干细胞
生物
祖细胞
川地34
造血
趋化因子受体
造血干细胞
细胞生物学
癌症研究
CXCL14型
移植
免疫学
干细胞因子
内皮干细胞
趋化因子
CXCL10型
趋化因子受体
内科学
医学
炎症
生物化学
体外
作者
Amy Sinclair,Laura Park,Mansi Shah,Mark E. Drotar,Simon D. J. Calaminus,Lisa Hopcroft,Ross Kinstrie,Amélie V. Guitart,Kirsty Dunn,Sheela A. Abraham,Owen J. Sansom,Alison M. Michie,Laura M. Machesky,Kamil R. Kranc,Gerard J. Graham,Francesca Pellicano,Tessa L. Holyoake
出处
期刊:Blood
[American Society of Hematology]
日期:2016-07-21
卷期号:128 (3): 371-383
被引量:50
标识
DOI:10.1182/blood-2015-08-661785
摘要
The regulation of hematopoietic stem cell (HSC) survival and self-renewal within the bone marrow (BM) niche is not well understood. We therefore investigated global transcriptomic profiling of normal human HSC/hematopoietic progenitor cells [HPCs], revealing that several chemokine ligands (CXCL1-4, CXCL6, CXCL10, CXCL11, and CXCL13) were upregulated in human quiescent CD34(+)Hoescht(-)Pyronin Y(-) and primitive CD34(+)38(-), as compared with proliferating CD34(+)Hoechst(+)Pyronin Y(+) and CD34(+)38(+) stem/progenitor cells. This suggested that chemokines might play an important role in the homeostasis of HSCs. In human CD34(+) hematopoietic cells, knockdown of CXCL4 or pharmacologic inhibition of the chemokine receptor CXCR2, significantly decreased cell viability and colony forming cell (CFC) potential. Studies on Cxcr2(-/-) mice demonstrated enhanced BM and spleen cellularity, with significantly increased numbers of HSCs, hematopoietic progenitor cell-1 (HPC-1), HPC-2, and Lin(-)Sca-1(+)c-Kit(+) subpopulations. Cxcr2(-/-) stem/progenitor cells showed reduced self-renewal capacity as measured in serial transplantation assays. Parallel studies on Cxcl4 demonstrated reduced numbers of CFC in primary and secondary assays following knockdown in murine c-Kit(+) cells, and Cxcl4(-/-) mice showed a decrease in HSC and reduced self-renewal capacity after secondary transplantation. These data demonstrate that the CXCR2 network and CXCL4 play a role in the maintenance of normal HSC/HPC cell fates, including survival and self-renewal.
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