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TC1(C8orf4) regulates hematopoietic stem/progenitor cells and hematopoiesis.

Jung Y, Kim M, Soh H, Lee S, Kim J, Park S, Song K, Lee I - PLoS ONE (2014)

Bottom Line: The expanded population mostly consists of CD150-CD48+ cells, suggesting the expansion of lineage-restricted hematopoietic progenitor cells.Our findings indicate that TC1 is a novel hematopoietic regulator.The mechanisms of TC1-dependent HSPC regulation and lineage determination are unknown.

View Article: PubMed Central - PubMed

Affiliation: Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

ABSTRACT
Hematopoiesis is a complex process requiring multiple regulators for hematopoietic stem/progenitor cells (HSPC) and differentiation to multi-lineage blood cells. TC1(C8orf4) is implicated in cancers, hematological malignancies and inflammatory activation. Here, we report that Tc1 regulates hematopoiesis in mice. Myeloid and lymphoid cells are increased markedly in peripheral blood of Tc1-deleted mice compared to wild type controls. Red blood cells are small-sized but increased in number. The bone marrow of Tc1-/- mice is normocellular histologically. However, Lin-Sca-1+c-Kit+ (LSK) cells are expanded in Tc1-/- mice compared to wild type controls. The expanded population mostly consists of CD150-CD48+ cells, suggesting the expansion of lineage-restricted hematopoietic progenitor cells. Colony forming units (CFU) are increased in Tc1-/- mice bone marrow cells compared to controls. In wild type mice bone marrow, Tc1 is expressed in a limited population of HSPC but not in differentiated cells. Major myeloid transcriptional regulators such as Pu.1 and Cebpα are not up-regulated in Tc1-/- mice bone marrow. Our findings indicate that TC1 is a novel hematopoietic regulator. The mechanisms of TC1-dependent HSPC regulation and lineage determination are unknown.

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Hematopoietic lineage- and pluripotent stem cell-regulators.(A) qPCR analysis for Pu.1 expression in total Lin− cells (left) or sorted Lin−Sca-1+ cell fraction (right) of Tc1−/− and wild type mice bone marrow. Data represent mean ± s.d. of 6 male, 8 week-old Tc1−/− mice, and 6 sex- and age-matched control mice over 3 independent experiments for the total Lin− cell assay, and 10 male, 8 to 9 week-old Tc1−/− mice, and 10 sex- and age-matched control mice over 2 independent experiments for the sorted-Lin−Sca-1+ fraction assay, respectively. (B–E) qPCR analysis for Cebpα (B), Gata-1 (C), c-Myc and Ccnd1 (D), and Klf4 (E) expression in Lin− cells. Data represent mean ± s.d. of 6 male, 9 week-old Tc1−/− mice, and 6 sex- and age-matched control mice over 3 independent experiments. **p<0.01; ***p<0.001.
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pone-0100311-g006: Hematopoietic lineage- and pluripotent stem cell-regulators.(A) qPCR analysis for Pu.1 expression in total Lin− cells (left) or sorted Lin−Sca-1+ cell fraction (right) of Tc1−/− and wild type mice bone marrow. Data represent mean ± s.d. of 6 male, 8 week-old Tc1−/− mice, and 6 sex- and age-matched control mice over 3 independent experiments for the total Lin− cell assay, and 10 male, 8 to 9 week-old Tc1−/− mice, and 10 sex- and age-matched control mice over 2 independent experiments for the sorted-Lin−Sca-1+ fraction assay, respectively. (B–E) qPCR analysis for Cebpα (B), Gata-1 (C), c-Myc and Ccnd1 (D), and Klf4 (E) expression in Lin− cells. Data represent mean ± s.d. of 6 male, 9 week-old Tc1−/− mice, and 6 sex- and age-matched control mice over 3 independent experiments. **p<0.01; ***p<0.001.

Mentions: Our data together supported a biological role of Tc1 in the regulation of HSPC in vivo. However, it was not clear how the relatively myeloid- and lymphoid-prone lineage fate was determined in Tc1−/− mice. We first investigated the expression of major transcriptional regulators for myelopoiesis [25]. Upon flow cytometry, the expression of Pu.1 was not increased in LSK cells of Tc1−/− mice compared to wild type controls (data not shown). By qPCR analysis, Pu.1 was down-regulated significantly in total Lin− from Tc1−/− mice bone marrow compared to controls (Figure 6A). Pu.1 expression was also down-regulated in sorted Lin−Sca-1+ cells of Tc1−/− mice. To investigate a potential TC1-dependent regulation of PU.1, HL-60 cells were transfected using TC1. No significant change in the PU.1 expression was shown in TC1-transfected HL-60 cells compared to vector-transfected control (data not shown). Cebpα, another major regulator of myelopoiesis, was also down-regulated marginally (p<0.07) in Lin− cells of Tc1−/− mice compared to controls (Figure 6B). Gata-1, a major regulator for erythroid cell fate, appeared to be up–regulated in Tc1−/− mice mildly, but the difference was not statistically significant (Figure 6C).


