The placenta is a phenomenal source of stem cells and regenerative exosomes, and their therapeutic potential extends far beyond conditions of pregnancy, says Bill Kalionis.

How did you get into stem cell research?
My interest in placental stem cells started quite early in my research career. There’s a classic stem cell type in the placenta called the trophoblast stem cell. I was particularly interested in which genes controlled the important properties of these stem cells.
Then, in 2004, mesenchymal stem cells (MSCs) [the major cell type of interest for stem cell therapy] were first isolated from the placenta. It turns out the placenta is a phenomenal source – the sheer number of MSCs is huge. Very quickly, people got interested, and so did I.
The therapeutic potential of these MSCs drives our current research.

Why the interest in mesenchymal stem cells?
MSCs are stem cells that can be triggered to form muscle, bone, cartilage and fat cells, or under certain conditions, even liver and nerve cells – so there’s a lot of interest in their potential ability to repair diseased or damaged tissues. Traditionally, MSCs were isolated from bone marrow – but getting stem cells out of bone marrow is an invasive procedure, and you don’t get very many cells.
But getting large numbers of stem cells out of the placenta is very easy – and placentas are an immense, under-utilised resource. Just at the Royal Women’s Hospital we have more than 9000 deliveries per year, and potential access to at least 4,500kg of placentas. The worldwide supply of placentas is essentially inexhaustible but most placentas are not utilised. Instead, they are disposed of as medical waste after delivery.

What medical conditions are you researching?
My interest is in preeclampsia. It’s the most important medical disorder of human pregnancy.
Preeclampsia usually arises in the second half of pregnancy, and it can come on very quickly. The woman is going through a normal pregnancy then suddenly her blood pressure rises dramatically, her extremities can swell, and if not treated it can lead to very serious seizures.
The condition is very difficult to detect early and there’s no cure except for delivery of the baby and removal of the placenta – regardless of how far the pregnancy has progressed. So doctors are faced with a dilemma, do they deliver the baby to save the mother, but then they have a premature baby – or let the pregnancy continue but risk more severe effects to the mother.
Preeclampsia is thought to be generated by substances released from the placenta, which damage the cells that line the blood vessels in the mother’s circulation. We’re working on ways to use stem cells to treat conditions of pregnancy such as preeclampsia and fetal growth restriction. Our recent study in Nature: Scientific Reports describes a stem cell based strategy for treating preeclampsia [1].

How is the field of stem cell therapy changing?
The stem cell field is moving into using exosomes – it’s a major change.
Around five years ago, the stem cell field realised that the way stem cells repaired diseased or damaged tissue did not happen the way we expected. The mechanism of action was previously thought to be that following the injection of stem cells into a patient they would home in to the area of damage, integrate into the tissue and form the appropriate cell type to repair the damage. It turns out stem cells don’t work that way and in fact very few stem cells integrate into the damaged tissue.
If you take just the nutrient solution the stem cells were growing in and inject that into the patient, you can get the same repair! The active component of the growth medium comprises tiny nanometre-sized particles, called extracellular vesicles (EVs), which are secreted by the stem cells. We are interested in a particular type of EV, called exosomes. Exosomes are taken up by damaged cells where they release a variety of different biomolecules that initiate repair mechanisms, which prevents the damaged cells from dying and gives them the chance to repair and to reproduce, and this culminates in healing of the tissue.
Exosomes have a few important advantages over whole stem cells. One of the issues with using whole stem cells is that they take a long time to act, weeks or even months, and the few stem cells that do integrate into the damaged tissue have some potential for long-term damage; in rare cases they can over-grow.
With pregnancy, you want a quick-acting treatment that goes away after the delivery is finished and the woman is no longer pregnant.
Exosomes are very tiny particles and they don’t persist in damaged cells after they are taken up. Because they are very small, they get taken up by damaged cells quickly, within just a few hours, and are quick-acting. So exosomes have properties that make them potentially useful for treating preeclampsia.

What are there challenges with using exosomes for therapeutic applications?
One of the main problems with working with exosomes is isolating them. All of the current methods give you low yields. And then, because there are different types of exosomes, it’s difficult to get pure populations of any one type of exosome. We’re looking to refine our isolation methods, refine our methods of working out their purity, and to develop tests for how potent the preparations of exosomes are. That’s work we would do in collaboration with Exopharm.
Exopharm’s LEAP exosome isolation technology offers the possibility of a really substantial improvement in exosome yield and purity. We’re very keen to get that technology working – and so far it looks quite promising.

When might we see exosomes put to the test in clinical trials?
There are about 600 clinical trials now using whole stem cells of various types, and a lot of those will switch over to using exosomes – we’re already seeing it happen.
All of the trials with whole stem cells have gone through a long process of regulatory approval, pre-clinical trials and ethics approval. These processes should be quicker with exosomes because that work has already been done with whole stem cells, and instead of using whole stem cells you are using the exosomes they release.
All you need is a few success stories, a few of these clinical trials to succeed, to justify investment in exosome technology.

What are you working on in your laboratory right now?
We work on a range of projects from basic research projects, to applied projects in collaboration with commercial partners.
I can’t talk in detail about our collaboration with Exopharm, but it is one of the most exciting things we are doing at the moment with regard to exosomes, and our preliminary results are promising.
In addition, we also have well-established projects on the basic characterisation of stem cells. There are at least six or seven different MSC types in the placenta, and we don’t fully understand the role they play individually or together. We’ve been working on this topic for more than 10 years now and we’re making encouraging progress in understanding the role of these stem cells, which we believe is a really important question. Our published studies so far show at least two MSC types play important roles in normal, as well as diseased placentas. Our long term goal is to translate these findings into designing new stem cell-based therapies to treat diseases of pregnancy, and other illnesses in the general population such as cardiovascular disease.

[1] Kusuma GD, Abumaree MH, Perkins AV, Brennecke SP, Kalionis B. Sci Rep. 2017 Feb 13;7:42397. doi: 10.1038/srep42397. – link

Further reading:
The Stem Cell Laboratory at the Royal Womens’ Hospital Melbourne