Basis of hematopoietic defects in platelet-derived growth factor (PDGF)-B and PDGF beta-receptor null mice.

Platelet-derived growth factor (PDGF)-B and PDGF beta-receptor (PDGFR beta) deficiency in mice is embryonic lethal and results in cardiovascular, renal, placental, and hematologic disorders. The hematologic disorders are described, and a correlation with hepatic hypocellularity is demonstrated. To explore possible causes, the colony-forming activity of fetal liver cells in vitro was assessed, and hematopoietic chimeras were demonstrated by the transplantation of mutant fetal liver cells into lethally irradiated recipients. It was found that mutant colony formation is equivalent to that of wild-type controls. Hematopoietic chimeras reconstituted with PDGF-B(-/-), PDGFR beta(-/-), or wild-type fetal liver cells show complete engraftment (greater than 98%) with donor granulocytes, monocytes, B cells, and T cells and display none of the cardiovascular or hematologic abnormalities seen in mutants. In mouse embryos, PDGF-B is expressed by vascular endothelial cells and megakaryocytes. After birth, expression is seen in macrophages and neurons. This study demonstrates that hematopoietic PDGF-B or PDGFR beta expression is not required for hematopoiesis or integrity of the cardiovascular system. It is argued that metabolic stress arising from mutant defects in the placenta, heart, or blood vessels may lead to impaired liver growth and decreased production of blood cells. The chimera models in this study will serve as valuable tools to test the role of PDGF in inflammatory and immune responses. (Blood. 2001;97:1990-1998)

[1]  D. Rinaudo,et al.  Sensitive ELISA for mouse erythropoietin. , 2000, BioTechniques.

[2]  M. Karin,et al.  Requirement for p38α in Erythropoietin Expression A Role for Stress Kinases in Erythropoiesis , 2000, Cell.

[3]  C. Heldin,et al.  PDGF-C is a new protease-activated ligand for the PDGF α-receptor , 2000, Nature Cell Biology.

[4]  H Li,et al.  PDGF-C is a new protease-activated ligand for the PDGF alpha-receptor. , 2000, Nature cell biology.

[5]  K. Chien,et al.  PPARγ Is Required for Placental, Cardiac, and Adipose Tissue Development , 1999 .

[6]  C. Betsholtz,et al.  PDGFB regulates the development of the labyrinthine layer of the mouse fetal placenta. , 1999, Developmental biology.

[7]  C. Betsholtz,et al.  Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. , 1999, Development.

[8]  C. Begley,et al.  Functional Analysis of Mature Hematopoietic Cells From Mice Lacking the βc Chain of the Granulocyte-Macrophage Colony-Stimulating Factor Receptor , 1998 .

[9]  C. Betsholtz,et al.  Paracrine PDGF-B/PDGF-Rbeta signaling controls mesangial cell development in kidney glomeruli. , 1998, Development.

[10]  Philippe Soriano,et al.  Chimaeric analysis reveals role of Pdgf receptors in all muscle lineages , 1998, Nature Genetics.

[11]  A. Roberts,et al.  Hematopoietic stem cell deficiencies in mice lacking c-Mpl, the receptor for thrombopoietin. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[12]  R. Willemze,et al.  The early phase of engraftment after murine blood cell transplantation is mediated by hematopoietic stem cells. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[13]  C. Begley,et al.  Functional analysis of mature hematopoietic cells from mice lacking the betac chain of the granulocyte-macrophage colony-stimulating factor receptor. , 1998, Blood.

[14]  B R Johansson,et al.  Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. , 1997, Science.

[15]  Y. Matsuzawa,et al.  Induction of Macrophage Colony-stimulating Factor Receptor (c-fms) Expression in Vascular Medial Smooth Muscle Cells Treated with Heparin Binding Epidermal Growth Factor-like Growth Factor* , 1996, The Journal of Biological Chemistry.

[16]  G. Fantuzzi,et al.  Effect of endotoxin in IL-1 beta-deficient mice. , 1996, Journal of immunology.

