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., Kinstrie, R., Guitart, A. V., Dunn, K., Abraham, S. A., Sansom, O., Michie, A. M., Machesky, L., Kranc, K. R., Graham, G. J., Pellicano, F., & 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
• 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.
• Contract Date: May 25, 2016