Aileen Anderson is a Professor at the University of California Irvine (CA, USA) and is also the Director of the Sue & Bill Gross Stem Cell Research Center at the institution.
In this interview, Aileen speaks to us about her talk at the 21st Spinal Research Annual Network Meeting (6–7 September 2019, London, UK) on traumatic CNS injury and the inflammatory stem cell niche. Aileen also discusses the obstacles involved with tissue regeneration following injury and the techniques she employs to help overcome the challenges with strong inflammatory responses.
1.What inspired you to work in the field of stem cells in relation to spinal cord injuries?
When I first started up my own lab, which focused on spinal cord injuries, I was really interested in the intersection between how the immune system might be communicating to the CNS and what role that might play in terms of either damage or recovery of function. Thus, I employed a number of spinal cord injury models in mice and at the time, there weren’t very many people who were manipulating mice in this way.
I was approached by collaborators who had isolated neural stem cells and they really wanted to transplant these cells and look at what happened following a spinal cord injury (i.e., whether they could have a therapeutic benefit). There weren’t many labs that were working on immunodeficient mice at all and our collaborators were particularly keen to look at the potential of those cells and the absence of immunorejection, so it was a match right from there.
This happened in the early 2000s and human neural stem cells had only really been revealed to be present in an adult niche in 1998, so it was early in the game of stem cells and regenerative medicine. It was easy to see that the potential of this field was going to be big.
2.You’ve presented a talk on ‘Traumatic CNS injury and the inflammatory stem cell niche’ – could you provide us with an overview of this?
“In contrast, if we delayed transplantation to weeks or months after injury, those cells didn’t exhibit the same characteristics – where they went and what they did was different. They migrated away from the injury and didn’t get trapped into making astrocytes.”
My talk was the culmination of a lot of work that has originally come out of those very translational projects that we did in my lab. When you go to clinical trial, or think about going to clinical trial, there are a lot of elements you have to know – that is, nitty gritty details that we would never think about asking when doing basic science research. For example, the dose of cells, timing of transplantation and all the variables that you would use to define a clinical trial.
Along the way of doing those translational studies, we made some observations that were surprising to us. One of them was that if we looked at timing and transplanted a multipotent human neural stem cell population super early and acutely after injury, those cells all got recruited into the epicenter. Additionally, these cells like to make astrocytes and we didn’t see functional recovery.
In contrast, if we delayed transplantation to weeks or months after injury, those cells didn’t exhibit the same characteristics – where they went and what they did was different. They migrated away from the injury and didn’t get trapped into making astrocytes. We saw many more oligodendrocytes and neurons and we did see functional recovery. Thus, this raises the question as to why does that happen? It was obvious that there had to be cues in the microenvironment that those cells were listening to.
Going back to my earlier research interests and in parallel with that work, we were profiling what happened to the immune response and had discovered that it was very dynamic after spinal cord injury. Those two sets of studies lined up when they came to fruition in the lab at the same time. Therefore, the obvious question to ask was whether there was an immune component that was affecting how these cells were responding.
We investigated this in several different ways and what I talked about in my presentation included published data indicating that in that very acute niche after injury, neutrophils are a very dominant cell source. They are at the injury in the epicenter very early on and are programming transplanted neural stem cells to come into the injury epicenter and to make astrocytes. This was surprising for us as people haven’t thought very much about neutrophils in the CNS because they mostly pop in and pop out super quickly. They peak at 24 hours and that’s about it. Thus, the idea that they could be playing such a dominant role in controlling either endogenous cells (the neural stem cells) or cells that we transplanted was a little surprising.
“…we demonstrated how C1q actually does signal via a classical signaling mechanism to neural stem cells by instructing those cells on what their fate and what their migration was going to be.”
We wanted to understand how that was happening from a mechanistic point of view, so we went after trying to understand the molecules that neutrophils are making and putting out into the microenvironment – that neural immune niche. We identified several that we became interested in. One was C1q and the other was C3a, which are part of the complement cascade. We demonstrated that those two molecules mediate almost all of the effects that neutrophils have in terms of programming transplanted neural stem cells.
For C3a, this makes a lot of sense because it has a known receptor and acts via a receptor-mediated mechanism. It was a big surprise to find that this receptor is on neural stem cells – we don’t really think about that being the case. There’s a whole story that has come out of this, but I didn’t go into detail about this in my talk.
For the other molecule in question, C1q, it was a big surprise because in the immune system, C1q is all about phagocytosis and clearing debris; it tags things and doesn’t signal to cells and it really doesn’t have any identified cell surface receptors. Therefore, we became curious about how it could be that C1q is having its effects. It seemed pretty obvious that it was either soaking up something else in the microenvironment and keeping it from signaling, or it had to be acting directly on the cells themselves, and that would have been surprising.
