CXCR2 and CXCL4 regulate survival and self-renewal of hematopoietic stem/progenitor cells

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; Holyoake, Tessa L.

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.

Citation

Sinclair, A., Park, L., Shah, M., Drotar, M., Calaminus, S., Hopcroft, L. E., …Holyoake, T. L. (2016). CXCR2 and CXCL4 regulate survival and self-renewal of hematopoietic stem/progenitor cells. Blood, 128(3), 371-383. https://doi.org/10.1182/blood-2015-08-661785

• Journal Article Type: Article
• Acceptance Date: May 12, 2016
• Online Publication Date: Jul 21, 2016
• Publication Date: Jul 21, 2016
• Deposit Date: May 25, 2016
• Publicly Available Date: Jul 21, 2016
• Journal: Blood
• Print ISSN: 0006-4971
• Electronic ISSN: 1528-0020
• Publisher: American Society of Hematology
• Peer Reviewed: Peer Reviewed
• Volume: 128
• Issue: 3
• Pages: 371-383
• DOI: https://doi.org/10.1182/blood-2015-08-661785
• Keywords: Chemokine ligands, Haematopoietic stem cell survival
• Public URL: https://hull-repository.worktribe.com/output/438742
• Publisher URL: http://www.bloodjournal.org/content/early/2016/05/24/blood-2015-08-661785?sso-checked=true
• Additional Information: Authors' accepted manuscript of article published in: Blood, 2016, v.128, issue 3.