Negative autoregulation by Fas stabilizes adult erythropoiesis and accelerates its stress response.

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...

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Autores principales:	Miroslav Koulnis, Ying Liu, Kelly Hallstrom, Merav Socolovsky
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2d1e88dd443f4927bf52770e7d30e2f2
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spelling	oai:doaj.org-article:2d1e88dd443f4927bf52770e7d30e2f22021-11-18T06:50:34ZNegative autoregulation by Fas stabilizes adult erythropoiesis and accelerates its stress response.1932-620310.1371/journal.pone.0021192https://doaj.org/article/2d1e88dd443f4927bf52770e7d30e2f22011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21760888/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Erythropoiesis 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.Miroslav KoulnisYing LiuKelly HallstromMerav SocolovskyPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 7, p e21192 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Miroslav Koulnis Ying Liu Kelly Hallstrom Merav Socolovsky Negative autoregulation by Fas stabilizes adult erythropoiesis and accelerates its stress response.
description	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.
format	article
author	Miroslav Koulnis Ying Liu Kelly Hallstrom Merav Socolovsky
author_facet	Miroslav Koulnis Ying Liu Kelly Hallstrom Merav Socolovsky
author_sort	Miroslav Koulnis
title	Negative autoregulation by Fas stabilizes adult erythropoiesis and accelerates its stress response.
title_short	Negative autoregulation by Fas stabilizes adult erythropoiesis and accelerates its stress response.
title_full	Negative autoregulation by Fas stabilizes adult erythropoiesis and accelerates its stress response.
title_fullStr	Negative autoregulation by Fas stabilizes adult erythropoiesis and accelerates its stress response.
title_full_unstemmed	Negative autoregulation by Fas stabilizes adult erythropoiesis and accelerates its stress response.
title_sort	negative autoregulation by fas stabilizes adult erythropoiesis and accelerates its stress response.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/2d1e88dd443f4927bf52770e7d30e2f2
work_keys_str_mv	AT miroslavkoulnis negativeautoregulationbyfasstabilizesadulterythropoiesisandacceleratesitsstressresponse AT yingliu negativeautoregulationbyfasstabilizesadulterythropoiesisandacceleratesitsstressresponse AT kellyhallstrom negativeautoregulationbyfasstabilizesadulterythropoiesisandacceleratesitsstressresponse AT meravsocolovsky negativeautoregulationbyfasstabilizesadulterythropoiesisandacceleratesitsstressresponse
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Negative autoregulation by Fas stabilizes adult erythropoiesis and accelerates its stress response.

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