Tomas Ganz

Publications (2)32.36 Total impact

• Article: Identification of TWSG1 as a second novel erythroid regulator of hepcidin expression in murine and human cells.

  Toshihiko Tanno, Prashanth Porayette, Orapan Sripichai, Seung-Jae Noh, Colleen Byrnes, Ajoy Bhupatiraju, Y Terry Lee, Julia B Goodnough, Omid Harandi, Tomas Ganz, Robert F Paulson, Jeffery L Miller
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  ABSTRACT: In thalassemia and other iron loading anemias, ineffective erythropoiesis and erythroid signaling molecules are thought to cause inappropriate suppression of a small peptide produced by hepatocytes named hepcidin. Previously, it was reported that the erythrokine GDF15 is expressed at very high levels in thalassemia and suppresses hepcidin expression. In this study, erythroblast expression of a second molecule named twisted gastrulation (TWSG1) was explored as a potential erythroid regulator of hepcidin. Transcriptome analyses suggest TWSG1 is produced during the earlier stages of erythropoiesis. Hepcidin suppression assays demonstrated inhibition by TWSG1 as measured by quantitative polymerase chain reaction (PCR) in dosed assays (1-1000 ng/mL TWSG1). In human cells, TWSG1 suppressed hepcidin indirectly by inhibiting the signaling effects and associated hepcidin up-regulation by bone morphogenic proteins 2 and 4 (BMP2/BMP4). In murine hepatocytes, hepcidin expression was inhibited by murine Twsg1 in the absence of additional BMP. In vivo studies of Twsg1 expression were performed in healthy and thalassemic mice. Twsg1 expression was significantly increased in the spleen, bone marrow, and liver of the thalassemic animals. These data demonstrate that twisted gastrulation protein interferes with BMP-mediated hepcidin expression and may act with GDF15 to dysregulate iron homeostasis in thalassemia syndromes.
  Blood 06/2009; 114(1):181-6. · 9.90 Impact Factor
• Source

  Available from: Y. Terry Lee

  Article: High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin.

  Toshihiko Tanno, Natarajan V Bhanu, Patricia A Oneal, Sung-Ho Goh, Pamela Staker, Y Terry Lee, John W Moroney, Christopher H Reed, Naomi L C Luban, Rui-Hong Wang, Thomas E Eling, Richard Childs, Tomas Ganz, Susan F Leitman, Suthat Fucharoen, Jeffery L Miller
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  ABSTRACT: In thalassemia, deficient globin-chain production during erythropoiesis results in anemia. Thalassemia may be further complicated by iron overload (frequently exacerbated by blood transfusion), which induces numerous endocrine diseases, hepatic cirrhosis, cardiac failure and even death. Accumulation of iron in the absence of blood transfusions may result from inappropriate suppression of the iron-regulating peptide hepcidin by an erythropoietic mechanism. To test this hypothesis, we examined erythroblast transcriptome profiles from 15 healthy, nonthalassemic donors. Growth differentiation factor 15 (GDF15), a member of the transforming growth factor-beta superfamily, showed increased expression and secretion during erythroblast maturation. Healthy volunteers had mean GDF15 serum concentrations of 450 +/- 50 pg/ml. In comparison, individuals with beta-thalassemia syndromes had elevated GDF15 serum levels (mean 66,000 +/- 9,600 pg/ml; range 4,800-248,000 pg/ml; P < 0.05) that were positively correlated with the levels of soluble transferrin receptor, erythropoietin and ferritin. Serum from thalassemia patients suppressed hepcidin mRNA expression in primary human hepatocytes, and depletion of GDF15 reversed hepcidin suppression. These results suggest that GDF15 overexpression arising from an expanded erythroid compartment contributes to iron overload in thalassemia syndromes by inhibiting hepcidin expression.
  Nature Medicine 09/2007; 13(9):1096-101. · 22.46 Impact Factor