TC1(C8orf4) regulates hematopoietic stem/progenitor cells and hematopoiesis.

Jung Y, Kim M, Soh H, Lee S, Kim J, Park S, Song K, Lee I - PLoS ONE (2014)

Hematopoietic lineage- and pluripotent stem cell-regulators.(A) qPCR analysis for Pu.1 expression in total Lin− cells (left) or sorted Lin−Sca-1+ cell fraction (right) of Tc1−/− and wild type mice bone marrow. Data represent mean ± s.d. of 6 male, 8 week-old Tc1−/− mice, and 6 sex- and age-matched control mice over 3 independent experiments for the total Lin− cell assay, and 10 male, 8 to 9 week-old Tc1−/− mice, and 10 sex- and age-matched control mice over 2 independent experiments for the sorted-Lin−Sca-1+ fraction assay, respectively. (B–E) qPCR analysis for Cebpα (B), Gata-1 (C), c-Myc and Ccnd1 (D), and Klf4 (E) expression in Lin− cells. Data represent mean ± s.d. of 6 male, 9 week-old Tc1−/− mice, and 6 sex- and age-matched control mice over 3 independent experiments. **p<0.01; ***p<0.001.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4061086&req=5

pone-0100311-g006: Hematopoietic lineage- and pluripotent stem cell-regulators.(A) qPCR analysis for Pu.1 expression in total Lin− cells (left) or sorted Lin−Sca-1+ cell fraction (right) of Tc1−/− and wild type mice bone marrow. Data represent mean ± s.d. of 6 male, 8 week-old Tc1−/− mice, and 6 sex- and age-matched control mice over 3 independent experiments for the total Lin− cell assay, and 10 male, 8 to 9 week-old Tc1−/− mice, and 10 sex- and age-matched control mice over 2 independent experiments for the sorted-Lin−Sca-1+ fraction assay, respectively. (B–E) qPCR analysis for Cebpα (B), Gata-1 (C), c-Myc and Ccnd1 (D), and Klf4 (E) expression in Lin− cells. Data represent mean ± s.d. of 6 male, 9 week-old Tc1−/− mice, and 6 sex- and age-matched control mice over 3 independent experiments. **p<0.01; ***p<0.001.
Mentions: Our data together supported a biological role of Tc1 in the regulation of HSPC in vivo. However, it was not clear how the relatively myeloid- and lymphoid-prone lineage fate was determined in Tc1−/− mice. We first investigated the expression of major transcriptional regulators for myelopoiesis [25]. Upon flow cytometry, the expression of Pu.1 was not increased in LSK cells of Tc1−/− mice compared to wild type controls (data not shown). By qPCR analysis, Pu.1 was down-regulated significantly in total Lin− from Tc1−/− mice bone marrow compared to controls (Figure 6A). Pu.1 expression was also down-regulated in sorted Lin−Sca-1+ cells of Tc1−/− mice. To investigate a potential TC1-dependent regulation of PU.1, HL-60 cells were transfected using TC1. No significant change in the PU.1 expression was shown in TC1-transfected HL-60 cells compared to vector-transfected control (data not shown). Cebpα, another major regulator of myelopoiesis, was also down-regulated marginally (p<0.07) in Lin− cells of Tc1−/− mice compared to controls (Figure 6B). Gata-1, a major regulator for erythroid cell fate, appeared to be up–regulated in Tc1−/− mice mildly, but the difference was not statistically significant (Figure 6C).

Bottom Line: The expanded population mostly consists of CD150-CD48+ cells, suggesting the expansion of lineage-restricted hematopoietic progenitor cells.Our findings indicate that TC1 is a novel hematopoietic regulator.The mechanisms of TC1-dependent HSPC regulation and lineage determination are unknown.

View Article: PubMed Central - PubMed

Affiliation: Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

ABSTRACT
Hematopoiesis is a complex process requiring multiple regulators for hematopoietic stem/progenitor cells (HSPC) and differentiation to multi-lineage blood cells. TC1(C8orf4) is implicated in cancers, hematological malignancies and inflammatory activation. Here, we report that Tc1 regulates hematopoiesis in mice. Myeloid and lymphoid cells are increased markedly in peripheral blood of Tc1-deleted mice compared to wild type controls. Red blood cells are small-sized but increased in number. The bone marrow of Tc1-/- mice is normocellular histologically. However, Lin-Sca-1+c-Kit+ (LSK) cells are expanded in Tc1-/- mice compared to wild type controls. The expanded population mostly consists of CD150-CD48+ cells, suggesting the expansion of lineage-restricted hematopoietic progenitor cells. Colony forming units (CFU) are increased in Tc1-/- mice bone marrow cells compared to controls. In wild type mice bone marrow, Tc1 is expressed in a limited population of HSPC but not in differentiated cells. Major myeloid transcriptional regulators such as Pu.1 and Cebpα are not up-regulated in Tc1-/- mice bone marrow. Our findings indicate that TC1 is a novel hematopoietic regulator. The mechanisms of TC1-dependent HSPC regulation and lineage determination are unknown.

Show MeSH
Related in: MedlinePlus