The End Is Just the Beginning: Megakaryocyte Apoptosis and Platelet Release

Abstract

Under influence of hematopoietic growth factors, particularly thrombopoietin (TPO), hematopoietic stem cells in the bone marrow go through a process of commitment, proliferation, differentiation, and maturation and become mature megakaryocytes. At this critical point, terminally differentiated megakaryocytes face a new fate: ending the old life as mature megakaryocytes by induction of apoptosis and beginning a new life as platelets by fragmentation of the large megakaryocyte cytoplasm. These events are as important as megakaryocyte commitment, proliferation, differentiation, and maturation, but the molecular mechanisms regulating these events are not well established. Although TPO drives megakaryocyte proliferation and differentiation and protects hematopoietic progenitor cells from death, it does not appear to promote platelet release from terminally differentiated megakaryocytes. Although mature megakaryocyte apoptosis is temporally associated with platelet formation, premature megakaryocyte death directly causes thrombocytopenia in cancer therapy and in diseases such as mvelodysplastic syndromes and human immunodeficiency virus infection. Also, genetic studies have shown that accumulation of megakaryocytes in bone marrow is not necessarily sufficient to produce platelets. All of these findings suggest that platelet release from megakaryocytes is an important and regulated aspect of platelet production, in which megakaryocyte apoptosis may also play a role. This review summarizes recent research progress on megakaryocyte apoptosis and platelet release.

Asialoerythropoietin is a nonerythropoietic cytokine with broad neuroprotective activity in vivo

“…Although it is inevitable that some erythrocyte precursors are recruited into the circulating pool, modulation of endogenous EPO concentrations (i.e., transient suppression) will tend to maintain red cell mass at the systemic set point. Although not directly assessed, similar kinetics for thrombocyte maturation (44)(45)(46) imply that asialoEPO would not appreciably increase the fraction of reactive platelets within the circulation.…”

From cytopenia to leukemia: the role of Gfi1 and Gfi1b in blood formation

“…In these experiments, the Gfi1 gene turned out to be one of the most frequent insertion sites selected in T-cell lymphomas that arose in infected Myc-or Pim-1-transgenic mice. 2,3,6,69 Because the proviral insertions were associated with a high-level expression of Gfi1 in these tumors, Gfi1 was suspected to function as a cooperating partner of Myc or Pim-1 in tumorigenesis. That Gfi1 indeed bears such an oncogenic potential was confirmed by the rapid induction of malignant T-cell lymphoma in Myc-or Pim-1-transgenic mice crossed to mice with targeted T-cell-specific overexpression of Gfi1.…”

Recombinant human thrombopoietin: basic biology and evaluation of clinical studies

“…39 Despite its activity on hematopoietic stem cells and early megakaryocytopoiesis, TPO has little effect on platelets and on the late stages of megakaryocyte development. [74][75][76][77] This contrasts with granulocyte colony-stimulating factor (G-CSF) and GM-CSF, for which an action on late myeloid precursor cells and mature myeloid cells is well established. 78,79 Perhaps the most significant consequence of TPO's minimal effect on late-stage megakaryocytes is the inability of TPO to hasten platelet shedding from megakaryocytes.…”