It’s (finally) here! The big paper from my PhD titled “Systemic conditioned medium treatment from interleukin-1 primed mesenchymal stem cells promotes recovery after stroke” was just published last week in Stem Cell Research & Therapy. Thanks to my fantastic co-workers who made it possible! It’s open access meaning anyone can read it here without an annoying paywall. To me it represents several years of work, lots of long days, several weekends in the lab and an epic battle to get it published including three rejections. To celebrate, here’s a summary of the paper.
To give some context, stroke occurs when there is a disruption in the blood flow to the brain. Without access to vital oxygen, brain cells begin to die within minutes. Stroke is a major global health problem and currently the second leading cause of death worldwide. For the 30 million patients living with the consequences of stroke, around half need help with activities of daily living including washing and dressing. Current treatments for stroke are very limited and targeted at minimising further damage. We are in great need of regenerative strategies to repair the injured brain and reduce the disability caused by this life changing disease.
One option showing great promise is mesenchymal stem cells, a type of adult stem cell present in bone marrow and fat tissue. There’s a large body of evidence showing these stem cells can improve recovery in mice and rats after stroke. While it was first thought that these stem cells worked by replacing brain cells lost after stroke, this has since been shown not to be the case. In fact, if you inject these stem cells in the bloodstream a very low percentage make it the brain and an even smaller percentage of those survive long-term and differentiate (turn into) brain cells. There’s really too few cells to be working by replacing the millions lost after stroke. Instead, we now think it’s the vast cocktail of growth factors and proteins made by the stem cells (collectively termed the secretome) that promotes brain repair. In my PhD research we therefore focused on harnessing the secretome as a therapy for stroke rather than using the cells themselves. I like to think of it as using the stem cells as mini cocktail factories.
What did we do?
In the work leading up to this paper, we tested different strategies to enhance the stem cell secretome to develop the best possible stroke therapy. We found in response to treatment with a mild inflammatory stimulus using a molecule called interleukin-1 alpha, the stem cells responded by making more growth factors and anti-inflammatory proteins. The next step was to test if this improved treatment would be effective after stroke and this is what we aimed to do in this paper. In our first study, mice were treated with conditioned medium (the cocktail of growth factors and proteins made by the stem cells) at the time of stroke onset. Really excitingly, we found this prevented brain cells from dying after stroke and we observed around 30% less brain damage on the MRI scans. We also found there were some modest improvements in measures of recovery. Mice that had received the conditioned medium treatment lost less weight after stroke and were better at building nests, a test we used as a measure of wellbeing and motivation. All healthy mice (both male and female) build nests. They do it to keep warm and because it’s a rewarding behaviour. We think it as the mouse equivalent of activities of daily living in people. Patients living with stroke often struggle with activities of daily living due to physical impairments, memory problems, fatigue, mental health difficulties or a combination of these.
We were really encouraged by these results and next wanted to understand if these improvements in recovery were a result of the reduction in brain damage or potentially due to other mechanisms such as encouraging the brain to repair itself by making new blood vessels and brain cells. To help answer this, we then did a follow-up study where we gave conditioned medium the day after stroke. In this study, as we expected, the treatment did not reduce brain damage after stroke. By this point there’s been widespread cell death in the brain and really, the damage is done. Nevertheless, the mice which received the conditioned medium treatment still recovered better after stroke than the control group. They built more complex nests and from day 7 to day 30 at the end of study, had much improved neurological scores showing they had less physical impairment.
What’s the bigger picture?
As a researcher with a medical degree, I’m always consciously thinking about how to develop treatment which could easily be given to patients. We therefore chose to give the conditioned medium treatment by subcutaneous injection (under the skin) which is minimally invasive and safe. It’s actually the way patients with diabetes administer their insulin on a daily basis. Another advantage of our treatment which could help translate it from the bench to the bedside is that conditioned medium is cell-free. This gets around the risk of stem cells being rejected by patient’s immune systems or going on to form tumours.
Our results suggest that the mesenchymal stem cell secretome has great potential as a therapy for stroke. For the first time, we showed that pre-conditioning these stem cells with the inflammatory molecule interleukin-1 alpha could be effective. A limitation of our paper is that we weren’t able to determine how our conditioned medium treatment promoted recovery after stroke. We were able to say in study 2 how it didn’t work (it didn’t reduce brain damage) but not how it did. There are a number of mechanisms through which the secretome could repair the injured brain after stroke as shown in the figure below. My personal view is that as conditioned medium is a combination of different proteins, it works in a combination of ways. I think it’s all about finding the right combination to give at right time.
There’s definitely still much to learn and we are still a long way from using the mesenchymal stem cell secretome in patients. However, I do think it’s such an exciting area of research with the potential to lead treatments not just for stroke but a range of diseases.