PubMed ID

21760888

UMMS Affiliation

Department of Pediatrics; Department of Cancer Biology

Date

7-2011

Document Type

Article

Subjects

Aging; Animals; Antigens, CD95; Apoptosis; Atmosphere; Cell Hypoxia; Cell Survival; Colony-Forming Units Assay; Erythroblasts; *Erythropoiesis; Erythropoietin; Fas Ligand Protein; Homeodomain Proteins; *Homeostasis; Mice; Models, Biological; Oxygen; Receptors, Fc; Signal Transduction; Spleen; *Stress, Physiological

Disciplines

Cancer Biology | Hematology | Life Sciences | Medicine and Health Sciences

Abstract

Erythropoiesis maintains a stable hematocrit and tissue oxygenation in the basal state, while mounting a stress response that accelerates red cell production in anemia, blood loss or high altitude. Thus, tissue hypoxia increases secretion of the hormone erythropoietin (Epo), stimulating an increase in erythroid progenitors and erythropoietic rate. Several cell divisions must elapse, however, before Epo-responsive progenitors mature into red cells. This inherent delay is expected to reduce the stability of erythropoiesis and to slow its response to stress. Here we identify a mechanism that helps to offset these effects. We recently showed that splenic early erythroblasts, 'EryA', negatively regulate their own survival by co-expressing the death receptor Fas, and its ligand, FasL. Here we studied mice mutant for either Fas or FasL, bred onto an immune-deficient background, in order to avoid an autoimmune syndrome associated with Fas deficiency. Mutant mice had a higher hematocrit, lower serum Epo, and an increased number of splenic erythroid progenitors, suggesting that Fas negatively regulates erythropoiesis at the level of the whole animal. In addition, Fas-mediated autoregulation stabilizes the size of the splenic early erythroblast pool, since mutant mice had a significantly more variable EryA pool than matched control mice. Unexpectedly, in spite of the loss of a negative regulator, the expansion of EryA and ProE progenitors in response to high Epo in vivo, as well as the increase in erythropoietic rate in mice injected with Epo or placed in a hypoxic environment, lagged significantly in the mutant mice. This suggests that Fas-mediated autoregulation accelerates the erythropoietic response to stress. Therefore, Fas-mediated negative autoregulation within splenic erythropoietic tissue optimizes key dynamic features in the operation of the erythropoietic network as a whole, helping to maintain erythroid homeostasis in the basal state, while accelerating the stress response.

Comments

Citation: Koulnis M, Liu Y, Hallstrom K, Socolovsky M (2011) Negative Autoregulation by Fas Stabilizes Adult Erythropoiesis and Accelerates Its Stress Response. PLoS ONE 6(7): e21192. doi:10.1371/journal.pone.0021192. Link to article on publisher's site

Copyright: © 2011 Koulnis et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Related Resources

Link to Article in PubMed