Cell-to-cell communication discovery unlocks new potential

Our School’s Dr Enrico Ferrari and an international team of scientists have discovered that ‘size matters’ in cell-to-cell communication. When it comes to the mechanisms that cells use to communicate with each other, cell size really does matter, according to pioneering new nanobiotechnology research which has important implications for the diagnosis and treatment of disease.

This research has been to advance the understanding of ‘exosomes’ – tiny biological structures (or ‘vesicles’) which are used by cells in the body to transfer information. The researchers believe the findings could be significant for several fields of medical science, from personalising medical treatments to better understanding the growth and spread of cancerous tumours.

Exosomes are packed with proteins and RNA. They can be generated by one cell, taken up by another, and trigger a specific response. To date, scientific research has focused on the content of exosomes, but a new study led by scientists at the University of Lincoln, UK, focused instead on the size of exosomes and how this affects the way they work.

Dr Ferrari (centre)
Dr Ferrari (centre)

Led by Dr Enrico Ferrari, a specialist in nanobiotechnology, the team discovered that the smaller the exosomes are, the easier it is for target cells to pick them up. This makes communication between cells much faster. The study examined exosomes taken from a patient with a high-grade glioma (rapidly growing brain tumour). The researchers had previously found that some stem cells within the patient’s brain were producing exosomes that were responsible for supporting cancer cells and making them more aggressive.

Their latest work suggests that the level of aggression in a tumour could be determined by the size of the exosomes produced by the cancerous cells – for example the smaller the exosomes, the faster the cells can communicate and reproduce, and the quicker the cancer develops.

These initial findings could therefore have important implications for the prognosis of different cancers in the future, as doctors may be able to examine the size of the exosomes produced and more accurately predict the course of a patient’s tumour. The study was carried out by researchers from our School of Life Sciences, the Department of Medical and Biological Sciences at the University of Udine, and the Department of Neuroscience at Santa Maria della Misericordia University Hospital, both in Italy. The findings are published in the scientific journal, Nanomedicine: Nanotechnology, Biology and Medicine.

“Rather than looking inside the exosome, we decided to take a detailed look at the nature of the vehicle, specifically its size”, explained Dr Ferrari. “If you think of an exosome as a package, regardless of the specific molecules it carries, the nature of the ‘envelope’ is likely to be of great importance to the delivery of the message. The larger the envelope, the more difficult it is to deliver!

“Previous research has examined how size affects the behaviour of artificial nanoparticles in a human body, and this new study found that biological particles like exosomes may act in much the same way – the smaller they are, the ‘louder’ their message is, as it is easier for target cells to take them up and ‘hear’ the message.

“Traditionally it has been difficult to observe this behaviour in exosomes because they are extremely small (well below optical resolution), very elusive, and difficult to isolate. However, our team developed a new set of techniques to overcome all of these factors and answer important questions about size-dependent uptake, which previously have not been addressed.

“The size of different exosomes has been explored in a few other studies, but never in relation to how effectively they can deliver their messages.”

The new research could also have future implications for the delivery of medicine, as exosomes could potentially be used as nanocarriers for specific drugs. The scientists predict that it may be possible to manipulate the size of exosomes used in therapeutics to make them more effective, and to use the personalised exosomes produced in the human body – or particles which mimic the way they behave – to achieve more targeted and efficient drug delivery. This process is called exotherapy.

The team now hopes to pursue further research in this area to more accurately understand the impact of exosome size on the way that cells communicate, and develop ways this knowledge can be used in the diagnosis, prognosis and treatment of individual patients. The research paper detailing the team’s findings in full, entitled Size-dependent cellular uptake of exosomes, will feature in the April issue of Nanomedicine: Nanotechnology, Biology and Medicine and is available to read online.

Scientists publish first complete record of genetic mutations behind rare vascular disease

Human anatomy - heart

The genetic architecture of a debilitating and potentially fatal vascular disease has for the first time been detailed in its entirety, providing clinicians with the comprehensive data needed to improve diagnosis and deliver more personalised patient care.

Scientists investigating Pulmonary Arterial Hypertension (PAH) have compiled the most up to date and complete record of all the defective variations found in the genes that cause the disease.

The new study, led by Dr Rajiv Machado from the University of Lincoln, UK, draws together the complete genetic information of hundreds of individuals affected by PAH. This advance will not only offer new opportunities to identify the mutation which causes PAH in individual patients but will also provide an important tool to correlate genetic data, allowing for more tailored approaches to the clinical management of the disease. It has been published in the online academic journal Human Mutation.

PAH is an often fatal disorder resulting from several causes, including an assortment of genetic defects. It is a progressive disease characterised by abnormally high blood pressure (hypertension) in the pulmonary artery, the blood vessel that carries blood from the heart to the lungs. Symptoms are shortness of breath, dizziness, swelling (oedema) of the ankles or legs, chest pain and a racing pulse.

Heritable PAH leads to a chronic elevation of pulmonary arterial pressure, which can result in heart failure.

While mutations in a gene called BMPR2 are the single most common cause for hereditary cases, mutations capable of causing disease have been observed in approximately 25 per cent of patients without a prior family history of disease.

The new study, which brings together data from specialist PAH centres based in Germany, France, North America and the UK,  describes molecular genetic analyses of the 10 functionally characterised genes that cause PAH and provides a compilation of all mutations identified to date.

It also describes an additional 370 independent mutations of BMPR2 in patients, either previously excluded from or identified since the last comprehensive mutation update by Dr Machado and colleagues in 2009. Of these, 81 are new variations.

Dr Machado, from the University of Lincoln’s School of Life Sciences, said: “This is the most comprehensive and complete compilation of all defective variations in the genetic risk factors for PAH. This will allow the clinical geneticists, with a greater degree of certainty, to conclude that the gene variations present in a patient are either disease causing or of unknown significance. This could inform a patient’s decisions about starting a family or undertaking pre-natal testing. Prior to this a clinician would have to try and understand genetic data received for a single patient by trawling through historic manuscripts to make a diagnosis. This report has the potential to be of great importance to the diagnostic centres around the world.

“The continuing identification of genetic factors, as explored in this paper, provides unique insight to the genetic mechanisms driving disorders of pulmonary vascular function. These data provide a key resource in data interpretation and how these genetic insights may lead to the potential discovery and delivery of novel targeted therapeutic options in PAH.”

This important resource of clinical and scientific data has now been posted on a freely available public repository, namely ClinVar, and will be accessible through Dr Machado’s Lincoln profile page.

The emergence of next-generation sequencing (NGS) allows scientists to sequence much more quickly and cheaply, and as such has revolutionised the study of genomics and molecular biology. NGS has allowed researchers to identify novel, rare genetic variations in the PAH disease spectrum, detailed in this study. It is likely that future avenues will include the use of more NGS technologies, the pinnacle of which is whole-genome sequencing – a process that determines the complete DNA sequence of an organism’s genome at a single time.