Researchers Identify Mechanism Controlling Red Blood Cell Development
Madison, Wisconsin - A research team at University of Wisconsin School of Medicine and Public Health has identified how a particular collection of proteins plays a critical role in the development of red blood cells, which carry oxygen to body tissues so organisms can survive.
Researchers with the school’s Blood Research Program published their findings in a recent issue of eLife, a peer-reviewed, open-access journal sponsored by the Howard Hughes Research Institute, Wellcome Trust, and the Max Planck Society.
Red blood cells (erythrocytes) die after circulating throughout the body for a certain period of time. New red blood cells develop when two complementary proteins act on stem cells and precursor cells in the bone marrow. One of the proteins, stem cell factor (SCF), prompts proliferation of the stem cells and precursor cells. The other, erythropoietin (Epo), signals “committed” precursor cells to differentiate into mature red blood cells.
Successfully replenishing the body’s erythrocytes depends on the correct balance between proliferation and differentiation. Too much proliferation can result in diseases such as polycythemia and leukemia, while excessive differentiation can deplete the stem cells and/or precursor cells, causing cytopenias and immunodeficiency.
The group directed by Dr. Emery Bresnick, professor of cell and regenerative biology and director of the UW-Madison Blood Research Program, had demonstrated previously that a particular assemblage of proteins, called the exosome complex, suppresses the production of red blood cells.
Specifically, it puts up a barrier to the process by which precursor cells differentiate into red blood cells. At the same time, GATA-1, another type of protein known as a transcription factor, acts to destroy that barrier.
The research team, headed by Bresnick and postdoctoral fellow Dr. Skye McIver, wanted to find out how the exosome complex blocks differentiation and interacts with the two complementary proteins. They took precursor cells from animal tissue and reduced the levels of the exosome complex within them.
When that happened, the precursor cells lost the ability to respond to the SCF that told them to proliferate. Disrupting the exosome complex – throwing it out of balance – made the precursor cells respond to the other protein, Epo, which causes them to differentiate.
This work provided a foundation for understanding the molecular circuitry involved in creating a blockade to red blood cell development and has catalyzed a new avenue of inquiry. Bresnick says future research should look at how the complex functions in living mice, in normal human blood-cell precursors, and in pathological contexts. A lucid picture of the cell signaling will enable efforts to forge strategies to control red blood cell development.
Ultimately, patients with disorders such as anemia that are resistant to the existing therapeutic forms of Epo might benefit from such strategies, and these findings might enable efforts to generate large numbers of red blood cells for experimental and clinical applications.
The UW research team included members of the Bresnick group: Dr. Skye McIver; Dr. Koichi Katsumura, Elsa Davids, and Dr. Yoon-A Kang; UW Carbone Cancer Center computational biologist Peng Liu; and Associate Professor of Pathology Dr. David Yang.
Date Published: 10/07/2016