF, SCF + granulocyte/macrophage (GM)-CSF, or SCF + thrombopoietin (TPO) for 7 days. Compared with SCF alone, SCF + G-CSF increased the number of divisions of cells from the lymphoid-biased HSC- enriched population but not that of cells from the My-bi HSC-enriched population. SCF + G-CSF enhanced the level of reconstitution of lymphoid- biased HSC but not that of myeloid-biased HSC. Clonal transplantation assay also showed that SCF + G-CSF did not increase the frequency of myeloid-biased HSC. These data showed that G-CSF directly acted on lym- phoid-biased HSC but not myeloid-biased HSC. Our study also revised the cytokine network at early stages of hematopoiesis: SCF directly acted on myeloid-biased HSC; TPO directly acted on myeloid-biased HSC and lym- phoid-biased HSC; and GM-CSF acted only on HPC. Early hematopoiesis is controlled differentially and sequentially by a number of cytokines.
Introduction
Hematopoietic stem cells (HSC) are able to self-renew and differentiate into all blood lineages.1 Granulocyte colony-stimulating factor (G-CSF) is widely used in clinical settings to mobilize HSC from the bone marrow (BM) to the peripheral blood (PB) for stem cell harvesting.2 However, the effect of G-CSF on HSC is poorly understood. Several studies have reported that G-CSF drives dormant HSC into the cell cycle,3-5 whereas other studies have reported that G-CSF does not.6,7 Since in vivo G-CSF administration results in complex changes in the BM microenviron- ment, such as disruption of the SDF-1/CXCR4 axis,8,9 it may be difficult to deter- mine the direct effect of G-CSF on HSC in vivo. To avoid this issue, Ogawa’s research group combined in vitro culture with transplantation assay and reported that G-CSF can induce HSC self-renewal.10
The above studies are informative but quite controversial. This study aimed to clarify whether G-CSF acts directly on HSC and drives them into cycling, thus changing their fates. HSC are a heterogeneous population. Muller-Sieburg’s research group was the first to classify HSC into myeloid-biased HSC (My-bi HSC), balanced HSC (Bala HSC), and lymphoid-biased HSC (Ly-bi HSC), based on the ratio of lymphoid to myeloid cells (the L/M ratio) in reconstituted mice.11,12 Given that G-CSF is a neutrophil-specific cytokine that is essential for granu-
Correspondence:
HIDEO EMA
hema@ihcams.ac.cn
Received: September 26, 2019. Accepted: February 17, 2020. Pre-published: February 20, 2020.
https://doi.org/10.3324/haematol.2019.239251
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