Although platelets were described as early as the 1840s, it was not until 1906, in a seminal study by James Homer Wright, that their origin from megakaryocytes was first recognized. Megakaryocytes are large polyploid cells that reside predominantly within the BM during postnatal life. They are rare cells, constituting only about 0.05% to 0.1% of nucleated BM cells under normal steady-state conditions. They develop from hematopoietic stem cells (HSCs) through a process known as megakaryocytopoiesis. According to the classical model of megakaryocytopoiesis, HSCs give rise to multipotent progenitor cells (MPPs) which sequentially transition to common myeloid progenitor (CMP) cells, bipotential mega karyocyte-erythroid progenitor (MEP) cells, and Mk progenitor (MkP) cells which will ultimately generate platelet-forming mature megakaryocytes (Fig. 1). In the past decade, single-cell trans plantation and lineage tracing studies have demonstrated the existence of lineage-biased HSCs and underscored the heterogeneity of traditionally defined HSC and MPP cell compartments. Thus, the canonical model of hematopoietic hierarchy has been challenged by the emerging concept that hematopoiesis is a dynamic continuous process in which lineage priming and multilineage potential coexist. Notably, megakaryocytopoiesis has been at the center of this paradigm shift. The first functional evidence that megakaryocytes derive from HSCs bypassing the MPP stage was suggested by Adolfsson and colleagues in 2005. Subsequently, several groups have shown that megakaryocyte-biased HSCs exist in both murine and human hematopoiesis supporting the concept that megakaryocytic lineage branches out earlier than previously appreciated. In vitro culture and transplantation assays have established that a common MEP capable of Mk-erythroid differentiation represents an inter mediate step between MMP and MkP. Recent evidence employing lineage tracing in situ has challenged the existence of MEPs during unperturbed hematopoiesis thus underscoring the potential limitations of stress hematopoiesis such as cell culture and transplantation models. Furthermore, the concept that megakaryocytic lineage undergoes a ”fast-tracked” differentiation process has been also documented in response to acute inflammation in murine models and in patients with myelofibrosis (MF) which is a condition characterized by Mk lineage hyperplasia. According to the revised model of megakaryocytopoiesis (see Fig. 1), megakaryocyte differentiation is initiated earlier during hematopoiesis from a pool of lineage primed HSCs and/or MMPs the fate of which is differentially modulated in conditions such as steady-state, stress hematopoiesis or inflammation. In recognizing the complexity and plasticity unveiled by this emerging research, it is conceivable that the new and the canonical pathways of megakaryocytic differentiation exist in the context of different physiological or experimental conditions.

Fig1. MEGAKARYOCYTOPOIESIS. In the classical model of megakaryocytopoiesis, hematopoietic stem cells (HSCs) give rise to multipotent progeni tor cells (MPP) which sequentially transition to common myeloid progenitor (CMP) cells, common bipotential megakaryocyte-erythroid progenitor (MEP) cells and megakaryocyte progenitor (MkP) cells which undergo proliferation and maturation events to generate platelet-forming megakaryocytes (Mk). These latter events include an increase in cell size, acquisition of a polyploid DNA content (>2 N), proplatelet formation and, the release of platelets into the circulation. This model has been challenged by recent evidence indicating that the HSC and MPP cell compartments are highly heterogeneous and exist as a ”continuum” comprising cells primed towards a megakaryocyte lineage capable of generating MkP directly.

Cellular Hierarchy of Megakaryocyte Development

Like other hematopoietic progenitor cells, once committed to the megakaryocytic lineage, MkPs undergo a series of dramatic maturational steps ultimately tailored to their final task of platelet production. These include changes in proliferative capacity, cell size, nuclear content, organelle biogenesis, membrane development, and cytoskeletal rearrangement.

This process can be conceptually divided into three broad stages: proliferating MkPs, which contain normal DNA content (2 N/4 N), nonproliferating immature megakaryocytes (4 N to 8 N DNA con tent), and nonproliferating mature megakaryocytes (DNA content 8 N to 128 N). In vitro culture using semisolid media and mitogenic cytokine cocktails revealed that within the MkP compartment reside cells with high-proliferative-potential colony-forming cell (Mk-HPP CFC), burst-forming unit-megakaryocyte (BFU-Mk) cells and more mature MkPs with very limited proliferative potential, the colony forming cell-megakaryocyte (CFU-Mk). The proliferative capacity of the cells within the MkPs compartment can be demonstrated in vitro by the size of the colonies and the number of Mk-HPP-CFC, BFU-Mk, and CFU-Mk.

The immature megakaryocytes have an intermediate DNA content and are transitional cells intermediate between proliferating progenitor cells and postmitotic, mature megakaryocytes. They cease to proliferate and switch to endomitosis, also known as abortive mitosis, a process in which cells replicate their DNA but fail to undergo cytokinesis. This is accompanied by an increase in cell size and DNA content (up to 64 to 128 N), organelle biogenesis, membrane development, and cytoskeletal rearrangement. This culminates with the generation of mature, polyploid megakaryocytes that reach diameters of 50 to 100 μm and DNA content as high as 64 to 128 N. On BM specimens, morphologically recognizable megakaryocytes can be defined as megakaryoblasts (stage I), promegakaryocytes (stage II) and granular or “platelet shedding” megakaryocytes (stages II and IV) (Fig.2).

