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Essential role for the p55 tumor necrosis factor receptor in regulating hematopoiesis at a stem cell level.

Rebel VI, Hartnett S, Hill GR, Lazo-Kallanian SB, Ferrara JL, Sieff CA - J. Exp. Med. (1999)

Bottom Line: In addition, a fourfold decrease in the number of HSCs could be demonstrated in a competitive repopulating assay.Secondary transplantations of marrow cells from primary recipients of p55(-/-) marrow revealed impaired self-renewal ability of p55-deficient HSCs.These data show that, in vivo, signaling through the p55 subunit of the TNF receptor is essential for regulating hematopoiesis at the stem cell level.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. vivienne_rebel@dfci.harvard.edu

ABSTRACT
Hematopoietic stem cell (HSC) self-renewal is a complicated process, and its regulatory mechanisms are poorly understood. Previous studies have identified tumor necrosis factor (TNF)-alpha as a pleiotropic cytokine, which, among other actions, prevents various hematopoietic progenitor cells from proliferating and differentiating in vitro. However, its role in regulating long-term repopulating HSCs in vivo has not been investigated. In this study, mice deficient for the p55 or the p75 subunit of the TNF receptor were analyzed in a variety of hematopoietic progenitor and stem cell assays. In older p55(-/-) mice (>6 mo), we identified significant differences in their hematopoietic system compared with age-matched p75(-/-) or wild-type counterparts. Increased marrow cellularity and increased numbers of myeloid and erythroid colony-forming progenitor cells (CFCs), paralleled by elevated peripheral blood cell counts, were found in p55-deficient mice. In contrast to the increased myeloid compartment, pre-B CFCs were deficient in older p55(-/-) mice. In addition, a fourfold decrease in the number of HSCs could be demonstrated in a competitive repopulating assay. Secondary transplantations of marrow cells from primary recipients of p55(-/-) marrow revealed impaired self-renewal ability of p55-deficient HSCs. These data show that, in vivo, signaling through the p55 subunit of the TNF receptor is essential for regulating hematopoiesis at the stem cell level.

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Transplantation of p55−/− marrow cells into irradiated recipients results in less donor repopulation than equal numbers of WT marrow cells. Depicted is the average percentage of donor-derived nucleated blood cells (% Donor-Repopulation) at 4, 8, and 16 wk after the transplantation in three groups of animals. Group 1 (•) recipients received 16,000 unseparated WT BM cells. Groups 2 (○) and 3 (▪) received p55−/− cells: group 2 16,000 cells per mouse, and group 3 64,000 cells per mouse. *Significantly different from the WT value at the corresponding time point, P < 0.01. ‡Significantly different from the WT value at the corresponding time point, P < 0.05.
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Figure 3: Transplantation of p55−/− marrow cells into irradiated recipients results in less donor repopulation than equal numbers of WT marrow cells. Depicted is the average percentage of donor-derived nucleated blood cells (% Donor-Repopulation) at 4, 8, and 16 wk after the transplantation in three groups of animals. Group 1 (•) recipients received 16,000 unseparated WT BM cells. Groups 2 (○) and 3 (▪) received p55−/− cells: group 2 16,000 cells per mouse, and group 3 64,000 cells per mouse. *Significantly different from the WT value at the corresponding time point, P < 0.01. ‡Significantly different from the WT value at the corresponding time point, P < 0.05.

Mentions: To further elucidate the extent of the stem cell defect in old p55−/− mice, we analyzed in detail the hematopoiesis of three sets of mice transplanted with low numbers of BM cells (Fig. 3, and Table ). Groups 1 and 2 represent animals transplanted with 16,000 total BM cells (WT and p55−/−, respectively). A comparison of their donor repopulation kinetics as measured at various time points after transplant illustrates a dramatic decline in donor reconstitution over a 4-mo time period by p55−/− BM cells, whereas the donor reconstitution by WT cells showed a slight increase over the same time period tested (Fig. 3). 16 wk after transplantation, the level of donor cells in recipients of p55−/− BM cells (group 2) was significantly lower (P < 0.05) compared with that in recipients of WT BM cells (group 1) (1.1 ± 1.0 vs. 10.2 ± 12.2, respectively). The difference in repopulating ability between WT and p55−/− HSCs becomes even more apparent when individual mice are analyzed (Table ). Between 4 and 16 wk after the transplantation, Ly5.2+ donor reconstitution did not increase in any of the recipients of p55−/− (Ly5.2+) BM cells. In contrast, more than half of all the animals that had received WT (Ly5.2+) BM cells showed an increase in Ly5.2+ cells, by as much as 38% in one of the recipients. Moreover, only 22% of the group 2 animals that were multilineage reconstituted at week 4 remained so at week 16, compared with nearly 80% of the animals in group 1 (Table ).


