Muscarinic acetylcholine receptor regulates self-renewal of early erythroid progenitors Journal Article

Authors: Trivedi, G.; Inoue, D.; Chen, C.; Bitner, L.; Chung, Y. R.; Taylor, J.; Gönen, M.; Wess, J.; Abdel-Wahab, O.; Zhang, L.
Article Title: Muscarinic acetylcholine receptor regulates self-renewal of early erythroid progenitors
Abstract: Adult stem and progenitor cells are uniquely capable of self-renewal, and targeting this process represents a potential therapeutic opportunity. The early erythroid progenitor, burst-forming unit erythroid (BFU-E), has substantial self-renewal potential and serves as a key cell type for the treatment of anemias. However, our understanding of mechanisms underlying BFU-E self-renewal is extremely limited. Here, we found that the muscarinic acetylcholine receptor, cholinergic receptor, muscarinic 4 (CHRM4), pathway regulates BFU-E self-renewal and that pharmacological inhibition of CHRM4 corrects anemias of myelodysplastic syndrome (MDS), aging, and hemolysis. Genetic down-regulation of CHRM4 or pharmacologic inhibition of CHRM4 using the selective antagonist PD102807 promoted BFU-E self-renewal, whereas deletion of Chrm4 increased erythroid cell production under stress conditions in vivo. Moreover, muscarinic acetylcholine receptor antagonists corrected anemias in mouse models of MDS, aging, and hemolysis in vivo, extending the survival of mice with MDS relative to that of controls. The effects of muscarinic receptor antagonism on promoting expansion of BFU-Es were mediated by cyclic AMP induction of the transcription factor CREB, whose targets up-regulated key regulators of BFU-E self-renewal. On the basis of these data, we propose a model of hematopoietic progenitor self-renewal through a cholinergic-mediated "hematopoietic reflex" and identify muscarinic acetylcholine receptor antagonists as potential therapies for anemias associated with MDS, aging, and hemolysis. Copyright © 2019 The Authors.
Keywords: signal transduction; survival; controlled study; human cell; nonhuman; genetic analysis; animal cell; mouse; animal tissue; disease association; anemia; erythroid precursor cell; erythropoiesis; hemolysis; protein targeting; animal experiment; animal model; in vivo study; myelodysplastic syndrome; regulatory mechanism; erythroid cell; stress; aging; down regulation; upregulation; cyclic amp responsive element binding protein; cholinergic receptor; adenosine phosphate; muscarinic receptor; cell self-renewal; burst forming unit e; human; male; female; priority journal; article
Journal Title: Science Translational Medicine
Volume: 11
Issue: 511
ISSN: 1946-6234
Publisher: American Association for the Advancement of Science  
Date Published: 2019-09-25
Start Page: eaaw3781
Language: English
DOI: 10.1126/scitranslmed.aaw3781
PUBMED: 31554738
PROVIDER: scopus
Notes: Article -- Export Date: 1 November 2019 -- Source: Scopus
Citation Impact
MSK Authors
  1. Mithat Gonen
    778 Gonen
  2. Young Rock Chung
    47 Chung
  3. Daichi   Inoue
    21 Inoue
  4. Justin   Taylor
    35 Taylor
  5. Lillian Elizabeth Bitner
    10 Bitner