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Glow-in-the-dark zebrafish overturn 100-year medical theory

Glow-in-the-dark zebrafish in a University of Auckland lab are overturning 100 years of medical thought about a vital bodily system, opening the door to future possible therapies for a painful chronic disorder, and to a better understanding of how cancer spreads.

The lymphatic system is a network of tissues and organs that help rid the body of toxins, waste and other unwanted materials. Lymphatic vessels drain fluid from our tissues and play a part in moving immune cells and fat around our bodies. They also play a role in some cancers, such as breast cancer and melanoma which ‘hijack’ lymphatic vessels to spread.

Treatment for cancer can lead to a painful and incurable condition called lymphoedema, where lymph fluid builds up in the limbs due to damaged lymphatic vessels failing to repair properly. Around one in five breast cancer survivors in New Zealand who undergo lymph node removal and/or radiotherapy will suffer from lymphoedema.

An international research team led by developmental biologist Dr Jonathan Astin, from the University of Auckland’s Faculty of Medical and Health Sciences, have now demonstrated in live animals how lymphatic vessels form. Published in EMBO Reports, their study offers the best evidence to date that lymphatic vessels sprout not solely from veins – as the medical textbooks currently say – but that a second type exists which is ‘topped up’ by other, mobile cells.

Dr Astin, from the School of Medical Sciences, says the findings will change how we look for new therapies for lymphatic-related diseases.

“If we think lymphatic vessels all come from one place, then one therapy might work for everything. But because we’ve shown they’re more complex, and can form in different ways, we may need an array of therapies to control lymphatic development when this process goes awry.”
The origins of these vessels have long eluded scientists. Dr Astin: “Despite over 100 years of investigation, we are still learning exactly how they form.”

Back in 1902, American scientist Florence Sabin was the first to produce evidence for the vein-origin theory by injecting dye into pig embryos.

But it’s the popular aquarium pet, zebrafish, that are the star of the new study. The fish were genetically modified so that the lymphatic and blood vessels express fluorescent proteins – red (from coral) for lymphatic, green (from jellyfish) for blood. This allowed the researchers to make high resolution, live imaging of developing lymphatics in the zebrafish larvae.

First author of the paper, Dr Tiffany Eng, carried out the study as part of her doctorate at the University of Auckland, and is now a postdoctoral researcher at Harvard Medical School.

“In essence, we created movies that captured in real-time the extraordinary process of vessels growing throughout the tissue spaces of a living embryo,” she explains.

“Intriguingly, we saw the developing lymphatic vessels fuse with highly active, migratory cells called angioblasts in tissue areas lacking veins. The main purpose of angioblasts is to form the first blood vessels in the body, but they have never before been observed to form lymphatic vessels. Our findings show for the first time that lymphatic vessels can form efficiently in areas of our bodies distant from veins – something that has puzzled scientists in the past.”

In fact, seven years ago the same research team published an atlas of all lymphatic vessels in the zebrafish embryo, and were perplexed to find a vessel in the head that they could not trace back to a vein.

Next, the team want to investigate whether the different types of lymphatic vessels have unique responses to anti-lymphatic drugs, and whether one type is more likely to be involved in tumour lymphatic growth or repair.

The other researchers were Wenxuan Chen, Pauline Misa, Christopher Hall, Kathryn Crosier and Philip Crosier from the University of Auckland; Yvonne Padberg and Stefan Schulte-Merker from WWU Münster, and Kazuhide Okuda and Benjamin Hogan from the University of Queensland.

The zebrafish lab is funded by the Health Research Council, the Marsden fund and the Auckland Medical Research Foundation.

Journal article: EMBO Reports: Zebrafish facial lymphatics develop through sequential addition of venous and non-venous progenitors

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