From University of California - San Francisco
UC researchers have discovered novel cell adhesion mechanism that may lead to improved treatment for sickle cell disease
Patients with sickle cell disease experience pain and organ failure when their abnormal red blood cells (erythrocytes) block flow through small vessels. This blockage may be initiated by blood cells sticking to blood vessel walls. Now, scientists from UC San Francisco and UC San Diego have described the discovery of a new mechanism that may trigger that adhesion.
The mechanism involves P-selectin, a glue-like molecule that, when activated, moves to the surface of blood cells called platelets to facilitate clotting. P-selectin also migrates to the surface of the cells that line blood vessel walls (endothelial cells), where it helps white blood cells adhere so they can fight infection in the body.
In a discovery that may lead to improved treatment for sickle cell disease, researchers know now that P-selectin also binds to red blood cells, and to a greater extent those that are sickle-shaped.
Prior to this research, red blood cells had been regarded as an example of cells that did not bind to P-selectin, according to Neil M. Matsui, PhD, UCSF assistant research hematologist in the department of pediatrics at San Francisco General Hospital Medical Center (SFGHMC) and lead author of a study that appears in the September 15 issue of Blood, the Journal of the American Society of Hematology.
“Animal studies and ultimately clinical trials will help us determine whether inhibiting P-selectin will prevent the clogging that leads to pain crises and organ failure in patients with sickle cell disease,” said Stephen H. Embury, UCSF professor of medicine at SFGHMC and senior investigator on the study.
Researchers discovered the adhesion mechanism when they exposed cells that line blood vessels to thrombin – an enzyme known to have increased activity in people with sickle cell disease. Within five minutes, P-selectin moved from its location in storage granules inside endothelial cells to the surface of the cells, where it facilitated the binding of sickle cells.
Since sickle cell anemia was first described in 1910, scientists have believed that sickle-shaped red blood cells have a rigidity that causes them to become log-jammed in small blood vessels. Approximately 20 years ago, scientists at the University of Minnesota determined that sickle cells were abnormally sticky and proposed that this quality may contribute to blood vessel blockages. These same investigators also discovered a correlation between the stickiness of a patient’s sickle cells and the severity of his or her disease.
Nearly 12 years ago, a research group based at the Albert Einstein School of Medicine discovered that the more sticky sickle cells may initiate blood vessel blockages by sticking to the vessel wall and that the more rigid sickle cells complete the process by log-jamming behind the stuck cells.
Separate studies identified several molecules on both sickle cells and endothelial cells that mediate adhesion. Additional studies determined that activating endothelial cells increased their adhesivity for sickle cell disease.
In the current study, the UC researchers noted that P-selectin blocking antibodies reduced the stickiness between sickle cells and cells that line blood vessel walls. “This demonstrates that P-selectin is specifically involved in sickle cell adhesion,” said Matsui.
They also noted that sickle cells stick to P-selectin that is attached to an artificial surface. “This confirms the specific importance of P-selectin in sickle cell binding,” he added.
UCSF/UCSD researchers are also studying the surface of sickle cells for clues. In this study, they noted that pre-treating sickle cells with sialidase (an enzyme that removes sialic acid from the surface of cells) reduces their adherence to activated blood vessel cells. This indicates that the presence of sialic acid on the surface of sickle cells may be important to their interaction with P-selectin, explained Matsui.
The parallels between mechanisms of sickle cell adhesion and those of other processes like inflammation, blood clotting, atherosclerosis and tumor metastasis are also important to sickle cell investigators, according to Embury. Of particular potential is a previous discovery by Ajit Varki, MD, UCSD professor of medicine and cellular and molecular medicine, director of the UCSD Glycobiology Research and Training Center and co-investigator on this study.
In earlier work, Varki and his colleagues reported that P-selectin mediated adhesion of various cancer cells can be inhibited by heparin (a common anticoagulant drug)—thus potentially stopping the spread of cancer in the body. Varki and his associates also noted that the extent of inhibition depended on the type of heparin used.
Sickle cell disease is inherited and affects 70,000 people in the U.S, who have an average life expectancy of 45 years. When sickle cells block small blood vessels, less blood can reach various parts of the body, leading to lung tissue damage, pain episodes and stroke. Blocked blood flow can also cause damage to the spleen, kidneys and liver.
It affects primarily people of African descent, as well as fewer numbers of those of Portuguese, Spanish, French Corsican, Sardinian, Sicilian, Italian, Greek and Turkish descent. The disease also appears in Cypriots and those from Middle Eastern countries and Asia.
There is currently no universal cure for sickle cell disease. However, Hydroxyurea (Droxia) has been found to reduce severe pain, acute chest syndrome (a sudden compromise in lung function related to vascular blockage and/or infection) and the need for blood transfusions. The drug, used for cancer treatment, helps patients with sickle cell disease produce red blood cells that are less rigid and sticky.
Additional authors on the paper include Lubor Borsig, PhD, a postdoctoral fellow in the Varki lab at UCSD; Steven D. Rosen, PhD, UCSF professor or anatomy; and Mitra Yaghmai, MS, formerly a graduate student in the San Francisco State University Center for Biomedical Laboratory Sciences.
This research was funded by the National Institutes of Health and the National Cancer Institute.