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Heme oxygenase-1 deletion affects stress erythropoiesis.

Cao YA, Kusy S, Luong R, Wong RJ, Stevenson DK, Contag CH - PLoS ONE (2011)

Bottom Line: Here, we describe the specific effects of HO-1 deficiency on stress erythropoiesis.In the spleens of mice that received hmox(+/-) cells, we show (i) decreases in the proerythroblast, basophilic, and polychromatophilic erythroblast populations; (ii) increases in the insoluble iron levels and decreases in the soluble iron levels; (iii) increased numbers of Mac-1(+)-cells expressing TNF-α; and (iv) decreased levels of CD49d expression in the basophilic and polychromatophilic erythroblast populations.As reflected by effects on secreted and cell surface proteins, HO-1 deletion likely affects stress erythropoiesis through the retention of erythroblasts in the erythroblastic islands of the spleen.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America.

ABSTRACT

Background: Homeostatic erythropoiesis leads to the formation of mature red blood cells under non-stress conditions, and the production of new erythrocytes occurs as the need arises. In response to environmental stimuli, such as bone marrow transplantation, myelosuppression, or anemia, erythroid progenitors proliferate rapidly in a process referred to as stress erythropoiesis. We have previously demonstrated that heme oxygenase-1 (HO-1) deficiency leads to disrupted stress hematopoiesis. Here, we describe the specific effects of HO-1 deficiency on stress erythropoiesis.

Methodology/principal findings: We used a transplant model to induce stress conditions. In irradiated recipients that received hmox(+/-) or hmox(+/+) bone marrow cells, we evaluated (i) the erythrocyte parameters in the peripheral blood; (ii) the staining intensity of CD71-, Ter119-, and CD49d-specific surface markers during erythroblast differentiation; (iii) the patterns of histological iron staining; and (iv) the number of Mac-1(+)-cells expressing TNF-α. In the spleens of mice that received hmox(+/-) cells, we show (i) decreases in the proerythroblast, basophilic, and polychromatophilic erythroblast populations; (ii) increases in the insoluble iron levels and decreases in the soluble iron levels; (iii) increased numbers of Mac-1(+)-cells expressing TNF-α; and (iv) decreased levels of CD49d expression in the basophilic and polychromatophilic erythroblast populations.

Conclusions/significance: As reflected by effects on secreted and cell surface proteins, HO-1 deletion likely affects stress erythropoiesis through the retention of erythroblasts in the erythroblastic islands of the spleen. Thus, HO-1 may serve as a therapeutic target for controlling erythropoiesis, and the dysregulation of HO-1 may be a predisposing condition for hematologic diseases.

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HO-1 participates in optimal iron re-utilization.(A) H&E staining of the spleen sections from hmox+/+ or hmox+/− cell recipients at day 14 post-transplantation is shown. The arrows indicate hemosiderin-laden macrophages. The transplantation of HO-1-deficient BM cells leads to an increase of hemosiderin. The magnification is 400×. The photograph shown is a representative of three experiments. (B) Prussian blue iron staining of the spleen sections from hmox+/+ or hmox+/− cell recipients at day 14 post-transplantation is shown. The transplantation of HO-1-deficient BM cells leads to an increase of Prussian blue-positive cells. The magnification is 100×. The photograph shown is a representative experiment out of the three that were performed. (C) The total and free iron levels in the splenic homogenates from hmox+/+ or hmox+/− cell recipients at day 14 post-transplantation are shown. The transplantation of HO-1-deficient BM cells leads to a decrease of soluble iron. The mean ± SEM is shown for six mice per genotype; *P≤0.05.
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pone-0020634-g003: HO-1 participates in optimal iron re-utilization.(A) H&E staining of the spleen sections from hmox+/+ or hmox+/− cell recipients at day 14 post-transplantation is shown. The arrows indicate hemosiderin-laden macrophages. The transplantation of HO-1-deficient BM cells leads to an increase of hemosiderin. The magnification is 400×. The photograph shown is a representative of three experiments. (B) Prussian blue iron staining of the spleen sections from hmox+/+ or hmox+/− cell recipients at day 14 post-transplantation is shown. The transplantation of HO-1-deficient BM cells leads to an increase of Prussian blue-positive cells. The magnification is 100×. The photograph shown is a representative experiment out of the three that were performed. (C) The total and free iron levels in the splenic homogenates from hmox+/+ or hmox+/− cell recipients at day 14 post-transplantation are shown. The transplantation of HO-1-deficient BM cells leads to a decrease of soluble iron. The mean ± SEM is shown for six mice per genotype; *P≤0.05.

Mentions: To test this possibility, histological analysis of the spleen was performed 14 days post-transplantation. Hemosiderin-laden macrophages, accounted for approximately 2% of the total red pulp nucleated cell population in the spleens of mice that received hmox+/− BM cells, compared to ∼1% in mice that received hmox+/+ BM cells (Figure 3A, upper levels; see Methods for quantification). Prussian blue staining showed an average of 2.6% of the splenic cross-sectional area to be positive for iron in the recipients of hmox+/− BM cells, compared to 0.9% in the recipients of hmox+/+ BM cells (Figure 3B, lower levels).


