Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0026986 (
myelodysplastic syndrome
)
14,926
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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.
...
PMID:Muscarinic acetylcholine receptor regulates self-renewal of early erythroid progenitors. 3155 38
