News / 20 June 2019

In a bid to help prevent disorders such as foetal growth restriction, researchers at the Monash University-based Australian Regenerative Medicine Institute (ARMI) are examining the body’s response to developmental defects.

Severe foetal growth restriction (also known as intrauterine growth restriction) accounts for about one in 20 stillborn births in Australia. The term refers to when a baby’s body, or particular organs, fails to grow at the expected rate during pregnancy.

In many cases, babies recover and catch up soon after birth, appearing normal and healthy. But as these babies grow, it’s been observed that long-term health effects associated with foetal growth restriction, such as cardiovascular and neurodegenerative diseases, emerge in later life. Not only does this negatively impact the quality of life of patients, it burdens the healthcare system, carers and families.

Severe foetal growth restriction (also known as intrauterine growth restriction) causes around 1 in 20 stillborn births in Australia.

With regular check-ups during pregnancy, foetal growth restriction can be diagnosed and managed, depending on the severity of restriction, and how early it began in the gestation. However, it’s not possible to reverse it, and some treatments may only help slow or lessen the effects.

Foetal growth restriction occurs when an abnormality prevents cells and tissues from growing at a normal rate or to their normal size, or causes cell size to decrease. It’s a result of the foetus not receiving the necessary nutrients and/or oxygen needed for the development of organs and limbs, or because of infection.

Untangling the complex interactions at this stage of development is difficult. The genetics of the foetus is a factor; the placenta is a factor; the mother’s health and nutrient intake is a factor.

And, it becomes even more complex. As an organ or limb grows, signals are sent to its immediate cellular neighbours (local signals), as well as to the whole body (systemic signals). This is how an embryo coordinates limb and organ growth – by constantly checking in and making sure everything is progressing as it should be. For example, when a particular organ is growing more slowly than others, the signals it sends out both locally and to the body will tell other organs to wait until it catches up. These signals are tightly controlled to ensure body proportions are maintained.

Sometimes, though, there can be too many signals sent to the whole body, causing an improper response and disrupting this delicate balance. This is what can happen during foetal growth restriction.

Unfortunately, little is yet known about the genes and the local and systemic signals involved in both healthy organ and limb development, and in foetal growth restriction. Without that knowledge, there’s no hope of being able to improve health outcomes. This is where the Monash researchers come in.

Unfortunately, we still do not know much about the genes nor the local and systemic signals involved in both healthy organ and limb development and in foetal growth restriction.

At ARMI, the Roselló-Díez group is investigating the network of genes and signals involved in the coordinated growth of the cartilage regions that drive bone elongation in the limbs. This knowledge will help us understand the major molecular players in fetal growth restriction. In previous work led by group leader Dr Alberto Roselló-Díez, it was found that blocking cell division (the process during which cells divide to give rise to more cells) in cartilage cells triggered a surprising response during development.

“When we increased the levels of p21 only in the mouse left limbs, we found that left and right limb growth remained coordinated,” Dr Roselló-Díez says. “This was unexpected, as we hypothesised that by interfering with levels of p21, we would disturb limb growth.

“We discovered that there were other signals and processes in the body that could compensate for the gain of p21. We found that at a local level, nearby normal cartilage cells could grow more to help recover any loss, while at a systemic level, increasing p21 levels in the cartilage led to problems in placental function and perturbed systemic growth factor signalling,” he added.

This work contributes to our understanding of what happens in an embryo and may, further in the future, help us improve IVF screening and genetic counselling, as well as provide us with the necessary tools to intervene in cases of fetal growth restriction.

For the next step in its research, the group is working to identify genes involved in controlling organ and limb growth, the type of signals they send out, and how they’re affected by signals they receive. They’re employing a number of sophisticated tools, including gene editing that’s only activated in a specific limb, complex animal models, and now light, in a collaboration with the Janovjak group.

“I’m excited to be working with Harald [Janovjak] and his group," says Dr Roselló-Díez. "Using optogenetics, that is, using light to control which genes are switched on and off in a specific area, will give us greater control. We can learn so much more about local signals in a highly specific and controlled manner as it helps deliver clearer results. This will help us unlock the mysteries of limb and organ growth, and fetal growth defects,” said Alberto. This is only one arm of Alberto’s research, with plans to look at systemic signals using a proteomics (investigating many proteins on a broader scale) approach.

This work contributes to our understanding of what happens in an embryo and may, further in the future, help us improve IVF screening and genetic counselling, as well as provide us with the necessary tools to intervene in cases of fetal growth restriction. Ultimately, the goal of this research is to help people affected by fetal growth defects and their families.

Support ARMI’s goal to understand more about limp development and the mechanisms of fetal growth restriction.

This article was first published in Monash Lens.

More information

The Roselló-Díez Group uses animal models to study the local and systemic mechanisms that orchestrate organ growth and repair in vertebrates. The ultimate goal is to lay the groundwork for regenerative therapies aimed at boosting these mechanisms. For more information on Dr Alberto Roselló-Díez and his group at ARMI, please visit the Roselló-Díez Group page. You can contact Dr Alberto Roselló-Díez via alberto.rosellodiez@monash.edu or follow him on Twitter @RoselloDiez.