Physiological regulation of early and late stages of megakaryocytopoiesis by thrombopoietin

Thrombopoietin (TPO) has recently been cloned and shown to regulate megakaryocyte and platelet production by activating the cytokine receptor c-mpl. To determine whether TPO is the only ligand for c-mpl and the major regulator of megakaryocytopoiesis, TPO deficient mice were generated by gene targeting. TPO-/- mice have a >80% decrease in their platelets and megakaryocytes but have normal levels of all the other hematopoietic cell types. A gene dosage effect observed in heterozygous mice suggests that the TPO gene is constitutively expressed and that the circulating TPO level is directly regulated by the platelet mass. Bone marrow from TPO-/- mice have decreased numbers of megakaryocyte-committed progenitors as well as lower ploidy in the megakaryocytes that are present. These results demonstrate that TPO alone is the major physiological regulator of both proliferation and differentiation of hematopoietic progenitor cells into mature megakaryocytes but that TPO is not critical to the final step of platelet production.

[1]  Esther,et al.  Platelets Generated in Vitro from Proplatelet-displaying Human Megakaryocytes Are Functional Isolation of Cd34+ Progenitor Cells from Peripheral Blood , 2022 .

[2]  S. Orkin,et al.  Transcription factor NF-E2 is required for platelet formation independent of the actions of thrombopoeitin/MGDF in megakaryocyte development , 1995, Cell.

[3]  R. Hoffman,et al.  Growth factors affecting human thrombocytopoiesis: potential agents for the treatment of thrombocytopenia. , 1992, Blood.

[4]  W P Sheridan,et al.  Evidence for a novel in vivo control mechanism of granulopoiesis: mature cell-related control of a regulatory growth factor. , 1989, Blood.

[5]  D. Beeler,et al.  The purification of megapoietin: a physiological regulator of megakaryocyte growth and platelet production. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[6]  V. Broudy,et al.  Promotion of megakaryocyte progenitor expansion and differentiation by the c-Mpl ligand thrombopoietin , 1994, Nature.

[7]  E. Robertson.  Teratocarcinomas and embryonic stem cells : a practical approach , 1987 .

[8]  R. Schreiber,et al.  In vitro megakaryocytopoietic and thrombopoietic activity of c-mpl ligand (TPO) on purified murine hematopoietic stem cells. , 1994, Blood.

[9]  W. Vainchenker,et al.  Oligodeoxynucleotides antisense to the proto-oncogene c-mpl specifically inhibit in vitro megakaryocytopoiesis. , 1993, Blood.

[10]  Scott R. Presnell,et al.  Cloning and expression of murine thrombopoietin cDNA and stimulation of platelet production in vivo , 1994, Nature.

[11]  J. Mornon,et al.  Molecular cloning and characterization of MPL, the human homolog of the v-mpl oncogene: identification of a member of the hematopoietic growth factor receptor superfamily. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[12]  R. Weinmann,et al.  Stimulation of erythropoietin gene transcription during hypoxia and cobalt exposure. , 1989, Blood.

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

[14]  T. Doetschman,et al.  Transgenesis by means of blastocyst-derived embryonic stem cell lines. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[15]  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.

[16]  F. Wendling,et al.  A putative truncated cytokine receptor gene transduced by the myeloproliferative leukemia virus immortalizes hematopoietic progenitors , 1990, Cell.

[17]  A R Dunn,et al.  Mice lacking granulocyte colony-stimulating factor have chronic neutropenia, granulocyte and macrophage progenitor cell deficiency, and impaired neutrophil mobilization. , 1994, Blood.

[18]  A. Gurney,et al.  Genomic Structure , Chromosomal Localization , and Conserved Alternative Splice Forms of Thrombopoietin , 2002 .

[19]  P. Vertino,et al.  Isolation of polyadenylated RNA from cultured cells and intact tissues. , 1993, BioTechniques.

[20]  H. Lu,et al.  Identification and cloning of a megakaryocyte growth and development factor that is a ligand for the cytokine receptor Mpl. , 1994, Cell.

[21]  M. Hokom,et al.  Platelets generated in vitro from proplatelet-displaying human megakaryocytes are functional. , 1995, Blood.

[22]  D. Goeddel,et al.  Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-Mpl ligand , 1994, Nature.

[23]  M. C. Hu,et al.  Identification and cloning of a megakaryocyte growth and development factor that is a ligand for the cytokine receptor MpI , 1994, Cell.

[24]  H. Avraham.  Regulation of megakaryocytopoiesis , 1993, Stem cells.

[25]  William Vainchenker,et al.  c-Mpl ligand is a humoral regulator of megakaryocytopoiesis , 1994, Nature.

[26]  C. Jackson.  Cholinesterase as a possible marker for early cells of the megakaryocytic series. , 1973, Blood.