Blood vessels may be a new niche for stem cells

Researchers at the Ansary Stem Cell Institute at Weill Cornell Medical College have discovered that endothelial cells (ECs) in blood vessels provide a functional niche for growing and sustaining large amounts of adult stem cells.

Adults have relatively few naturally occurring sources of stem cells in their bodies, making them an impractical source of cells for organ regeneration and other uses. Until now, growing the cells in culture has had limited success because even in the presence of necessary cytokines and serum, the cultures die within four to five days.

Described in a recent paper in Cell Stem Cell, the team developed a cell culture technique that prolongs the life of the cells for longer than 21 days and promotes increased cell expansion. Researchers achieved these results by co-culturing hematopoietic stem cells with ECs. They found that ECs, which line the interior surface of blood vessels, produce growth factors that support the survival and regeneration of stem cells.

For this study, researchers used sinusoids, small blood vessels found in bone marrow. It was speculated that bone-forming osteoblasts were responsible for sustaining stem cells. But by using molecular imaging, researchers showed that blood stem cells are in close proximity to marrow ECs that express notch ligands, which are growth factors that support stem cell growth. “This finding indicates that endothelial cells could directly—independent of osteoblasts—stimulate expansion of stem cells,” said first-author Jason Butler, senior investigator at Weill Cornell Medical College and first author of the study.

Studying the pathways involved in this process had been a challenge because maintaining long term growth of ECs in culture requires the use of cytokines and serum, which can spur the loss of the ECs’ angiogenic properties. Also introducing external growth factors can induce artificial growth of the stem cells.

To resolve this issue, researchers inserted the adenoviral E40RF1 gene into the ECs using a lentivirus. E40RF1 modulates cell migration and apoptosis by increasing the presence of certain enzymes and proteases without promoting cell proliferation. ECs with the inserted E40RF1 gene exist in a “chronic suspended animated” state and can survive without the need for added growth factors.

Next researchers isolated the stem cells produced from the co-culture and transplanted them into mice that could not produce red blood cells because of radiation treatment. The scientists discovered that the transplanted cells produced different types of red blood cells for more than a year with no indication of cancer.

Shahin Rafii, a Howard Hughes Medical Institute investigator at Weill Cornell Medical College and senior author of the study, said that the research has implications for the treatment of blood-related disorders requiring stem cells. “Currently, stem cells derived from bone marrow or umbilical cord blood are used to treat patients who require bone marrow transplants. Most stem cell transplants are successful, but because of the shortage of genetically matched bone marrow and umbilical cord blood cells, many patients cannot benefit from the procedure,” he said.

Looking forward, the researchers believe that the vascular cell model developed in this study has the potential to grow large quantities of functional stem cells from other organs—such as the brain, heart, skin, and lungs—or cancer cells. Rafii said that one of the next steps would be to discover growth factors responsible for stem cell growth that are specific to these organs.

The paper “Endothelial cells are essential for the self-renewal and repopulation of notch-dependent hematopoietic stem cells” was published in the March 5 issue of Cell Stem Cell.