期刊
BLOOD
卷 128, 期 3, 页码 371-383出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2015-08-661785
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资金
- Leukaemia and Lymphoma Research [11017, 13035, 08071]
- Kay Kendall Leukaemia Fund [690, 501]
- Howat Foundation
- Friends of Paul O'Gorman
- Cancer Research UK [C11074/A11008]
- Biotechnology and Biological Sciences Research Council [BB/F016050/1]
- Medical Research Council [G0600782, MR/K014854/1]
- Cancer Research UK Glasgow Centre [C596/A18076]
- Biological Service Unit facilities at the Cancer Research UK Beatson Institute [C596/A17196]
- Glasgow Experimental Cancer Medicine Centre (Cancer Research UK)
- Glasgow Experimental Cancer Medicine Centre (Chief Scientist's Office, Scotland)
- MRC [G0901113, MR/M019764/1, G0600782, MR/K014854/1] Funding Source: UKRI
- Cancer Research UK [15673, 11008, 14633] Funding Source: researchfish
- Medical Research Council [G0901113, MR/K014854/1, MR/M019764/1, G0600782] Funding Source: researchfish
- Versus Arthritis
- Cancer Research UK [21139] Funding Source: researchfish
- Wellcome Trust [099251/Z/12/Z] Funding Source: researchfish
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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