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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.

SUBMITTER: Trivedi G

PROVIDER: S-EPMC7194030 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Muscarinic acetylcholine receptor regulates self-renewal of early erythroid progenitors.

Trivedi Gaurang G Inoue Daichi D Chen Cynthia C Bitner Lillian L Chung Young Rock YR Taylor Justin J Gönen Mithat M Wess Jürgen J Abdel-Wahab Omar O Zhang Lingbo L Zhang Lingbo L

Science translational medicine 20190901 511

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 ...[more]

PMID: 31554738

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Project description:Many acute and chronic anaemias, including haemolysis, sepsis and genetic bone marrow failure diseases such as Diamond-Blackfan anaemia, are not treatable with erythropoietin (Epo), because the colony-forming unit erythroid progenitors (CFU-Es) that respond to Epo are either too few in number or are not sensitive enough to Epo to maintain sufficient red blood cell production. Treatment of these anaemias requires a drug that acts at an earlier stage of red cell formation and enhances the formation of Epo-sensitive CFU-E progenitors. Recently, we showed that glucocorticoids specifically stimulate self-renewal of an early erythroid progenitor, burst-forming unit erythroid (BFU-E), and increase the production of terminally differentiated erythroid cells. Here we show that activation of the peroxisome proliferator-activated receptor ? (PPAR-?) by the PPAR-? agonists GW7647 and fenofibrate synergizes with the glucocorticoid receptor (GR) to promote BFU-E self-renewal. Over time these agonists greatly increase production of mature red blood cells in cultures of both mouse fetal liver BFU-Es and mobilized human adult CD34(+) peripheral blood progenitors, with a new and effective culture system being used for the human cells that generates normal enucleated reticulocytes. Although Ppara(-/-) mice show no haematological difference from wild-type mice in both normal and phenylhydrazine (PHZ)-induced stress erythropoiesis, PPAR-? agonists facilitate recovery of wild-type but not Ppara(-/-) mice from PHZ-induced acute haemolytic anaemia. We also show that PPAR-? alleviates anaemia in a mouse model of chronic anaemia. Finally, both in control and corticosteroid-treated BFU-E cells, PPAR-? co-occupies many chromatin sites with GR; when activated by PPAR-? agonists, additional PPAR-? is recruited to GR-adjacent sites and presumably facilitates GR-dependent BFU-E self-renewal. Our discovery of the role of PPAR-? agonists in stimulating self-renewal of early erythroid progenitor cells suggests that the clinically tested PPAR-? agonists we used may improve the efficacy of corticosteroids in treating Epo-resistant anaemias.

Dataset Information

Muscarinic acetylcholine receptor regulates self-renewal of early erythroid progenitors.

Publications

Muscarinic acetylcholine receptor regulates self-renewal of early erythroid progenitors.

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