Scientists have uncovered new details about endothelial cell differentiation that could lead to better management of vascular disease. Endothelial cells are often damaged in conditions like coronary artery disease. This damage can be repaired through the transplantation of healthy endothelial cells. But acquiring these cells at the quantities and purity needed for therapeutic transplantation is no easy task. To help solve this problem, the researchers took a closer look at the molecular factors that direct stem cells to adopt an endothelial phenotype.
The team started by isolating mononuclear cells from just 1 mL of blood. They later reprogrammed these cells into induced pluripotent stem cells. To accomplish this, they used an optimized, non-integrating protocol – with very good results. The stem cells were then differentiated into endothelial cells, and the researchers tracked gene expression throughout the process. Their goal was to identify lineage-specific genes that could potentially enrich the endothelial cell population.
Comparing gene expression profiles between undifferentiated stem cells, stem cellderived endothelial cells, and human umbilical vein endothelial cells revealed thousands of candidate genes. One gene – ESM1 – stood out to the team due to its high expression in endothelial cells and its known role in angiogenesis. ESM1 is primarily expressed in endothelial cells of vascular tissues including capillaries and arterioles but can also be found in the endothelial cells of other tissues such as human lung and kidney.
They found that ESM1 expression progressively increased during endothelial cell differentiation, and this enhanced the endothelial cell characteristics of the differentiated cells. Overexpression of the gene promoted the expression of several other endothelial cell markers. It also improved neovascularization and blood flow recovery in a mouse model of ischemia.
Overall, the work makes two important contributions to the field. The researchers showed that it is possible to generate induced pluripotent stem cells using a nonintegrating approach from a very small amount of blood. And they demonstrated that overexpressing ESM1 in these cells can enhance the production and functioning of newly generated endothelial cells. This improved understanding of the molecular mechanisms involved in endothelial cell differentiation is expected to boost the clinical potential of cell therapy, especially for the treatment of vascular disease.