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

Sansom, O.; Dunn, K.; Kinstrie, R.; Park, L.; Shah, M.; Drotar, M.; 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.

Authors

O. Sansom

K. Dunn

R. Kinstrie

L. Park

M. Shah

M. Drotar

Amy Sinclair

Laura Park

Mansi Shah

Mark Drotar

Simon Calaminus

Lisa E.M. Hopcroft

Ross Kinstrie

Amelie V. Guitart

Karen Dunn

Sheela A. Abraham

Owen Sansom

Alison M. Michie

Laura Machesky

Kamil R. Kranc

Gerard J. Graham

Francesca Pellicano

Tessa L. Holyoake



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. doi: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.

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