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Penn researchers show single drug and soft environment can increase platelet production
Date:7/13/2011

on, such as flexing one's muscles. In many cells, it is responsible for the integrity of the outer membranes, for cell division and for key aspects of adhesion. Because megakaryocytes are best when they are large, multi-nucleated and fragment easily, inhibiting myosin-II helps produce more platelets in three distinct ways.

"The first factor is when cells normally divide, there is a contracting force between the dividing cells that cleave them apart," Shin said. "But if you inhibit myosin, there is no contracting force and cells grow without dividing. That's how they become multi-nucleated and how the cell mass becomes bigger.

"The second factor is cytoskeletal stiffness and tension in the cell. When myosin is active, the cell is stiff and tense like well-toned muscle, but if you inhibit the myosin, the cell becomes flaccid and more easy to push around and fragment," he said.

"The third factor is that cells are able to sense the stiffness of their microscopic environment and react to it, which is also regulated by cellular contractivity," Shin said. "Adhering to bone inhibits megakaryocyte growth; without myosin-II, they grow as if they were adhering to something soft."

By testing the megakaryocytes' growth in different cell culture dishes and gels, the researchers were also able to show that a soft matrix, similar to squishy bone marrow, induced more platelet production than a rigid matrix.

After growing the platelets in Petri dishes saturated with the myosin-II inhibitor blebbistatin, the megakaryocytes were soft enough to spontaneously fragment into platelets. Because platelets need functioning myosin-II to form rigid clots, the researchers subsequently washed away the drug to show that the platelets could still activate.

While the researchers also transplanted blebbistatin-treated human megakaryocytes into genetically modified mice to show that they maintained their increased platelet production within l
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Contact: Evan Lerner
elerner@upenn.edu
215-573-6604
University of Pennsylvania
Source:Eurekalert

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