A research team centered at Osaka University have discovered the elusive stem cell, providing evidence for adult vascular endothelial stem cells ( VESCs ) capable of generating fully functional blood vessels . The research was reported in the journal Cell Stem Cell .
The research team had previously identified a population of endothelial cells (ECs), isolated from the innermost layer of blood vessels, with properties resembling those of stem cells. The cells were actually isolated by functional analysis, so the team was interested in finding molecular markers that specifically defines endothelial stem cells.
The researchers intended to study cell-surface protein that is expressed in the endothelial stem-like population, but not in other ECs, said study leader Nobuyuki Takakura. "Once we found a clear stem marker of ECs, we could then sort the cells based on the proteins expressed on their surface. This would theoretically allow us to isolate a homogeneous pool of candidate endothelial stem cells."
The researchers found a highly abundant glycoprotein, called CD157 , expressed in the small fraction of EC population. After isolating just the ECs that expressed CD157, they set out to determine whether they were truly VESCs.
The key characteristic of these cells is their ability to regenerate themselves, so they hypothesized that the CD157-positive ECs would be able to form new blood vessels. The team tested this idea by experimentally damaging the mice blood vessels that supply blood to the liver, and injecting them with CD157-positive ECs isolated from the liver.
Takakura says, "A month after transplantation, the CD157-enriched cells generated fully functional portal veins, portal venules, sinusoids, hepatic venules, and arteries-essentially, every type of blood vessel found in a healthy liver."
In addition to repairing injured tissue, stem cells are crucial to maintaining healthy tissue. As further confirmation that they had discovered to VESC , the team used a fluorescent reporter to follow the fate of these cells in non-injured healthy mice. A year later, the cells continued to replenish normal blood vessel tissue in the liver.
The team also sought to determine how versatile the cells might be in treating other blood vessel-related diseases. Hemophilia A , a rare bleeding disorder in which blood is unable to clot properly, is caused by a genetic mutation that prevents liver blood vessels from making clotting factor VIII (FVIII).
When VESCs were collected from healthy mice they were injected into mice with hemophilia A, the cells started generating new blood vessels – and the level of FVIII in the blood shot up, from less than 1% of normal to over 60%.
The researchers also used VESCs from muscle tissue to treat limb ischemia in mice, where a lack of oxygenated blood can lead to tissue damage and foot necrosis. The study represents a turning point in cell-based therapies for blood vessel disorders.
"Our findings show that CD157-positive vascular endothelial stem cells give rise to a hierarchy of cell types that can repair vascular injury and maintain the normal blood vessel architecture," Takakura says. "We believe these findings represent an entirely new way of thinking about how blood vessels are formed and, ultimately, how stem cells can be used to treat disorders related to blood vessel malfunction."