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ARP, A Peptide Derived from the Stress-Associated Acetylcholinesterase Variant, Has Hematopoietic Growth Promoting Activities

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Abstract

Background

Psychological stress induces rapid and long-lasting changes in blood cell composition, implying the existence of stress-induced factors that modulate hematopoiesis. Here we report the involvement of the stress-associated “readthrough” acetylcholinesterase (AChE-R) variant, and its 26 amino acid C-terminal domain (ARP) in hematopoietic stress responses.

Materials and Methods

We studied the effects of stress, cortisol, antisense oligonucleotides to AChE, and synthetic ARP on peripheral blood cell composition and clonogenic progenitor status in mice under normal and stress conditions, and on purified CD341 cells of human origin. We employed in situ hybridization and immunocytochemical staining to monitor gene expression, and 5-bromo-2-deoxyuridine (BrdU), primary liquid cultures, and clonogenic progenitor assays to correlate AChE-R and ARP with proliferation and differentiation of hematopoietic progenitors.

Results

We identified two putative glucocorticoid response elements in the human ACHE gene encoding AChE. In human CD341 hematopoietic progenitor cells, cortisol elevated AChE-R mRNA levels and promoted hematopoietic expansion. In mice, a small peptide crossreacting with anti-ARP antiserum appeared in serum following forced swim stress. Ex vivo, ARP was more effective than cortisol and equally as effective as stem cell factor in promoting expansion and differentiation of early hematopoietic progenitor cells into myeloid and megakaryocyte lineages.

Conclusions

Our findings attribute a role to AChE-R and ARP in hematopoietic homeostasis following stress, and suggest the use of ARP in clinical settings where ex vivo expansion of progenitor cells is required.

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Acknowledgments

The authors are grateful to Dr. Haim Gilon (Jerusalem) for preliminary peptide synthesis, to Drs. David Glick and Shlomo Seidman (Jerusalem) and to Dr. Roger Kornberg (Palo Alto) for reviewing this manuscript, and to Ms. Shoshana Baron for her assistance. Support was by the U.S.-Israel Binational Science Foundation (to H.S.) and the B. Adler Fund, the Israel Ministry of Health (to V.D.). D.G. was the incumbent of a research fellowship from the Tel-Aviv Sourasky Medical Center and of a Meirbaum Award, from Tel-Aviv University.

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Authors and Affiliations

  1. Department of Biological Chemistry, Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem, Israel

    Dan Grisaru, Michael Shapira, Meira Sternfeld, Naomi Melamed-Book, Daniela Kaufer, Nilly Galyam & Hermona Soreq

  2. Department of Hematology, Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Varda Deutsch, Marjorie Pick & Amiram Eldor

  3. Laboratory of Molecular Biology, Medical Research Council, Hills Road, Cambridge, UK

    Michael J. Gait & David Owen

  4. Department of Obstetrics-Gynecology, Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Dan Grisaru & Joseph B. Lessing

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  1. Dan Grisaru
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  2. Varda Deutsch
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  3. Michael Shapira
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  13. Hermona Soreq
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Correspondence to Hermona Soreq.

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The first two authors contributed equally to this investigation.

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Grisaru, D., Deutsch, V., Shapira, M. et al. ARP, A Peptide Derived from the Stress-Associated Acetylcholinesterase Variant, Has Hematopoietic Growth Promoting Activities. Mol Med 7, 93–105 (2001). https://doi.org/10.1007/BF03401943

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