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Blood, 15 April 2006, Vol. 107, No. 8, pp. 3397-3406. Prepublished online as a Blood First Edition Paper on December 27, 2005; DOI 10.1182/blood-2005-08-3240.
Submitted August 11, 2005
Department of Hematology and Bone Marrow Transplantation, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Department of Biological Chemistry, The Institute of Life Sciences, The Hebrew University, Jerusalem, Israel * Corresponding author; email: soreq{at}cc.huji.ac.il.
To study the role of the stress-induced "readthrough" acetylcholinesterase splice variant, AChE-R, in thrombopoiesis, we utilized transgenic mice over-expressing human AChE-R (TgR). Increased AChE hydrolytic activity in the peripheral blood of TgR mice was associated with increased thrombopoietin levels and platelet counts. Bone marrow (BM) progenitor cells from TgR mice presented an elevated capacity to produce mixed (GEMM) and megakaryocytes (Mks) colonies, which showed intensified labeling of AChE-R and its interacting proteins RACK1 and PKC
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| Copyright © 2005 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
. When injected with bacterial lipopolysaccharide (LPS), parent strain FVB/N mice, but not TgR mice, showed reduced platelet counts. Therefore, we primed human CD34+ cells with the synthetic ARP26 peptide, derived from the cleavable C-terminus of AChE-R prior to transplantation into sub-lethally irradiated NOD/SCID mice. Engraftment of human cells (both CD45+ and CD41+ Mk) was significantly increased in mice that received ARP26 primed CD34+ human cell mice that received fresh non-primed CD34+ human cells. Moreover, ARP26 induced polyploidization and proplatelet shedding in human MEG-01 promegakaryotic cells, and human platelet engraftment increased following ex vivo expansion of ARP26-treated CD34+ cells as compared to cells expanded with thrombopoietin and stem cell factor. Our findings implicate AChE-R in thrombopoietic recovery, suggesting new therapeutic modalities for supporting platelet production.
