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Decoding Lymphatic Anomalies: Breakthroughs from Mouse Studies

Ever wondered how scientists make big medical discoveries? One way is by studying mice, and this method has recently led to some fascinating findings about lymphatic malformations. These are tricky medical conditions where the body's lymphatic system (a crucial part of our immune and drainage system) develops abnormally, forming cysts or growths.

There are two main types of these lymphatic malformations: one where you get large fluid-filled cysts, often in the neck and head, and another where tiny cysts spread deep into body tissues, making them hard to treat. What's interesting is that about 80% of these conditions are due to a glitch in a specific gene, PIK3CA, which is crucial for cell growth and movement.

Hans Schoofs, PhD student, from Uppsala Universitet, Sweden, and his team been especially interested in a common error in this gene – PIK3CA H1047R and have created mouse models to study it more closely.  They found that depending on when they trigger the expression of the PIKCA gene mutation in the mice – either when they're just embryos or after they're born – the outcomes are quite different. If expressed during development, macrocysts develop.  If expressed postnatally, microcystic LMs develop.  This finding helps explain some of the phenotypic diversity seen in patients. 

In studying the microcytic LM in more detail, they found that in young mice, the lymphatic malformations progressively grew over time. To understand why, they looked at individual cells in the lymphatic system of both normal and PIK3CA-mutant mice. This led to the discovery of new cell types in mutant mice characterized by expression of high levels of the protein Ptx3.  These cells expanded over time and were also found in tissue samples from patients with microcystic LMs.

When investigating the function of these cells, they found the PTX3 cells were making a lot of a protein called CCL2. This protein is like a beacon, calling in immune cells like macrophages and dendritic cells. These immune cells, in turn, seem to stimulate the growth of lymphatic malformations.

They found similar findings when studying tissue from patients with microcystic LMs. This discovery opens potential new treatments.  The investigators used various methods to modulate the immune response, which resulted in a decrease in inflammation and a subsequent reduction in the growth of the LMs. 

The lab’s latest finding found these malformations in mice's internal organs, adding another layer to this medical puzzle. It appears that the same genetic error can have different effects depending on where it occurs in the body.

In short, their journey with these genetically engineered mice has given us valuable insights into complex biological pathways, paving the way for new treatments. It's a great example of how animal studies can help us understand human health better. And it's all thanks to a team of dedicated scientists and their tiny, furry research partners!

Research was presented during the 2023 International Scientific Conference on Complex Lymphatic Anomalies. Some of the materials are not yet published.

Watch the complete presentation.