Abstract
Author SummaryMegakaryocytes are huge bone marrow cells that shed platelets into the blood stream to promote clotting at sites of injury. Mature megakaryocytes differentiate from precursor cells in response to a hormone called thrombopoetin. Here, we show that as part of this normal differentiation process mature megakaryocytes enter a state called senescence in which cell division stops—a feature normally associated with cell aging and death. By studying megakaryocytes in culture, we were able to determine the biochemical pathway induced by thrombopoetin that leads to gene activation associated with senescence. We conclude that thrombopoietin acts differently at two steps in megakaryocyte differentiation: in the early stages it induces megakaryocyte proliferation, and at a latter stage it arrests the cell division cycle leading to platelet production by these cells. Interestingly, certain malignant megakaryocytes did not undergo senescence in response to thrombopoetin, which might explain the abnormal proliferation of these cancerous cells.
Highlights
Hematopoietic stem cells (HSCs) in adults are maintained in a long term-quiescence state
By studying megakaryocytes in culture, we were able to determine the biochemical pathway induced by thrombopoetin that leads to gene activation associated with senescence
We conclude that thrombopoietin acts differently at two steps in megakaryocyte differentiation: in the early stages it induces megakaryocyte proliferation, and at a latter stage it arrests the cell division cycle leading to platelet production by these cells
Summary
Hematopoietic stem cells (HSCs) in adults are maintained in a long term-quiescence state. On rare occasion HSCs may enter the cell cycle, and their proliferative state is usually coupled to a differentiation process regulated by both intrinsic and extrinsic factors such as cytokines (reviewed in [1]). Proliferation is dependent on mitogen-activated protein kinase (MAPK) signaling, shown to be involved in the transition through the early G1 phase of the cell cycle (reviewed in [2]). When megakaryocytes become 16N, the endomitosis process stops and is followed by terminal differentiation leading to cytoplasmic fragmentation and platelet shedding. TPO binds to and activates the TPO receptor (MPL: GeneID: 4352) signaling to regulate both early and late stages of differentiation [8]
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