in the bone marrow
Scientists say they’ve shed new light on the mechanism of platelet formation, paving the way to accelerating and enhancing platelet production using stem cells.
The group uncovered their findings by studying the effects of shear stress on megakaryocyte maturation and the formation of preplatelets, platelet-like particles, and megakaryocyte microparticles.
“Until recently, these microparticles were viewed as inconsequential cell debris,” said Terry Papoutsakis, PhD, of the University of Delaware in Newark.
“We now know that they play a significant biological role in platelet formation. The enhanced generation of preplatelets and platelet-like particles under shear stress correlates with physiological observations—in healthy adults, both acute and prolonged exercise leads to elevated platelet counts.”
“Now, these findings can be used to develop better bioreactor technologies for producing platelets, preplatelets, platelet-like particles, and megakaryocyte microparticles for transfusion medicine, using stem cells as starting material.”
Dr Papoutsakis and his colleagues described these findings in Blood.
The researchers discovered that shear stress accelerated DNA synthesis of immature megakaryocytes, and this was dependent upon exposure time and the shear stress level.
Physiological shear stress increased the formation of preplatelets and platelet-like particles up to 10.8-fold. And it increased megakaryocyte microparticle production up to 47-fold. Platelet-like particles generated under shear flow showed improved function.
Experiments also revealed that phosphatidylserine exposure and caspase-3 activation were enhanced by shear stress. But inhibiting caspase-3 reduced the formation of preplatelets, platelet-like particles, and megakaryocyte microparticles.
Finally, the researchers found that coculturing megakaryocyte microparticles with hematopoietic stem and progenitor cells promoted differentiation to mature megakaryocytes that synthesized α- and dense-granules, and formed preplatelets without exogenous thrombopoietin.
The team noted that, unlike platelets themselves, these microparticles can be frozen, which will enable them to be stored and used for platelet production on an as-needed basis.
“Knowing that these microparticles have a biological function opens the door to other applications, including genetic therapies,” Dr Papoutsakis said. “We’re hopeful that our discovery can break the vicious cycle of [immune thrombocytopenia] as well as other conditions that cause reduced platelet count and cause life-threatening bleeding.”
