From brain to blood
http://www.100md.com
《血液学杂志》
In this issue, Pick and colleagues provide proof for the hematopoietic activity of an enzyme, acetylcholinesterase (AChE), initially described as a regulator of neurotransmission.
Using a transgenic (TgR) mouse and a xenogeneic, human into severe combined immunodeficiency (SCID) mouse bone marrow transplantation model, the authors (several of whom pioneered the investigation of "`non-classical' actions of this enzyme"1p294,2) show evidence that the so-called stress-induced "readthrough" (R) variant of the acetylcholine (ACh)–hydrolyzing enzyme acetylcholinesterase (AChE)1 could potentially modulate the growth of megakaryocytes through its capacity for hydrolyzing ACh. These data obtained with human AChE-R–transgenic mice are in line with a recent report demonstrating a crucial role of ACh as a signaling agent in inflammatory processes.3 Based on previous work and data obtained with the SCID xenotransplantation model described here, the authors also suggest an alternative, or additional, mode of action for AChE. According to the latter model, AChE-R could also operate as a preprotein for its cleavable C-terminal peptide, which has hematopoietic functions of its own.
In their first model, the authors analyzed thrombocytopenic responses to inflammatory challenges of TgR mice overexpressing human AChE-R compared with that of sex- and age-matched FVB/N control mice. TgR mice showed increased thrombopoietin levels and platelet counts associated with higher steady-state levels of the proinflammatory cytokine IL-6. Thrombopoietin, a target of IL-6 during stress response, was also increased. Both AChE-R activity and IL-6 but not TNF- levels were significantly higher in the transgenic compared with control mice. These data suggested that a shift toward the AChE-R splice variant facilitates an inflammatory state, thus inducing progenitor cell expansion. Compatible with this finding, TgR bone marrow cells displayed significantly larger capacity, 2- and 5-fold over control, to proliferate into multipotential colony-forming units–granulocyte/erythrocyte/monocyte/megakaryocyte (CFU-GEMMs) as well as the more committed colony-forming units–megakaryocyte (CFU-MKs).
In an alternative experimental setting, priming as well as ex vivo expansion of human CD34 progenitor cells with ARP26, the cleavable C-terminus of AChE-R, before infusion significantly improved human platelet engraftment in nonobese diabetic (NOD)/SCID mice. Although the underlying mechanism of ARP26 peptide action has not been verified in detail yet, the same group has recently suggested that micro-RNA modulation is involved.4
The findings by Pick and colleagues demonstrate a crucial role of AChE-R in the thrombopoietic recovery from postinflammatory thrombocytopenia, suggesting that cholinergic signaling controls balanced platelet production in both health and disease states. Deeper understanding of underlying mechanisms may facilitate development of novel strategies for improving postengraftment thrombopoiesis after hematopoietic stem cell transplantation and in vivo stem cell expansion. This could be of considerable value for alleviating severe pancytopenia and thrombocytopenia, serious complications encountered in cancer patients treated with high-dose chemotherapy or following bone marrow transplantation.
Last but not least, the presented work strongly adds to our understanding of molecular mechanisms controlling stress reactions. It might not be a surprise that similar or even identical pathways are used—in brain and blood.
References
Soreq H, Seidman S. Acetylcholinesterase: new roles for an old actor. Nat Rev Neurosci. 2001;2: 294-302.
Deutsch VR, Pick M, Perry C, et al. The stress-associated acetylcholinesterase variant AChE-R is expressed in human CD34(+) hematopoietic progenitors and its C-terminal peptide ARP promotes their proliferation. Exp Hematol. 2002;30: 1153-1161.
Metz CN, Tracey KJ. It takes nerve to dampen inflammation. Nat Immunol. 2005;6: 756-757.
Guimaraes-Sternberg C, Meerson A, Shaked I, Soreq H. MicroRNA modulation of megakaryoblast fate involves cholinergic signaling. Leuk Res. 2005 Oct 21;(Axel R. Zander, and Boris)
Using a transgenic (TgR) mouse and a xenogeneic, human into severe combined immunodeficiency (SCID) mouse bone marrow transplantation model, the authors (several of whom pioneered the investigation of "`non-classical' actions of this enzyme"1p294,2) show evidence that the so-called stress-induced "readthrough" (R) variant of the acetylcholine (ACh)–hydrolyzing enzyme acetylcholinesterase (AChE)1 could potentially modulate the growth of megakaryocytes through its capacity for hydrolyzing ACh. These data obtained with human AChE-R–transgenic mice are in line with a recent report demonstrating a crucial role of ACh as a signaling agent in inflammatory processes.3 Based on previous work and data obtained with the SCID xenotransplantation model described here, the authors also suggest an alternative, or additional, mode of action for AChE. According to the latter model, AChE-R could also operate as a preprotein for its cleavable C-terminal peptide, which has hematopoietic functions of its own.
In their first model, the authors analyzed thrombocytopenic responses to inflammatory challenges of TgR mice overexpressing human AChE-R compared with that of sex- and age-matched FVB/N control mice. TgR mice showed increased thrombopoietin levels and platelet counts associated with higher steady-state levels of the proinflammatory cytokine IL-6. Thrombopoietin, a target of IL-6 during stress response, was also increased. Both AChE-R activity and IL-6 but not TNF- levels were significantly higher in the transgenic compared with control mice. These data suggested that a shift toward the AChE-R splice variant facilitates an inflammatory state, thus inducing progenitor cell expansion. Compatible with this finding, TgR bone marrow cells displayed significantly larger capacity, 2- and 5-fold over control, to proliferate into multipotential colony-forming units–granulocyte/erythrocyte/monocyte/megakaryocyte (CFU-GEMMs) as well as the more committed colony-forming units–megakaryocyte (CFU-MKs).
In an alternative experimental setting, priming as well as ex vivo expansion of human CD34 progenitor cells with ARP26, the cleavable C-terminus of AChE-R, before infusion significantly improved human platelet engraftment in nonobese diabetic (NOD)/SCID mice. Although the underlying mechanism of ARP26 peptide action has not been verified in detail yet, the same group has recently suggested that micro-RNA modulation is involved.4
The findings by Pick and colleagues demonstrate a crucial role of AChE-R in the thrombopoietic recovery from postinflammatory thrombocytopenia, suggesting that cholinergic signaling controls balanced platelet production in both health and disease states. Deeper understanding of underlying mechanisms may facilitate development of novel strategies for improving postengraftment thrombopoiesis after hematopoietic stem cell transplantation and in vivo stem cell expansion. This could be of considerable value for alleviating severe pancytopenia and thrombocytopenia, serious complications encountered in cancer patients treated with high-dose chemotherapy or following bone marrow transplantation.
Last but not least, the presented work strongly adds to our understanding of molecular mechanisms controlling stress reactions. It might not be a surprise that similar or even identical pathways are used—in brain and blood.
References
Soreq H, Seidman S. Acetylcholinesterase: new roles for an old actor. Nat Rev Neurosci. 2001;2: 294-302.
Deutsch VR, Pick M, Perry C, et al. The stress-associated acetylcholinesterase variant AChE-R is expressed in human CD34(+) hematopoietic progenitors and its C-terminal peptide ARP promotes their proliferation. Exp Hematol. 2002;30: 1153-1161.
Metz CN, Tracey KJ. It takes nerve to dampen inflammation. Nat Immunol. 2005;6: 756-757.
Guimaraes-Sternberg C, Meerson A, Shaked I, Soreq H. MicroRNA modulation of megakaryoblast fate involves cholinergic signaling. Leuk Res. 2005 Oct 21;(Axel R. Zander, and Boris)