The new work may provide essential background for new therapeutic strategies in red blood cell and platelet disorders
Researchers at Jefferson Medical College have uncovered a potential switch that helps control the manufacture of red blood cells and blood-clotting platelets. By better understanding how the body keeps tight reins on this process, the scientists hope to someday therapeutically control blood cell production.
For our tissues to have the oxygen they crave, we need to have enough circulating red blood cells. Athletes, for example, may artificially increase the number of blood cells using a hormone, erythropoietin, which helps immature red blood cells mature. But at the same time, too many cells can cause sluggish circulation and stroke.
Controlling the amount of the hormone is one way of regulating red blood cell production. But there's another way, called "negative regulation," which involves blocking the growth and differentiation of red cell precursors. By activating the cell's own programmed suicide process, called apoptosis, researchers can halt the excessive production of red blood cells.
Cesare Peschle, M.D., professor of microbiology and immunology at Thomas Jefferson University in Philadelphia, Ruggero De Maria, M.D., and their co-workers at Jefferson's Kimmel Cancer Center and the Istituto Superiore di Sanita in Rome, found evidence that by activating so-called "death receptors" on the surface of immature red blood cells, an important protein called GATA-1 can be turned off. GATA-1 is crucial to the development of immature blood cells.
They report their work September 30 in the journal Nature. A News and Views article accompanies the research publication.
The scientists found that turning on immature red blood cell death receptors triggers caspases, a family of 14 cysteine enzymes that degrade critical cellular proteins, such as GATA-1. This culminates in a reversible blockade of growth and differentiation of red cell precursors, which may lead to cell death. They detail part of the intricate cascade of cellular events leading to activation of these enzymes in the blockade of red blood cell development.
Apoptosis is a fundamental biological process that is vital to cell differentiation and normal development. In human embryos, for example, apoptosis creates fingers from mitt-like hands. It occurs during normal aging and sometimes during irreversible cell injury from radiation and other poisons. Scientists believe apoptosis gone awry underlies neurodegenerative diseases such as Alzheimer's and Parkinson's diseases, autoimmune diseases such as lupus, and cancer.
Apoptosis has received a great deal of attention in the popular press in recent years when scientists discovered that part of the reason cancer cells grow with abandon is because they lose the ability to die at a preset time.
The Jefferson group's work indicates a "new frontier" in understanding apoptosis, Dr. Peschle says. He explains that "mild stimulation of death receptors and caspases induces a reversible inhibition of red cell development rather than apoptosis." This provides a key mechanism in fine tuning cell growth and differentiation.
Such a novel mechanism may be of general significance, he says, and apply to diverse cell types, in addition to red blood cells and platelets. Failures in the mechanism may lead to either abnormal cell growth inhibition or excessive cell proliferation, such as occurs in some anemias and leukemias.
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