Stress-induced cholinergic signaling promotes inflammation-associated thrombopoiesis

Marjorie Pick, Chava Perry, Tsvee Lapidot, Cinthya Guimaraes-Sternberg, Elizabeth Naparstek, Varda Deutsch, Hermona Soreq

Research output: Contribution to journalArticlepeer-review

Abstract

To study the role of the stress-induced "readthrough" acetylcholinesterase splice variant, AChE-R, in thrombopoiesis, we used transgenic mice overexpressing 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 megakaryocyte (Mk) colonies, which showed intensified labeling of AChE-R and its interacting proteins RACK1 and PKC. 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 sublethally irradiated NOD/SCID mice. Engraftment of human cells (both CD45+ and CD41+ Mk) was significantly increased in mice that received ARP26-primed CD34 + human cells versus mice that received fresh nonprimed 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 ARP 26-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.

Original languageEnglish
Pages (from-to)3397-3406
Number of pages10
JournalBlood
Volume107
Issue number8
DOIs
StatePublished - 15 Apr 2006

Fingerprint

Dive into the research topics of 'Stress-induced cholinergic signaling promotes inflammation-associated thrombopoiesis'. Together they form a unique fingerprint.

Cite this