Lymphatic disorder may cause stillbirth, chronic disease in affected children

In a breakthrough discovery, South Australian researchers have identified a genetic mutation responsible for a lymphatic disorder that may be responsible for causing stillbirth or severe, chronic disease in affected children.

The findings were published in the journal 'Science Translational Medicine'.

An anomaly in the development of lymphatic vessels in unborn children, leading to fluid accumulating in the heart, lungs, and other organs, was uncovered by the scientists from the Centre for Cancer Biology (CCB) based at the University of South Australia (UniSA) and SA Pathology.

CCB Director Professor Natasha Harvey said a genetic study of six families affected by stillbirth or lymphoedema revealed the link between a mutated protein-coding gene called MDFIC and fluid accumulation in vital organs and tissues.

This demonstrated that MFDIC is important for controlling the growth and development of the lymphatic vessels in the foetus for the first time.

"The lymphatic system is a network of vessels (pipes) and nodes (filters and control centres) important for maintaining fluid balance in our tissues and transporting infection-fighting white blood cells throughout our bodies," Prof Harvey said.

"We determined that MDFIC controls cell migration, an important early event during the formation of the lymphatic vessel valves. The genetic variants we have found in our study reveal a crucial, previously unrecognized role for MDFIC in the lymphatic vasculature."

"If the lymphatic valves don't form properly, lymph fluid accumulates in critical organs such as the heart and lungs, causing major respiratory problems that may eventuate in stillbirth or chronic disease."

An SA Pathology research team headed by Professor Hamish Scott initially found the genetic link in an Australian family. Their international colleagues in Belgium, Germany, and the US reported variants in the same gene, MDFIC, in several patients with the same lymphatic disorder.

Prof Harvey said, the disorder, known as the central conducting lymphatic anomaly (CCLA), is one of a group of severe lymphatic disorders and may result in stillbirth, or severe chronic disease in affected children.

Few effective treatments are available but with continued identification of the genetic causes of CCLAs, Prof Harvey says the next step is to develop new therapeutic drugs to combat the disease.

"There are existing drugs that may be used to treat these disorders, but we need to make sure that the signalling pathway that's treated by those drugs is the same pathway that is affected in our patients.

"This project is about the power of collaboration at a local level, national level, and international level, so that's been really important. Science is done in teams and we have great research teams here in Adelaide at the Centre for Cancer Biology. Our Ph.D. students and postdoctoral fellows have been integral to this work. They have really driven it and we're delighted to be working with such a group of talented people."

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Scientists 3D-print living skin with blood vessels

Scientists in the US have created 3D-printed skin complete with blood vessels, an advancement which they hope could be a significant step toward creating grafts that are more like the skin our bodies naturally produce. 

The team of researchers at Rensselaer Polytechnic Institute in New York and Yale School of Medicine combined cells found in human blood vessels with other ingredients, including animal collagen, and printed a skin-like material.

After a few weeks, the cells started to form into vasculature (the arrangement of blood vessels in an organ or part), after which the skin was transplanted onto a mouse. Following this procedure, the team found the skin connected with the animal’s vessels.

“Right now, whatever is available as a clinical product is more like a fancy Band-Aid,” said Pankaj Karande, an associate professor of chemical and biological engineering and member of the Center for Biotechnology and Interdisciplinary Studies (CBIS) at Rensselaer.

“It provides some accelerated wound healing, but eventually it just falls off. It never really integrates with the host cells,” he added.

A significant barrier to the integration between cells has been the absence of a functioning vascular system in the skin grafts. For several years, Karande and his team have been working to tackle this challenge.

In one of the team’s first papers on the subject, the researchers found they could take two types of living human cells, make them into ‘bio-inks’ and print them into a skin-like structure.

Since then, he and his team have been working with researchers from Yale School of Medicine to incorporate vasculature to these cells.

In their latest study, the researchers demonstrated that if they add key elements – including human endothelial cells, which line the inside of blood vessels, and human pericyte cells, which wrap around the endothelial cells – with animal collagen and other structural cells typically found in a skin graft, the cells start communicating and forming a biologically relevant vascular structure within the span of a few weeks.

Karande said: “As engineers working to recreate biology, we’ve always appreciated and been aware of the fact that biology is far more complex than the simple systems we make in the lab.

“We were pleasantly surprised to find that, once we start approaching that complexity, biology takes over and starts getting closer and closer to what exists in nature.”

Once the Yale team grafted it onto a special type of mouse, the vessels from the skin printed by the Rensselaer team began to communicate and connect with the mouse’s own vessels.

“That’s extremely important because we know there is actually a transfer of blood and nutrients to the graft which is keeping the graft alive,” Karande added.

In order to make this process usable at a clinical level, however, the researchers would need to be able to edit the donor cells using CRISPR (gene editing) technology to ensure that the vessels can integrate and be accepted by the patient’s body.

“We are still not at that step, but we are one step closer,” Karande said.

“This significant development highlights the vast potential of 3D bioprinting in precision medicine, where solutions can be tailored to specific situations and eventually to individuals,” said Deepak Vashishth, the director of CBIS. “This is a perfect example of how engineers at Rensselaer are solving challenges related to human health.”

Karande added that more work will need to be done to address the challenges associated with burn patients, which include the loss of nerve and vascular endings.

However, the grafts his team have created bring researchers closer to helping people with more discrete issues such as diabetic or pressure ulcers.

“For those patients, these would be perfect, because ulcers usually appear at distinct locations on the body and can be addressed with smaller pieces of skin,” Karande explained. “Wound healing typically takes longer in diabetic patients and this could also help to accelerate that process.”

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Anxiety linked to higher risk of stroke

The greater your anxiety level, the higher your risk of having a stroke, according to a new study.
The study is the first in which researchers have linked anxiety and stroke independent of other factors such as depression.

Anxiety disorders are one of the most prevalent mental health problems. Symptoms include feeling unusually worried,stressed, nervous or tense.

Over a 22 year period, researchers studied a nationally representative group of 6,019 people 25 to 74 years old in the first National Health and Nutrition Examination Survey (NHANES I) in US.
Participants underwent an interview and took blood tests, medical examinations and completed psychological questionnaires to gauge anxiety and depression levels.

Researchers tracked strokes through hospital or nursing home reports and death certificates. After accounting for other factors, they found that even modest increases in anxiety were associated with greater stroke risk.

People in the highest third of anxiety symptoms had a 33 per cent higher stroke risk than those with the lowest levels.

"Everyone has some anxiety now and then. But when it's elevated and/or chronic, it may have an effect on your vasculature years down the road," said Maya Lambiase, study author and cardiovascular behavioural medicine researcher in the Department of Psychiatry at the University of Pittsburgh School of Medicine.

People with high anxiety levels are more likely to smoke and be physically inactive, possibly explaining part of the anxiety-stroke link. Higher stress hormone levels, heart rate or blood pressure could also be factors, Lambiase said.

The research was published in the American Heart Association journal Stroke.

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