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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 hematopoietic stem/progenitor cells, revealing that several chemokine ligands (CXCL1-4, CXCL6, CXCL10, CXCL11, CXCL13) were up-regulated in human quiescent CD34+Hoescht-Pyronin Y- and primitive CD34+38-, as compared to proliferating CD34+Hoechst+Pyronin Y+ and CD34+38+ stem/progenitor cells. This suggested that chemokines may play an important role in the homeostasis of HSCs. In human CD34+ hematopoietic cells, knock-down of CXCL4 or pharmacological 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 HSC, hematopoietic progenitor cell (HPC)-1, HPC-2 and Lin-Sca-1+c-Kit+ sub-populations. 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 knock-down 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 hematopoietic stem/progenitor cell fates, including survival and self-renewal.

Type

Journal article

Journal

Blood

Publisher

American Society of Hematology

Publication Date

21/07/2016

Volume

128

Pages

371 - 383