Open AccessMuscarinic acetylcholine receptor regulates self-renewal of early erythroid progenitors
Author(s) -
Gaurang Trivedi,
Daichi Inoue,
Cynthia Chen,
Lillian Bitner,
Young Rock Chung,
Justin Taylor,
Mithat Gönen,
Jürgen Wess,
Omar Abdel-Wahab,
Lingbo Zhang
Publication year - 2019
Publication title -
science translational medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.819
H-Index - 216
eISSN - 1946-6242
pISSN - 1946-6234
DOI - 10.1126/scitranslmed.aaw3781
Subject(s) - muscarinic acetylcholine receptor , acetylcholine , muscarinic acetylcholine receptor m5 , progenitor cell , muscarinic acetylcholine receptor m3 , microbiology and biotechnology , acetylcholine receptor , muscarinic acetylcholine receptor m1 , progenitor , neuroscience , receptor , biology , chemistry , medicine , endocrinology , stem cell
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.