Shahin Rafii says “To regenerate long-lasting liver, we may need to transplant hepatocytes with the properly activated endothelium, which produces the right growth factors for the hepatocytes to attach, grow, and connect with other parts of the liver.”
The endothelium is the innermost layer of blood vessels, made up of cells that had largely been assumed to function primarily as delivery vehicles for oxygen and nutrients. But earlier this year, Howard Hughes Medical Institute investigator Shahin Rafii figured out that these endothelial cells also release growth factors that direct bone marrow stem cells to multiply and differentiate into different types of blood cells.
During development, embryonic stem cells can differentiate into just about any tissue in the body. But adult stem cells, which are in short supply, are more tissue specific and employed mostly for maintenance and repair of the types of tissue they reside in. Being able to prompt these adult stem cells to proliferate and differentiate on command could have a profound impact on the field of regenerative medicine: Injury from therapeutic chemotherapy and radiation could be repaired; heart muscle damaged during a heart attack could be restored, and a failing liver could be rescued and rebuilt.
The idea that endothelial cells might play a role in tissue regeneration was an unorthodox one, but Rafii and his team noticed that evidence was beginning to build in support of that theory. His and other labs had observed that adult stem cells in a number of body parts—bone marrow, brain, muscle, testes, even fat—clustered near the endothelium.
“Some people would say, ‘Of course stem cells like to hang out with blood vessels, because they can conveniently extract oxygen, glucose, and nutrients very well that way,’” says Rafii, a professor of genetic and regenerative medicine and co-director of the Ansary Stem Cell Institute at Weill Cornell Medical College in New York.
But he and his colleagues noticed something else. After endothelial cells in bone marrow had been damaged by chemotherapy or radiation, the blood vessels still delivered oxygen but the blood stem cells weren’t dividing. “I hypothesized that, in addition to delivering nutrients, maybe endothelial cells are also releasing growth factors,” Rafii says.
“For the last decade, physician-scientists have been trying to transplant hepatocytes to regenerate the liver. But they grow for a few months then the majority die off,” Rafii says. “Based on our data, one could argue that just transplanting hepatocytes is not going to work. To regenerate long-lasting liver, we may need to transplant hepatocytes with the properly activated endothelium, which produces the right growth factors for the hepatocytes to attach, grow, and connect with other parts of the liver. Co-transplantation of primed activated endothelium with liver cells may be an important step to design future therapies to regenerate liver.”
The lab is already building evidence that activation of the endothelium may play an essential role in prompting tissue regeneration in the lungs and pancreas. Rafii predicts their research will ultimately be applicable to many organs, including the heart and brain, and possibly even have a role in preventing tumor growth.
“One of the most remarkable findings of our studies is the realization that endothelial cells within each organ are functionally different, and once activated produce unique sets of growth factors,” Rafii explains. “The challenge that lies ahead is to discover the organ-specific growth factors produced by the endothelial cells that initiate the regeneration of that particular organ. Then, these factors could be exploited therapeutically to induce selective regeneration of one organ without affecting others.”
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