Fig2. MEGAKARYOCYTOPOIESIS AND MEGAKARYOCYTES. (A) Megakaryoblast (stage I) with intermediate ploidy level. The cytoplasm is scant. Note prominent cytoplasmic pseudopods. (B) Promegakaryocyte with early platelet production (stage II). (C) Mature, high-ploidy megakaryocyte (stage III or IV) with abundant cytoplasm. Note cells traveling through the cytoplasm. This is referred to as emperipolesis and is not uncommonly seen in large mega karyocytes. (D) A portion of megakaryocyte cytoplasm in a long strand. Fragments of these can sometimes be seen in the blood and are referred to as proplatelets. (E) Megakaryocyte nucleus denuded of its platelets and cytoplasm. (F) Mature megakaryocyte seen in a tissue section of bone marrow biopsy. (G) Megakaryoblast from a patient with acute megakaryoblastic leukemia. Note cytoplasmic pseudopods. (H) Micromegakaryocyte from a patient with myelodysplasia. Note small, low-ploidy (2−4 N) nucleus, but mature cytoplasm. (I and J) Transmission electron micrographs of two stage III and IV human megakaryocytes. Openings of the demarcation membrane system (arrowheads). AG, α-Granules; n, nucleolus; N, nucleus; P, a platelet field within the megakaryocyte cytoplasm. (Courtesy Dr. Maryann Weller.)

Mature megakaryocytes contain a large multilobulated polyploid nucleus and have abundant cytoplasm, which contains platelet-specific secretory granules, alpha (α-) granules, and dense granules (see Fig. 2). The biogenesis of α-granules and dense granules begins in immature megakaryocytes, and both granule types develop concomitantly. α-Granules are 200 to 500 nm in diameter and have a dense center and fine granular matrix. Megakaryocytes synthesize many of the constituents of α-granules and target them to the granules. These include vWF, fibronectin, P-selectin, fibrinogen receptors, PF4, coagulation factor V, and plasminogen activator inhibitor-1, among others. In addition, some constituents, such as fibrinogen, are taken up by megakaryocytes via endocytosis and/or pinocytosis and stored in α-granules. It was once thought that α-granules were a homogeneous population of vesicles. However, it has become clear that there are distinct populations of α-granules containing different constituents, and that these can be differentially released during platelet activation. Dense granules are 200 to 300 nm in diameter and consist of a halo encircling an electron opaque core. They contain many soluble hemostatic factors such as serotonin, catecholamines, adenosine, adenosine 5′-diphosphate, adenosine 5′-triphosphate, and calcium. Their limiting membranes contain glycoproteins such as αIIbβ3, glycoprotein Ib (GPIb), and P-selectin, which are also present in α-granules, as well as unique membrane proteins such as granulophysin. Multivesicular bodies serve as intermediates in the biogenesis of both α-granules and dense granules. It has been proposed that they constitute a sorting compartment between α-granule and dense granule components.

Mutations in the NBEAL2 gene have recently been linked to gray platelet syndrome (GPS) (OMIM 139090), a disorder of impaired platelet α-granule synthesis. This gene encodes a large BEACH domain containing protein that shares homology with the LYST gene product. LYST is involved in vesicular trafficking and is mutated in Chediak–Higashi syndrome (OMIM 214500), a disorder that includes impaired platelet dense granule biogenesis.

The megakaryocyte cytoplasm contains at least two complex membranous systems: the demarcation membrane system (DMS) and the dense tubular network (DTS) (see Fig. 2). The DMS con sists of an extensive network of tubular and flattened membranous structures that interconnect with one another and communicate with the extracellular space. Whole-cell patch-clamp studies in living rat megakaryocytes show that they are electrophysiologically contiguous with the plasma membrane. The open canalicular system of platelets share many features of the megakaryocyte DMS and may represent a remnant of this structure. The DMS serves as a vast membrane reservoir for proplatelet and platelet formation. The DTS of mega karyocytes is distinct from the DMS. Unlike the DMS, it fails to stain with surface membrane tracer dyes, indicating a lack of communication with the plasma membrane. The DTS is thought to be a site of platelet prostaglandin synthesis.

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مواضيع ذات صلة

Cellular and Molecular Mechanisms in Development: Morphogens and Cell-to-Cell Signaling

Thrombopoietin Signaling

Mechanisms of Endomitosis in Megakaryocytes

Ontogeny of Erythropoiesis

Cellular Dynamics in Erythropoiesis: Steady State and Stress Erythropoiesis

Erythropoiesis and Iron Regulation

Hematopoietic Microenvironment

Intrinsic Control of Erythropoiesis:Erythropoietin

Nuclear Organization

Unfolded Protein Response

Autophagy

Nonapoptotic forms of cell death