On the Maturation of Megakaryocytes: A Review with Original Observations on Human In Vivo Cells Emphasizing Morphology and Ultrastructure

Abstract

Megakaryocytes engage in the synthesis of a variety of molecular and macromolecular constituents to build-up characteristic megakaryocyte structure and form proplatelets in a series of cells from megakaryocyte precursors to the fully matured cell. The process is illustrated in this review by light microscope morphology and transmission electron microscopy, which emphasizes new findings in human in vivo megakaryocytes, thereby making a contrast with the abundant literature on megakaryocytes from experimental animal and human in vitro material. Four stages are identified and described, based on the development of characteristic structures including α-granules, dense granules (dense-core granules), the demarcation membrane system (DMS), and proplatelets. The mechanism of DMS development is discussed, in terms of hypotheses suggesting origin from the plasma membrane, and contributions of membrane from the Golgi apparatus and endoplasmic reticulum. The formation of the marginal zone is also discussed, which is suggested to result from a circumscription of the peripheral organelle-free cytoplasmic fringe by peripheral circular cytoskeletal elements such as cytoplasmic actin and microtubules.

Single cell transcriptional characterization of human megakaryocyte lineage commitment and maturation

“…Bone marrow MKs high energy requirement, particularly those of higher ploidy, is the likely explanation for the high levels of mitochondrial and other genes involved in cellular metabolism since the production of ribosomes consumes large amounts of energy 44 . Our data are in keeping with electron microscopy studies of MK ultrastructure at different points of maturation [39][40][41] .…”

“…Our transcriptome data is, however, in keeping with observed changes in MK ultrastructure during in vivo maturation. While stage 2 MKs (low ploidy) have free ribosomes, smooth endoplasmic reticulum and few granules, stage 3 MKs (high ploidy) are characterized by rough endoplasmic reticulum, formed alpha and dense granules, increases in heterochromatin and smaller nucleoli indicating a reduction of transcription [39][40][41] (Fig. 5b).…”

Pathophysiological Significance of Store-Operated Calcium Entry in Megakaryocyte Function: Opening New Paths for Understanding the Role of Calcium in Thrombopoiesis

“…Specifically, in the early maturation stage, megakaryocytes usually present the lowest cytoplasmic/nuclear ratio, compact nucleus and small size, with fewer and undeveloped non-specific membranous organelles, such as mitochondria, Golgi apparatus, and smooth and rough ER. In the successive stages a progressive cytoplasmic mass increase and appearance of highly lobulated nuclei are accompanied by the expansion of all organelles, especially of Golgi apparatus and ER, which contribute to a continuous membrane supply for the growth of the demarcation membrane system (DMS), an extensive system that provide a membrane reservoir for the formation of future platelets [152,153]. The ER plays primarily a key role in regulating Ca 2+ signaling through SERCA and IP3Rs.…”

Road blocks in making platelets for transfusion

“…Primary human MKs should serve as a physiological control . To bypass current inefficiencies in MK differentiation, Nakamura et al .…”

“…As this field advances, efforts should be made to narrow these criteria to a smaller targeted set of metrics that predict (or otherwise correlate with) platelet functionality and safety. [41]. To bypass current inefficiencies in MK differentiation, Nakamura et al [20] recently developed stable, immortalized MK progenitor cell lines (imMKCLs) from pluripotent stem cell-derived hematopoietic progenitors by over-expressing both BMI1 and BCL-XL.…”