1. CXCR2 and CXCL4 regulate survival and self-renewal of hematopoietic stem/progenitor cells
- Author
-
Sinclair, Amy, Park, Laura, Shah, Mansi, Drotar, Mark, Calaminus, Simon, Hopcroft, Lisa E.M., Kinstrie, Ross, Guitart, Amelie V., Dunn, Karen, Abraham, Sheela A., Sansom, Owen, Michie, Alison M., Machesky, Laura, Kranc, Kamil R., Graham, Gerard J., Pellicano, Francesca, and Holyoake, Tessa
- Subjects
musculoskeletal diseases ,Male ,Mice, Knockout ,Hematopoiesis and Stem Cells ,Cell Survival ,hemic and immune systems ,Bone Marrow Cells ,respiratory system ,Hematopoietic Stem Cells ,Platelet Factor 4 ,biological factors ,Receptors, Interleukin-8B ,respiratory tract diseases ,Mice ,Animals ,Humans ,Female ,Spleen ,Cell Proliferation - Abstract
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.
- Published
- 2016