Essential role for the p55 tumor necrosis factor receptor in regulating hematopoiesis at a stem cell level.

Rebel VI, Hartnett S, Hill GR, Lazo-Kallanian SB, Ferrara JL, Sieff CA - J. Exp. Med. (1999)

Transplantation of p55−/− marrow cells into irradiated recipients results in less donor repopulation than equal numbers of WT marrow cells. Depicted is the average percentage of donor-derived nucleated blood cells (% Donor-Repopulation) at 4, 8, and 16 wk after the transplantation in three groups of animals. Group 1 (•) recipients received 16,000 unseparated WT BM cells. Groups 2 (○) and 3 (▪) received p55−/− cells: group 2 16,000 cells per mouse, and group 3 64,000 cells per mouse. *Significantly different from the WT value at the corresponding time point, P < 0.01. ‡Significantly different from the WT value at the corresponding time point, P < 0.05.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195701&req=5

Figure 3: Transplantation of p55−/− marrow cells into irradiated recipients results in less donor repopulation than equal numbers of WT marrow cells. Depicted is the average percentage of donor-derived nucleated blood cells (% Donor-Repopulation) at 4, 8, and 16 wk after the transplantation in three groups of animals. Group 1 (•) recipients received 16,000 unseparated WT BM cells. Groups 2 (○) and 3 (▪) received p55−/− cells: group 2 16,000 cells per mouse, and group 3 64,000 cells per mouse. *Significantly different from the WT value at the corresponding time point, P < 0.01. ‡Significantly different from the WT value at the corresponding time point, P < 0.05.
Mentions: To further elucidate the extent of the stem cell defect in old p55−/− mice, we analyzed in detail the hematopoiesis of three sets of mice transplanted with low numbers of BM cells (Fig. 3, and Table ). Groups 1 and 2 represent animals transplanted with 16,000 total BM cells (WT and p55−/−, respectively). A comparison of their donor repopulation kinetics as measured at various time points after transplant illustrates a dramatic decline in donor reconstitution over a 4-mo time period by p55−/− BM cells, whereas the donor reconstitution by WT cells showed a slight increase over the same time period tested (Fig. 3). 16 wk after transplantation, the level of donor cells in recipients of p55−/− BM cells (group 2) was significantly lower (P < 0.05) compared with that in recipients of WT BM cells (group 1) (1.1 ± 1.0 vs. 10.2 ± 12.2, respectively). The difference in repopulating ability between WT and p55−/− HSCs becomes even more apparent when individual mice are analyzed (Table ). Between 4 and 16 wk after the transplantation, Ly5.2+ donor reconstitution did not increase in any of the recipients of p55−/− (Ly5.2+) BM cells. In contrast, more than half of all the animals that had received WT (Ly5.2+) BM cells showed an increase in Ly5.2+ cells, by as much as 38% in one of the recipients. Moreover, only 22% of the group 2 animals that were multilineage reconstituted at week 4 remained so at week 16, compared with nearly 80% of the animals in group 1 (Table ).

Bottom Line: In addition, a fourfold decrease in the number of HSCs could be demonstrated in a competitive repopulating assay.Secondary transplantations of marrow cells from primary recipients of p55(-/-) marrow revealed impaired self-renewal ability of p55-deficient HSCs.These data show that, in vivo, signaling through the p55 subunit of the TNF receptor is essential for regulating hematopoiesis at the stem cell level.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. vivienne_rebel@dfci.harvard.edu

ABSTRACT
Hematopoietic stem cell (HSC) self-renewal is a complicated process, and its regulatory mechanisms are poorly understood. Previous studies have identified tumor necrosis factor (TNF)-alpha as a pleiotropic cytokine, which, among other actions, prevents various hematopoietic progenitor cells from proliferating and differentiating in vitro. However, its role in regulating long-term repopulating HSCs in vivo has not been investigated. In this study, mice deficient for the p55 or the p75 subunit of the TNF receptor were analyzed in a variety of hematopoietic progenitor and stem cell assays. In older p55(-/-) mice (>6 mo), we identified significant differences in their hematopoietic system compared with age-matched p75(-/-) or wild-type counterparts. Increased marrow cellularity and increased numbers of myeloid and erythroid colony-forming progenitor cells (CFCs), paralleled by elevated peripheral blood cell counts, were found in p55-deficient mice. In contrast to the increased myeloid compartment, pre-B CFCs were deficient in older p55(-/-) mice. In addition, a fourfold decrease in the number of HSCs could be demonstrated in a competitive repopulating assay. Secondary transplantations of marrow cells from primary recipients of p55(-/-) marrow revealed impaired self-renewal ability of p55-deficient HSCs. These data show that, in vivo, signaling through the p55 subunit of the TNF receptor is essential for regulating hematopoiesis at the stem cell level.

Show MeSH
Related in: MedlinePlus