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3. The novel function of SWAP-70 in hematopoiesis/erythropoiesis

Author

Stewart, Francis, Jessberger, Rolf, Ripich, Tatsiana, Stewart, Francis, Jessberger, Rolf, and Ripich, Tatsiana

Abstract

SWAP-70 originally identified as a signaling protein exclusively expressed in B-cells has been recently described in other cells of the hematopoietic system, such as mast cells and dendritic cells. Here we describe a novel role of SWAP-70 in hematopoiesis, specifically in regulation of erythropoiesis. SWAP-70 protein expression is detected at the stage of the hematopoietic stem cell (HSC). Its expression persists throughout several stages of multipotent and myeloid progenitors. In erythroid development SWAP-70 is found from early committed to erythroid lineage precursors, burst-forming unit erythroid (BFU-E) and colony-forming unit erythroid (CFU-E); however its expression declines with erythroid maturation and it is lastly detectable at the basophilic erythroblast stage. The protein’s deficiency leads to 3-fold increase in HSC numbers in the bone marrow (BM). The lack of SWAP-70 does not affect intermediate myeloid progenitors and the first erythroid committed progenitor, BFU-E. Hematopoietic tissues (BM and spleen) of Swap-70-/- mice carry 2-times less CFU-Es, thus SWAP-70 appears to be important at this stage. Swap-70-/- mice have the same frequencies of later erythroid progenitors, Ter-119+ erythroblasts, in the BM but fewer in the spleen. BM and splenic Ter-119+ erythroid Swap-70-/- compartment (basophilic, polychromatic and orthochromatic erythroblasts) exhibit an altered profile that is characterized by the delayed maturation of cells at the polychromatic stage. SWAP-70 deficiency is not critical for steady state erythropoiesis and does not influence blood homeostasis. Yet SWAP-70 is essential for proper stress response in conditions of anemia. Swap-70-/- mice have normal steady state hematocrite level but fail to restore it after induced anemia, thus showing sluggish blunted response to erythropoietic stress. In resting conditions Swap-70-/- early erythroid progenitors (CFU-Es) exhibit aberrant preactivation of the integrin VLA-4, which supports hom

Published
2009

5. HIF-1α is a protective factor in conditional PHD2-deficient mice suffering from severe HIF-2α–induced excessive erythropoiesis

Author

Franke, Kristin, primary, Kalucka, Joanna, additional, Mamlouk, Soulafa, additional, Singh, Rashim Pal, additional, Muschter, Antje, additional, Weidemann, Alexander, additional, Iyengar, Vasuprada, additional, Jahn, Steffen, additional, Wieczorek, Kathrin, additional, Geiger, Kathrin, additional, Muders, Michael, additional, Sykes, Alex M., additional, Poitz, David M., additional, Ripich, Tatsiana, additional, Otto, Teresa, additional, Bergmann, Sybille, additional, Breier, Georg, additional, Baretton, Gustavo, additional, Fong, Guo-Hua, additional, Greaves, David R., additional, Bornstein, Stefan, additional, Chavakis, Triantafyllos, additional, Fandrey, Joachim, additional, Gassmann, Max, additional, and Wielockx, Ben, additional

Published
2013
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7. SWAP-70 regulates erythropoiesis by controlling α4 integrin.

Author

Ripich T and Jessberger R

Subjects
Actins genetics, Actins metabolism, Anemia genetics, Anemia metabolism, Animals, Cell Adhesion physiology, Cytoskeleton genetics, Cytoskeleton metabolism, DNA-Binding Proteins genetics, Erythroblasts cytology, Fibronectins genetics, Fibronectins metabolism, Guanine Nucleotide Exchange Factors genetics, Integrin alpha4 genetics, Mice, Mice, Knockout, Minor Histocompatibility Antigens, Nuclear Proteins genetics, Cell Differentiation physiology, DNA-Binding Proteins metabolism, Erythroblasts metabolism, Erythropoiesis physiology, Guanine Nucleotide Exchange Factors metabolism, Integrin alpha4 metabolism, Nuclear Proteins metabolism
Abstract

Unlabelled: Background The regulation of normal and stress-induced erythropoiesis is incompletely understood. Integrin-dependent adhesion plays important roles in erythropoiesis, but how integrins are regulated during erythropoiesis remains largely unknown., Design and Methods: To obtain novel insights into the regulation of erythropoiesis, we used cellular and molecular approaches to analyze the role of SWAP-70 and the control of integrins through SWAP-70. In addition, mice deficient for this protein were investigated under normal and erythropoietic stress conditions., Results: We show that SWAP-70, a protein involved in cytoskeletal F-actin rearrangements and integrin regulation in mast cells, is expressed in hematopoietic stem cells and myeloid-erythroid precursors. Although Swap-70(-/-) mice are not anemic, erythroblastic differentiation is perturbed, and SWAP-70 is required for an efficient erythropoietic stress response to acute anemia and for erythropoietic recovery after bone marrow transplantation in irradiated mice. SWAP-70 deficiency impairs colony-forming unit erythroid development, while burst-forming unit erythroid development is normal, and significantly affects development of late erythroblasts in the spleen and bone marrow. The α(4) integrin is constitutively hyper-activated in Swap-70(-/-) colony-forming unit erythroid cells, which hyper-adhere to fibronectin. Blocking α(4) and β(1) integrin chains in vivo restored erythroblastic differentiation and the erythropoietic stress response in Swap-70(-/-) mice. Conclusions Our study reveals that SWAP-70 is a novel regulator of integrin-mediated red blood cell development and stress-induced erythropoiesis.

Published
2011
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