[17]  V. Broudy,et al.  Interaction of stem cell factor and its receptor c-kit mediates lodgment and acute expansion of hematopoietic cells in the murine spleen. , 1996, Blood.

[18]  C. Betsholtz,et al.  PDGF-A Signaling Is a Critical Event in Lung Alveolar Myofibroblast Development and Alveogenesis , 1996, Cell.

[19]  T. Sato,et al.  Tie1, a receptor tyrosine kinase essential for vascular endothelial cell integrity, is not critical for the development of hematopoietic cells. , 1996, Oncogene.

[20]  V. D’Agati,et al.  Differential effects of an erythropoietin receptor gene disruption on primitive and definitive erythropoiesis. , 1996, Genes & development.

[21]  A. Keating,et al.  Biology of Bone Marrow Stroma , 1995, Annals of the New York Academy of Sciences.

[22]  Rudolf Jaenisch,et al.  Generation of committed erythroid BFU-E and CFU-E progenitors does not require erythropoietin or the erythropoietin receptor , 1995, Cell.

[23]  Mo Yang,et al.  Recombinant PDGF enhances megakaryocytopoiesis in vitro , 1995, British journal of haematology.

[24]  J. C. Keutzer,et al.  Regulated production of a pleiotropic cytokine-platelet-derived growth factor--by differentiating erythroid cells in vitro and in vivo. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[25]  V. Broudy,et al.  Thrombopoietin (c-mpl ligand) acts synergistically with erythropoietin, stem cell factor, and interleukin-11 to enhance murine megakaryocyte colony growth and increases megakaryocyte ploidy in vitro. , 1995, Blood.

[26]  M. Hansmann,et al.  Detection and quantification of transforming growth factor beta (TGF-beta) and platelet-derived growth factor (PDGF) release by normal human megakaryocytes. , 1995, Leukemia.

[27]  S. Orkin,et al.  Hematopoiesis: how does it happen? , 1995, Current opinion in cell biology.

[28]  D. Goeddel,et al.  Decreased sensitivity to tumour-necrosis factor but normal T-cell development in TNF receptor-2-deficient mice , 1994, Nature.

[29]  A. Gurney,et al.  Thrombocytopenia in c-mpl-deficient mice. , 1994, Science.

[30]  Philippe Soriano,et al.  Abnormal kidney development and hematological disorders in PDGF beta-receptor mutant mice. , 1994, Genes & development.

[31]  B Swolin,et al.  Mice deficient for PDGF B show renal, cardiovascular, and hematological abnormalities. , 1994, Genes & development.

[32]  A. Dunn,et al.  Granulocyte/macrophage colony-stimulating factor-deficient mice show no major perturbation of hematopoiesis but develop a characteristic pulmonary pathology. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[33]  C. Heldin,et al.  Negative feedback regulation of human platelets via autocrine activation of the platelet-derived growth factor alpha-receptor. , 1994, The Journal of biological chemistry.

[34]  G. Dranoff,et al.  Involvement of granulocyte-macrophage colony-stimulating factor in pulmonary homeostasis. , 1994, Science.

[35]  J. Sprent,et al.  Turnover of Naive-and Memory-phenotype T Cells , 1994 .

[36]  N. Iscove,et al.  Overexpression of PDGF-B in murine hematopoietic cells induces a lethal myeloproliferative syndrome in vivo. , 1994, Oncogene.

[37]  D. Metcalf.  Hematopoietic regulators: redundancy or subtlety? , 1993, Blood.

[38]  T. Dexter,et al.  Influence of growth factors and substrates on differentiation of haemopoietic stem cells. , 1993, Current opinion in cell biology.

[39]  Y. Yazaki,et al.  Expression of platelet-derived growth factor beta receptor on human monocyte-derived macrophages and effects of platelet-derived growth factor BB dimer on the cellular function. , 1993, The Journal of biological chemistry.

[40]  R. Zinkernagel,et al.  Mice lacking the tumour necrosis factor receptor 1 are resistant to IMF-mediated toxicity but highly susceptible to infection by Listeria monocytogenes , 1993, Nature.

