Blood is composed of 3 cell types: red blood cells, white blood cells, and platelets. Platelets circulate in the bloodstream to facilitate clotting and halt bleeding. Platelets are derived from a specialized bone marrow cell called a megakaryocyte. A mature megakaryocyte extends long cytoplasmic processes (termed proplatelets) from its cell surface that, in one of the most dramatic morphological changes known to cell biologists, simultaneously fragments into thousands of new platelet cells.
Dr. Nagata and colleagues set out to identify the cellular signal of this remarkable event. Previous work identified a gene regulator (what scientists refer to as a transcription factor) named p45 NF-E2 as being expressed in megakaryocyte cells and required for proplatelet formation. However, the target(s) of p45 NF-E2 were, until now, unknown.
Dr. Nagata found that the 3b-HSD gene is normally turned-on by p45 NF-E2 during megakaryocyte development. 3b-HSD encodes an enzyme that regulates all steroid hormone biosynthesis. Thus, Dr. Todokoro and colleagues explored which steroid hormones are produced in megakaryocyte cells. Much to their surprise, they found estrogen.
Dr. Nagata and colleagues determined that 3b-HSD induces the production of estrogen, in the form of estradiol, in both male and female megakaryocyte cells. Further work demonstrated a crucial role for estradiol in proplatelet formation, as evidenced by their finding that the addition of exogenous estradiol increased proplatelt formation by more than %50, while the inhibition of estradiol receptors blocked proplatelet formation in live mice.
Taken together, this work by Dr. Nagata and colleagues delineates a genetic mechanism for regulating the formation of blood platelets: The p45 NF-E2 transcription factor turns on 3b-HSD gene expression, leading to the synthesis of estradiol and the subsequent activation of proplatelet formation. Such insight will enable researchers and clinicians to devise therapeutic strategies to manipulate this process, either to increase or decrease proplatelet formation.
The authors suggest that patients suffering from low platelet counts, such as those with anemia, bone marrow abnormalities, or undergoing chemotherapy, may benefit from the administration of estradiol and/or a 3b-HSD activator, as an alternative to blood transfusions to increase platelet levels. Conversely, patients with abnormally high platelet counts, who are prone to forming clots and therefore at an increased risk for strokes, heart attacks, or even miscarriage (ie. from placental clots) would be candidates for drugs designed to specifically block 3b-HSD or estradiol receptors to effectively normalize their platelet levels.