One way of studying the function of a gene is to examine the effect on cells when the gene is blocked. In a new study in Nature Communications researchers from Uppsala University show that it is important that the blocking is achieved in all cells, a results that should be considered in the development of gene therapy for diseases.

The Uppsala researchers have studied the development of lymphatic vessels in mice. The lymphatic vasculature develops by growth and branching of the vessel tips to form a vessel network in the body. To determine how the gene Vegfr3 is involved in lymphatic vessel development the reseachers used genetically modified mice where they could delete the Vegfr3 gene, which encodes the receptor for a lymphatic growth factor, in a controlled manner in cells lining lymphatic vessels.

“When we deleted the Vegfr3 gene early in development, already in the embryo, we found that the vessel tip cells were not functioning normally and the lymphatic vessels did not develop properly. This shows that Vegfr3 is essential for lymphatic vessel development at this stage”, says Taija Mäkinen, senior lecturer at the Department of Immunology, Genetics and Pathology, who has led the study.

In mice, lymphatic vessel growth continues after birth. The researchers therefore moved on to study the effect of deleting the Vegfr3 gene at other developmental stages.

“To our surprise we saw that if Vegfr3 was deleted later in development this instead resulted in an excessive growth of the lymphatic vessels. We found that at this stage, Vegfr3 was deleted in some cells but not others and that the cells that lack the gene affect the neighbouring cells, that have a functioning Vegfr3, to act abnormally, which led to the excessive growth”, says Taija Mäkinen.

In addition to demonstrating how Vegfr3 controls lymphatic vessel development, both in cells where the protein is missing and in nearby cells where it remains, the new findings indicate what can happen if a signalling pathway is blocked in some but not all cells. Such an unanticipated mechanism, whereby gene-deleted cells can affect the behavior of normal cells, can be envisaged to apply to other tissues and the knowledge from this study could have implications for the development of gene therapy.

“In gene therapy the aim is to block or replace a disease-causing gene by transferring a new gene. A major problem with such therapeutic approaches is an incomplete delivery of the new gene to the target cells, resulting in a mix of cells that have or lack the new gene. We have now shown that in such situations it is important to understand if the cells influence each other in an unwanted way. This will be an important consideration for future studies,” says Taija Mäkinen

Article:

Nature Communications. Heterogeneity in 1 VEGFR3 levels drives lymphatic vessel hyperplasia through cell-autonomous and non-cell-autonomous mechanisms