[41]  P. Martin,et al.  Donor CD8 cells prevent allogeneic marrow graft rejection in mice: potential implications for marrow transplantation in humans , 1993, The Journal of experimental medicine.

[42]  N. Iscove,et al.  Platelet-derived growth factor (PDGF) activates primitive hematopoietic precursors (pre-CFCmulti) by up-regulating IL-1 in PDGF receptor-expressing macrophages. , 1993, Journal of immunology.

[43]  B. Westermark,et al.  Biology of platelet-derived growth factor , 1993 .

[44]  R. Daynes,et al.  Platelet-derived growth factor is a potent biologic response modifier of T cells , 1991, The Journal of experimental medicine.

[45]  B. Westermark,et al.  Inhibition of Human Natural Killer Cell Activity by Platelet‐Derived Growth Factor (PDGF) , 1991, Scandinavian journal of immunology.

[46]  J. Hamilton,et al.  Cytokine regulation of colony-stimulating factor production in cultured human synovial fibroblasts: I. Induction of GM-CSF and G-CSF production by interleukin-1 and tumor necrosis factor. , 1990, Blood.

[47]  J. Falkenburg,et al.  Gene-expression and release of macrophage-colony stimulating factor in quiescent and proliferating fibroblasts. Effects of serum, fibroblast growth-promoting factors, and IL-1. , 1990, Journal of immunology.

[48]  W. Wiktor-Jedrzejczak,et al.  Total absence of colony-stimulating factor 1 in the macrophage-deficient osteopetrotic (op/op) mouse. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[49]  C. Eaves,et al.  Mechanisms that regulate the cell cycle status of very primitive hematopoietic cells in long-term human marrow cultures. I. Stimulatory role of a variety of mesenchymal cell activators and inhibitory role of TGF-beta. , 1990, Blood.

[50]  M. Armstrong,et al.  Characterization of biologically active, platelet-derived growth factor-like molecules produced by murine erythroid cells in vitro and in vivo. , 1990, The Journal of clinical investigation.

[51]  P. Phillips,et al.  Two different subunits associate to create isoform-specific platelet-derived growth factor receptors. , 1989, The Journal of biological chemistry.

[52]  R. Ross,et al.  PLATELET-DERIVED GROWTH FACTOR , 1989, The Lancet.

[53]  C. Heldin,et al.  Platelet-derived growth factor: three isoforms and two receptor types. , 1989, Trends in genetics : TIG.

[54]  C. Heldin,et al.  Binding of different dimeric forms of PDGF to human fibroblasts: evidence for two separate receptor types. , 1988, The EMBO journal.

[55]  C. Heldin,et al.  Role of Platelet-Derived Growth Factor in Vivo , 1988 .

[56]  P. Simmons,et al.  Host origin of marrow stromal cells following allogeneic bone marrow transplantation , 1987, Nature.

[57]  J. Adamson,et al.  Tumor necrosis factor type alpha stimulates human endothelial cells to produce granulocyte/macrophage colony-stimulating factor. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[58]  G. Janossy,et al.  Platelet‐derived growth factor stimulates growth of highly enriched multipotent haemopoietic progenitors , 1986, British journal of haematology.

[59]  J. Adamson,et al.  Platelet-derived growth factor enhances in vitro erythropoiesis via stimulation of mesenchymal cells. , 1985, The Journal of clinical investigation.

[60]  A. Hoffbrand,et al.  The role of platelet-derived growth factor on human pluripotent progenitor (CFU-GEMM) growth in vitro. , 1985, Leukemia research.

[61]  M. Kalmanti,et al.  Platelet-derived growth factor promotes proliferation of erythropoietic progenitor cells in vitro. , 1983, The Journal of clinical investigation.

[62]  R. Anderson,et al.  Ionizing radiation and the immune response. , 1976, Advances in immunology.

[63]  E. Borghese.  The present state of research on WW mice. , 1959, Acta anatomica.