The stress-associated acetylcholinesterase variant AChE-R is expressed in human CD34+ hematopoietic progenitors and its C-terminal peptide ARP promotes their proliferation

Deutsch, Varda; Pick, Marjorie; Perry, Chava; Grisaru, Dan; Hemo, Yoram; Golan-Hadari, Dita; Grant, Alastair; Eldor, Amiram; Soreq, Hermona

doi:10.1016/s0301-472x(02)00900-1

Cited by 57 publications

(47 citation statements)

References 51 publications

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“…Ex vivo, ARP 26 treatment was shown to yield considerably higher numbers of platelet-producing Mks than in untreated cells. 47 Our current findings present proplatelet formation and nuclear polyploidization effects in ARP 26 -treated MEG-01 cells and enhanced platelet formation following ARP priming in vivo, in NOD/SCID mice. Increasing the numbers of Mk precursors in the graft should shorten the extended nadir period of severe thrombocytopenia, promoting successful engraftment of long-term repopulating stem cells, the appropriate targets for endogenous or exogenous TPO.…”

supporting

confidence: 58%

“…AChE-R is expressed in Mks 10-12 and promotes Mk proliferation in vitro. 47 While the C-termini of mouse and human AChE-R Enhanced human blood cell engraftment in NOD/SCID mice. 100 000 human CB CD34 ϩ cells were injected into the tail vein of pre-irradiated NOD/SCID mice with no priming of cells (none, छ) or following priming of cells with ARP26 for 2 to 4 hours and injection with human ARP26 (f) or ASP43 (OE).…”

mentioning

confidence: 99%

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Stress-induced cholinergic signaling promotes inflammation-associated thrombopoiesis

Pick

Perry

Lapidot

et al. 2006

Blood

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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 ARP 26 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 ARP 26 IntroductionThe number of circulating blood cells is tightly regulated by cytokines and chemokines capable of immediate response to various stimuli. 1 Adjustment to changing needs involves rapid mobilization of cells from the bone marrow (BM) and the vascular marginal pool in response to inflammation, stress, or injury. 2 An example is inflammation-inducible hematopoiesis, which was thoroughly studied in murine models using bacterial lipopolysaccharide (LPS), the main cell-wall component of gram-negative bacteria. 3 LPS is an endotoxin that stimulates an acute inflammatory response via the CD14 receptor and the Toll-like receptor-4 (TLR4) found on monocytes and tissue macrophages. 4 LPS-TLR4 interaction initiates a signal transduction cascade that leads to the release of pro-inflammatory cytokines, 3 including tumor necrosis factor (TNF)-␣, interleukin (IL)-1␤, -6, and -8, and others. These cytokines activate the mobilization of hematopoietic cells from the BM 5 and set in motion the migration of leukocytes from blood vessel walls, increasing their numbers in the circulation. 6 The net result of this process is an immediate and dramatic increase in the number of circulating peripheral blood (PB) cells, needed to mount the immune response, accompanied by a corresponding decrease in BM cell numbers, which in turn induces a compensatory increase in their production. 7 Many factors are involved in abating the inflammatory response and allowing the recovery of hemostasis. Acetylcholine (ACh), one of these factors, acts by attenuating the secretion of proinflammatory cytokines at the posttranscriptional level via activation of nicotinic receptors on tissue macrophages. 8 Circulating acetylcholinesterase (AChE) controls the levels of ACh, suggesting promotion of the inflammatory process under AChE excess. 9 There are 3 C-terminally variant forms of AChE: synaptic (S), erythrocytic (E), and readthrough (R). All are ubiquitously expressed in hematopoietic cell lineages, especially in megakaryocytes (Mks) and erythrocytes. [10][11][12] Importantly, AChE contri...

