NoBlood

Blood First Edition Paper

prepublished online February 13, 2003; DOI 10.1182/blood-2002-08-2363


Blood, 15 June 2003, Vol. 101, No. 12, pp. 4687-4694

CHEMOKINES
Platelet factor 4 promotes adhesion of hematopoietic progenitor cells and binds IL-8: novel mechanisms for modulation of hematopoiesis

Arkadiusz Z. Dudek, Irina Nesmelova, Kevin Mayo, Catherine M. Verfaillie, Simon Pitchford and Arne Slungaard
From the Department of Medicine, Division of Hematology, Oncology, and Transplantation, the Stem Cell Institute, and the Departments of Biochemistry, Molecular Biology, and Biophysics, and the Biomedical Engineering Center, University of Minnesota, Minneapolis, MN; and Molecular Devices, Sunnyvale, CA.


Platelet factor 4 (PF4) is an abundant platelet -granule C-X-C chemokine that has weak chemotactic potency but strongly inhibits hematopoiesis through an unknown mechanism. We find that PF4 binds to human CD34+ hematopoietic progenitor cells (HPCs) with a median effective concentration of 1 µg/mL but not after exposure to chondroitinase ABC. PF4 enhances adhesion of HPCs to intact stroma. Committed progenitors also adhere avidly to immobilized PF4. This adhesion is time-dependent, requires metabolic activity, causes cytoskeletal rearrangement, and induces cell-cycle inhibition. Using extracellular acidification rate to indicate transmembrane signaling, we find that interleukin-8 (IL-8), but not PF4, activates CD34+ progenitors, and PF4 blocks IL-8–mediated activation. Surface plasmon resonance analysis shows that PF4 binds IL-8 with high (dissociation constant [Kd] = 42 nM) affinity. Nuclear magnetic resonance analysis of IL-8 and PF4 in solution confirms this interaction. We conclude that PF4 has the capacity to influence hematopoiesis through mechanisms not mediated by a classical high-affinity, 7-transmembrane domain chemokine receptor. Instead, PF4 may modulate the hematopoietic milieu both directly, by promoting progenitor adhesion and quiescence through interaction with an HPC chondroitin sulfate–containing moiety, and indirectly, by binding to or interfering with signaling caused by other, hematopoietically active chemokines, such as IL-8.

__________________
Mr. Jan B. Wade
Blood Management Consultant
Enhance Outcomes - Control Cost
For Information Call - 360 296-1807
Email