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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 deficiency increases the number of TNF-α-expressing cells.(A) Representative FACS profiles of freshly isolated splenic cells from hmox+/+ or hmox+/− BM cell recipients at day 15 post-transplantation are shown. Cells were labeled with and PE-conjugated anti-TNF-α and PE-Cy7-conjugated anti-Mac-1. Dead cells (stained positive with propidium iodide) were excluded from the analysis. The engraftment of HO-1-deficient BM cells modifies the FACS profile of Mac-1 TNF-α-stained splenic cells. (B) The frequencies of Mac-1+ TNF-α+ splenic cells from hmox+/+ and hmox+/− BM cell recipients are shown. The transplantation of HO-1-deficient BM cells leads to an increase of the Mac-1+ TNF-α+ splenic population. The mean ± SEM is shown for six mice per genotype; *P≤0.05.
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pone-0020634-g004: HO-1 deficiency increases the number of TNF-α-expressing cells.(A) Representative FACS profiles of freshly isolated splenic cells from hmox+/+ or hmox+/− BM cell recipients at day 15 post-transplantation are shown. Cells were labeled with and PE-conjugated anti-TNF-α and PE-Cy7-conjugated anti-Mac-1. Dead cells (stained positive with propidium iodide) were excluded from the analysis. The engraftment of HO-1-deficient BM cells modifies the FACS profile of Mac-1 TNF-α-stained splenic cells. (B) The frequencies of Mac-1+ TNF-α+ splenic cells from hmox+/+ and hmox+/− BM cell recipients are shown. The transplantation of HO-1-deficient BM cells leads to an increase of the Mac-1+ TNF-α+ splenic population. The mean ± SEM is shown for six mice per genotype; *P≤0.05.

Mentions: To test whether HO-1 deficiency alters the expression of TNF-α in stress erythropoiesis, we assessed the number of Mac-1+-cells expressing TNF-α in the spleens of recipients following hmox+/− and hmox+/+ BM cells transplantation (Figure 4A). At day 15 post-engraftment, 16.0±2.9% of Mac-1+ TNF-α+ cells were analyzed in the spleens of hmox+/+ BM cells-recipients, compared to 22.7±3.6% in those of hmox+/− BM cells-recipients (n = 6; *P = 0.016) (Figure 4B). This 40% increase due to HO-1 deficiency suggests that TNF-α expression might be involved in the disrupted stress erythropoiesis in HO-1 deficiency.


Heme oxygenase-1 deletion affects stress erythropoiesis.

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

HO-1 deficiency increases the number of TNF-α-expressing cells.(A) Representative FACS profiles of freshly isolated splenic cells from hmox+/+ or hmox+/− BM cell recipients at day 15 post-transplantation are shown. Cells were labeled with and PE-conjugated anti-TNF-α and PE-Cy7-conjugated anti-Mac-1. Dead cells (stained positive with propidium iodide) were excluded from the analysis. The engraftment of HO-1-deficient BM cells modifies the FACS profile of Mac-1 TNF-α-stained splenic cells. (B) The frequencies of Mac-1+ TNF-α+ splenic cells from hmox+/+ and hmox+/− BM cell recipients are shown. The transplantation of HO-1-deficient BM cells leads to an increase of the Mac-1+ TNF-α+ splenic population. 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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pone-0020634-g004: HO-1 deficiency increases the number of TNF-α-expressing cells.(A) Representative FACS profiles of freshly isolated splenic cells from hmox+/+ or hmox+/− BM cell recipients at day 15 post-transplantation are shown. Cells were labeled with and PE-conjugated anti-TNF-α and PE-Cy7-conjugated anti-Mac-1. Dead cells (stained positive with propidium iodide) were excluded from the analysis. The engraftment of HO-1-deficient BM cells modifies the FACS profile of Mac-1 TNF-α-stained splenic cells. (B) The frequencies of Mac-1+ TNF-α+ splenic cells from hmox+/+ and hmox+/− BM cell recipients are shown. The transplantation of HO-1-deficient BM cells leads to an increase of the Mac-1+ TNF-α+ splenic population. The mean ± SEM is shown for six mice per genotype; *P≤0.05.
Mentions: To test whether HO-1 deficiency alters the expression of TNF-α in stress erythropoiesis, we assessed the number of Mac-1+-cells expressing TNF-α in the spleens of recipients following hmox+/− and hmox+/+ BM cells transplantation (Figure 4A). At day 15 post-engraftment, 16.0±2.9% of Mac-1+ TNF-α+ cells were analyzed in the spleens of hmox+/+ BM cells-recipients, compared to 22.7±3.6% in those of hmox+/− BM cells-recipients (n = 6; *P = 0.016) (Figure 4B). This 40% increase due to HO-1 deficiency suggests that TNF-α expression might be involved in the disrupted stress erythropoiesis in HO-1 deficiency.

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