The results of their study describing how endothelial cells are activated to initiate organ regeneration.
It has long been known that endothelial cells passively conduct blood, passing oxygen, nutrients and metabolic waste to and from tissues through capillary walls. However, in studies published in recent years, the Weill Cornell researchers have demonstrated that endothelial cells actively influence the self-renewal of certain stem cell populations and the regeneration of tissue.
Now, these scientists have uncovered the endothelial cells' "instructive role" in liver regeneration. Further, the researchers believe that in the coming years it will be possible to facilitate healing damaged livers by transplanting certain types of endothelial cells with liver cells.
"We have found that specialised blood vessel cells in the liver - a specific type of sinusoidal endothelial cell - initiate and sustain liver regeneration by producing growth factors that we have identified. This finding will open the door for designing new therapies to treat damaged livers," says the study's senior author, Doctor Shahin Rafii, who is the Arthur B. Belfer Professor in Genetic Medicine and co-director of the Ansary Stem Cell Institute at Weill Cornell Medical College and a Howard Hughes Medical Institute investigator.
The liver performs many physiological functions, including converting nutrients into essential blood components; storing vitamins and minerals; producing bile for digesting fats; regulating blood clotting; and metabolizing and detoxifying substances that would otherwise be harmful. When the liver malfunctions, the consequences can be grave. Liver failure, due to cirrhosis, various forms of hepatitis, and other diseases, kills some 60,000 Americans per year. But the liver's capacity for regeneration is amazing.
"Until our study, the molecular and cellular pathways that would initiate and maintain liver regeneration were not known," says Doctor Bi-Sen Ding, the study's first author and a senior postdoctoral fellow in Doctor Rafii's lab. "Attempts to transplant hepatocytes [liver cells] directly into the liver led to very limited success. But now we have identified liver sinusoidal endothelial cells (LSECs) -- that, when activated, are critical to liver regeneration and may enable proper engraftment when hepatocytes are implanted into the injured liver."
Rafii's team determined the mechanism by which LSECs regulate liver regeneration by studying this process in genetically engineered mice whose livers were 70 percent removed. Through a series of experiments involving strategic endothelial cell implantation, the team found that only those LSECs whose genes were producing the angiocrine growth factors Id1 or Wnt2 and "hepatocyte growth factor" (HGF) would initiate and sustain liver regeneration. It is thought that Wnt2 and HGF work together in initiating regeneration, and that the LSECs and the liver cells must be next to each other for successful regeneration were key findings.
"Therefore, to regenerate a long-lasting liver, we may need to co-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 the liver," says Doctor Ding.
Despite these new insights, Rafii points to an unsolved enigma: How do endothelial cells sense the loss of liver tissue and initiate the regeneration process? "Change of blood flow might be one of the possibilities," suggests Doctor Sina Rabbany, study co-senior author. "It is well known that endothelial cells can sense subtle changes in the flow of blood because they are located at the interface between the blood flow and vessel wall. The loss of a liver lobe will inevitably alter the local blood flow patterns and resulting shear stresses that are redirected into the remaining lobes. This alteration in the biomechanical transduction process is part of a complex system likely to 'activate' endothelial cells to produce hepatocyte-active growth factors."
Doctor David Lyden, a co-author on the paper and the Stavros Niarchos Associate Professor in Pediatric Cardiology at Weill Cornell Medical College, says, "This is an important study. By targeting endothelial-specific genes such as Id1, as identified in this research, I hope that it will facilitate the design of new therapies to treat people with liver disease, whether due to infection, cancer, or acute or long-term damage."