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confidence: 58%

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confidence: 99%

Stress-induced cholinergic signaling promotes inflammation-associated thrombopoiesis

Pick

Perry

Lapidot

et al. 2006

Blood

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“…1,20,21 Cholinergic signaling during the development of platelets was proposed by several groups. [21][22][23] In previous microarray-based platelet RNA profiling studies, we found positive RNA signals for various nAChR subunits, especially ␣7. 24,25 These findings encouraged us to investigate platelets and cells of the megakaryocytic lineage for the expression of nAChR␣7 subunits and its possible involvement in platelet function.…”

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confidence: 79%

Human Platelets Express Functional α7-Nicotinic Acetylcholine Receptors

Schedel

Thornton

Schloss

et al. 2011

ATVB

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Objective-Nicotinic acetylcholine receptors, especially ␣7 (nAChR␣7), form Ca 2ϩ channels and are expressed on a variety of neuronal and nonneuronal cells. Also, megakaryocytic cells have been shown to contain components of a nonneuronal cholinergic system, including acetylcholine and acetylcholine esterase. However, the corresponding nAChRs and their role in platelet function have not been demonstrated until now. Our previous platelet transcriptome data indicated the presence of nAChR gene transcripts. Methods and Results-Here, we present evidence that human platelets and megakaryocytic precursor cells express nAChR␣7 subunits, as revealed by mRNA and protein expression. The subunits form functional Ca 2ϩ channels, as demonstrated by Ca 2ϩ entry in platelets induced by the nAChR␣7-selective agonist PNU-282987. PNU-282987 also enhanced fibrinogen receptor activation induced by classical platelet agonists (the thromboxane A 2 analog U46619 and ADP). Furthermore, agonist-induced platelet aggregation was significantly inhibited by the nAChR␣7-selective antagonists ␣-bungarotoxin and methyllycaconitine. Conclusion-Ca2ϩ influx via nAChR␣7 channels represents a novel pathway for human platelets with significant impact on platelet function. Because platelets were suggested to contain acetylcholine, we conclude that on activation, stored acetylcholine is released, which activates nAChR␣7 channels and thereby contributes to maintaining intracellular Ca

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“…This unique peptide is derived from the cleavable C-terminus of the stress associated form of acetylcholinesterase (AChE), a molecule known to be involved in the regulation of megakaryocytopoiesis (Long et al, 1982;Lev-Lehman et al, 1997). This readthrough variant (AChE-R), is physiologically functional during stress thrombopoiesis and is currently in preclinical development as a new thrombopoietic factor (Grisaru et al, 2001;Deutsch et al, 2002;Pick et al, 2005).…”

Section: Additional Growth Factorsmentioning

confidence: 99%

Megakaryocyte development and platelet production

2006

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SummaryMegakaryocytopoiesis involves the commitment of haematopoietic stem cells, and the proliferation, maturation and terminal differentiation of the megakaryocytic progenitors. Circulating levels of thrombopoietin (TPO), the primary growth-factor for the megakaryocyte (MK) lineage, induce concentration-dependent proliferation and maturation of MK progenitors by binding to the c-Mpl receptor and signalling induction. Decreased platelet turnover rates results in increased concentration of free TPO, enabling the compensatory response of marrow MKs to increased platelet production. C-Mpl activity is orchestrated by a complex cascade of signalling molecules that induces the action of specific transcription factors to drive MK proliferation and maturation. Mature MKs form proplatelet projections that are fragmented into circulating particles. Newly developed thrombopoietic agents operating via c-Mpl receptor may prove useful in supporting platelet production in thrombocytopenic state. Herein, we review the regulation of megakaryocytopoiesis and platelet production in normal and disease state, and the new approaches to thrombopoietic therapy.

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The stress-associated acetylcholinesterase variant AChE-R is expressed in human CD34+ hematopoietic progenitors and its C-terminal peptide ARP promotes their proliferation

Cited by 57 publications

References 51 publications

Stress-induced cholinergic signaling promotes inflammation-associated thrombopoiesis

Stress-induced cholinergic signaling promotes inflammation-associated thrombopoiesis

Human Platelets Express Functional α7-Nicotinic Acetylcholine Receptors

Megakaryocyte development and platelet production

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