Heme oxygenase-1 deletion affects stress erythropoiesis.

Cao YA, Kusy S, Luong R, Wong RJ, Stevenson DK, Contag CH - PLoS ONE (2011)

HO-1 participates in optimal iron re-utilization.(A) H&E staining of the spleen sections from hmox+/+ or hmox+/− cell recipients at day 14 post-transplantation is shown. The arrows indicate hemosiderin-laden macrophages. The transplantation of HO-1-deficient BM cells leads to an increase of hemosiderin. The magnification is 400×. The photograph shown is a representative of three experiments. (B) Prussian blue iron staining of the spleen sections from hmox+/+ or hmox+/− cell recipients at day 14 post-transplantation is shown. The transplantation of HO-1-deficient BM cells leads to an increase of Prussian blue-positive cells. The magnification is 100×. The photograph shown is a representative experiment out of the three that were performed. (C) The total and free iron levels in the splenic homogenates from hmox+/+ or hmox+/− cell recipients at day 14 post-transplantation are shown. The transplantation of HO-1-deficient BM cells leads to a decrease of soluble iron. The mean ± SEM is shown for six mice per genotype; *P≤0.05.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3105104&req=5

pone-0020634-g003: HO-1 participates in optimal iron re-utilization.(A) H&E staining of the spleen sections from hmox+/+ or hmox+/− cell recipients at day 14 post-transplantation is shown. The arrows indicate hemosiderin-laden macrophages. The transplantation of HO-1-deficient BM cells leads to an increase of hemosiderin. The magnification is 400×. The photograph shown is a representative of three experiments. (B) Prussian blue iron staining of the spleen sections from hmox+/+ or hmox+/− cell recipients at day 14 post-transplantation is shown. The transplantation of HO-1-deficient BM cells leads to an increase of Prussian blue-positive cells. The magnification is 100×. The photograph shown is a representative experiment out of the three that were performed. (C) The total and free iron levels in the splenic homogenates from hmox+/+ or hmox+/− cell recipients at day 14 post-transplantation are shown. The transplantation of HO-1-deficient BM cells leads to a decrease of soluble iron. The mean ± SEM is shown for six mice per genotype; *P≤0.05.
Mentions: To test this possibility, histological analysis of the spleen was performed 14 days post-transplantation. Hemosiderin-laden macrophages, accounted for approximately 2% of the total red pulp nucleated cell population in the spleens of mice that received hmox+/− BM cells, compared to ∼1% in mice that received hmox+/+ BM cells (Figure 3A, upper levels; see Methods for quantification). Prussian blue staining showed an average of 2.6% of the splenic cross-sectional area to be positive for iron in the recipients of hmox+/− BM cells, compared to 0.9% in the recipients of hmox+/+ BM cells (Figure 3B, lower levels).

Bottom Line: Here, we describe the specific effects of HO-1 deficiency on stress erythropoiesis.In the spleens of mice that received hmox(+/-) cells, we show (i) decreases in the proerythroblast, basophilic, and polychromatophilic erythroblast populations; (ii) increases in the insoluble iron levels and decreases in the soluble iron levels; (iii) increased numbers of Mac-1(+)-cells expressing TNF-α; and (iv) decreased levels of CD49d expression in the basophilic and polychromatophilic erythroblast populations.As reflected by effects on secreted and cell surface proteins, HO-1 deletion likely affects stress erythropoiesis through the retention of erythroblasts in the erythroblastic islands of the spleen.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America.

ABSTRACT

Background: Homeostatic erythropoiesis leads to the formation of mature red blood cells under non-stress conditions, and the production of new erythrocytes occurs as the need arises. In response to environmental stimuli, such as bone marrow transplantation, myelosuppression, or anemia, erythroid progenitors proliferate rapidly in a process referred to as stress erythropoiesis. We have previously demonstrated that heme oxygenase-1 (HO-1) deficiency leads to disrupted stress hematopoiesis. Here, we describe the specific effects of HO-1 deficiency on stress erythropoiesis.

Methodology/principal findings: We used a transplant model to induce stress conditions. In irradiated recipients that received hmox(+/-) or hmox(+/+) bone marrow cells, we evaluated (i) the erythrocyte parameters in the peripheral blood; (ii) the staining intensity of CD71-, Ter119-, and CD49d-specific surface markers during erythroblast differentiation; (iii) the patterns of histological iron staining; and (iv) the number of Mac-1(+)-cells expressing TNF-α. In the spleens of mice that received hmox(+/-) cells, we show (i) decreases in the proerythroblast, basophilic, and polychromatophilic erythroblast populations; (ii) increases in the insoluble iron levels and decreases in the soluble iron levels; (iii) increased numbers of Mac-1(+)-cells expressing TNF-α; and (iv) decreased levels of CD49d expression in the basophilic and polychromatophilic erythroblast populations.

Conclusions/significance: As reflected by effects on secreted and cell surface proteins, HO-1 deletion likely affects stress erythropoiesis through the retention of erythroblasts in the erythroblastic islands of the spleen. Thus, HO-1 may serve as a therapeutic target for controlling erythropoiesis, and the dysregulation of HO-1 may be a predisposing condition for hematologic diseases.

Show MeSH
Related in: MedlinePlus