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Inhibition of Myosin-II cells Augments Platelet Production

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A new research by the scientists of Pennsylvania University has brought to light a new drug which promises to increase the production of platelets in the bone marrow by as much as four times. This research was a joint effort of pharmacologists, chemical and bio molecular engineers. The lead researchers included Jae-Won Shin, a pharmacologist from Penn’s Perelman School of Medicine, and Dennis E. Discher from Department of Chemical and Biomolecular Engineering in the School of Engineering and Applied Science. Joe Swift and Kyle R. Spinner, with PhDs in Chemical and Biomolecular Engineering also put in their efforts and hard work in the research aforementioned.

This research was published in the official journal of United States National Academy, Proceedings of National Academy of Sciences. Precursors of platelets are large cells called megakaryocytes which mature in size and replicate their DNA. These larger megakaryocytes break down to release smaller fragments; called platelets (also called thrombocytes). These platelets then help in clot formation and seal off damaged blood vessels. A growth pattern unique to megakaryocytes is that when they grow, they double the amount of DNA but do not undergo duplication. Cytokinesis does not take place in the maturation of megakaryocytes and therefore they are multinucleated and very large in size.

Dennis E. Discher from the engineering department explained that this growth in size and addition of nuclei to become multinucleated is unusual and in some ways unique to megakaryocytes. A multinucleated, a mature and a larger megakaryocyte is better than a smaller megakaryocyte with less number of nuclei. More mass renders multinucleated megakaryocytes fit for producing more number of platelets.

When fully developed, a megakaryocyte extends its tendrils into a nearby blood vessel, thereby pulling off pieces of the cell and thus forming thrombocytes. A conventional myosin (myosin-II) which is responsible for muscle contraction in muscle cells plays multiple roles in the process of forming platelets as well. The researchers exploited this function of myosin-II and inhibited it by a drug called belebbistatin. It was observed that after the inhibition of myosin-II, the production of platelets was increased in three different ways.

When megakaryocytes divide normally, a force of contraction between the dividing cells helps in cleaving them apart. Since myosin-II provides this force by inducing muscle contraction, its absence makes way for unregulated growth of megakaryocytes without further cell division. In this way, the megakaryocytes become multinucleated and enormous in size and mass.

Another factor that comes into play is the stiffness of the cytoskeleton and the inner tension of the cell. Presence of myosin-II makes it stiff and well-toned but when inhibited, the cell loses its stiffness and becomes flaccid and easier to push around and fragment.

Shin explained that a third factor also played an important role. According to him, the cells can sense the stiffness of their microscopic environment and then react to it by cellular contractivity. When megakaryocytes attach themselves to bone, their growth is inhibited. In the absence of myosin-II, the megakaryocytes continue to grow in a way that illusions them the presence of a softer adherence.

Many laboratory tests were conducted for examining the growth of megakaryocytes in different culture mediums. It was observed that a soft matrix, similar to squishy bone marrow increased the rate of platelet production as compared to a rigid matrix.

When grown in petri dishes saturated with blebbstatin, the drug that inhibits myosin-II, the megakaryocytes became soft enough to fragment into smaller platelets on their own. The action of platelets requires proper functioning of myosin-II for the formation of rigid clots. To overcome this difficulty, the scientists washed away the blebbstatin to demonstrate that platelets could still be activated. To further prove their point, the team of chemists and engineers transplanted blebbstatin treated megakaryocytes into rats. The introduction of blebbstatin maintained a steady increase in platelet production in mice. It was emphasized through their research that producing platelets in laboratory was as much possible as in vivo.

The lead researchers explained that this was an important step for biomedical sciences since platelet transfusions are much more difficult than normal blood transfusions. Owing to contamination issues and their short life span, platelets are difficult to transfuse. The ability to produce larger amount of platelets could save many people suffering from bleeding disorders, invasive surgeries and injuries.

This research was partly sponsored by the National Institute of Health, Human Frontier Science Program and the American Heart Association.

By information from University of Pennsylvania.
published: 30 Nov 2011 (11:25)

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