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

Sinclair, A. et al. (2016) CXCR2 and CXCL4 regulate survival and self-renewal of hematopoietic stem/progenitor cells. Blood, 128(3), pp. 371-383. (doi:10.1182/blood-2015-08-661785) (PMID:27222476) (PMCID:PMC4991087)

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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 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Abraham, Dr Sheela and Shah, Dr Mansi and Machesky, Professor Laura and Sinclair, Miss Amy and Drotar, Mr Mark and Pellicano, Dr Francesca and Michie, Dr Alison and Kinstrie, Dr Ross and Holyoake, Professor Tessa and Miller, Ms Laura and Dunn, Mrs Karen and Hopcroft, Dr Lisa and Sansom, Professor Owen and Graham, Professor Gerard
Authors: Sinclair, A., Park, L., Shah, M., Drotar, M., Calaminus, S., Hopcroft, L. E.M., 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., and Holyoake, T.
College/School:College of Medical Veterinary and Life Sciences > Institute of Biodiversity Animal Health and Comparative Medicine
College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Blood
Publisher:American Society of Hematology
ISSN:0006-4971
ISSN (Online):1528-0020
Published Online:24 May 2016
Copyright Holders:Copyright © 2016 The American Society of Hematology
First Published:First published in Blood 128(3): 371-383
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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