We investigated both things in parallel and I had a tremendously talented graduate student in the lab who took on the project of trying to figure out whether it was possible that there were actually receptors that C1q was signaling to on neural stem cells. In fact, we think she did identify a set of those receptors, which is what I spoke about in my talk. One of those receptors that we identified included CD44 and we demonstrated how C1q actually does signal via a classical signaling mechanism to neural stem cells by instructing those cells on what their fate and what their migration was going to be.
3.One of the challenges involved with tissue regeneration following injury is the development of strong inflammatory responses, which can result in cell death. What techniques are you employing in your work to help overcome this?
The immune system is the classic double-edged sword – it has really good aspects that it does and others that are not so good in terms of immune-mediated cell death, or in the case of regenerative medicine, immunorejection in cell transplantation.
“The CNS isn’t an immunoprivileged place – there is a lot of immunosurveillance that occurs all the time, especially after injury. When your immune system sees those transplanted cells, they happily reject them and kill them off.”
One element that is very limiting right now that everyone is struggling with in the context of using stem cells as therapeutics for various neurological diseases and injuries, is that what we were taught in graduate school isn’t true. The CNS isn’t an immunoprivileged place – there is a lot of immunosurveillance that occurs all the time, especially after injury. When your immune system sees those transplanted cells, they happily reject them and kill them off. In some cases, that might be okay if the cells are mediating an effect that doesn’t have to do with cell replacement. There are plenty of examples where we know that’s the case in terms of CNS disease or injury – the cells are making trophic factors or they’re modulating the immune response itself and these are elements that are beneficial. However, if you need to get to a stably engrafted cell population then that’s a big problem.
We do cheat in our experiments in the lab. The way we do this is that we want to test human cells – where on top of regular immunorejection, there’s also a xenogeneic barrier that is even more efficient in terms of rejection. Thus, we use constitutively immunodeficient animal models. This has some problems. We use animal models that are lacking the adaptive immune response (i.e., T cells and B cells) but where the innate immune response (i.e., macrophages, neutrophils, etc.) are mostly intact or partially intact. However, we can’t do this when we go to clinical trials, so being able to control the rejection response is a huge area of interest that we need to deal with.
There has been tremendous progress made in this area. One is in programming the cell populations that get transplanted to do one of two things: 1) either put up something on their cell membranes called the “don’t eat me signal”, which downregulates what the hose immune response is like to those cells, or 2) to induce tolerance and find a different way where you upregulate, for example, a population of regulatory T cells that can put the lid on what that rejection response looks like – and we know this can work.
“There are a lot of strategies in place to look at upregulating Tregs or educating Tregs for a particular cell population that you might be transplanting. Those have all made incredible progress in the last 5 years or so.”‘
We know this can work because there’s central tolerance and peripheral tolerance. Central tolerance is mediated by your thymus and we know that in young kids, for example, when they receive an organ transplant, much more immunosurveillance is happening. If you do this when they’re young and have a thymus that’s largely active – which goes down later with aging – you can establish organ tolerance if you transplant young enough.
In adults that’s not such a great option and we have to take advantage of peripheral tolerance, which is heavily depending on Tregs. There are a lot of strategies in place to look at upregulating Tregs or educating Tregs for a particular cell population that you might be transplanting. Those have all made incredible progress in the last 5 years or so. I really think that this is a nut we’re going to crack and it’s going to have a huge impact for regenerative medicine and cell-transplant therapies, as not everything has to be autologous, which could dramatically decrease the cost of what regenerative medicine and cell therapies are like. We could open up a different clinical array.
4.Looking forward, what developments are you most excited about in the field?
I’m really excited about this immunotolerance aspect!
“I’ve heard some talks from the conference about repurposing drugs and doing molecular screens for new druggable targets and those are fantastic approaches. However, stem cells and regenerative medicine of stem cells does something different. It’s messy…”
There’s an awful lot to be excited about for stem cells and regenerative medicine. In California, the California Institute of Regenerative Medicine (CIRM; CA, USA) has had a massive impact on stem cell research, certainly everywhere across the USA and really globally because at a time when we could just identify these cells and people were excited about being able to go forward, the federal restrictions that were being put in place on stem cell research at that time would have had a field-killing effect. Thus, having CIRM provide the funding that it did at the time, and having Californians come together to say that it was something we wanted to see the potential for in the regenerative medicine context, had a huge impact. Over the last 13 years of CIRM’s existence, there have been more than 55 CIRM-funded clinical trials that have gone forward.
With stem cells, either transplanting them or targeting a stem cell population from a therapeutic perspective for all kinds of diseases, has been wildly successful for juvenile diseases where it’s been possible to target a protein replacement or fixing a stem cell population (e.g., hematopoietic stem cells) in kids that have severe combined immunodeficiency, for example. Thus, it’s a stem cell organized therapy but it’s really cell replacement or cell fixing at a time and development when it’s relatively possible to do that.
Now we’re at a phase where those clinical trials that are going forward aren’t just for juvenile diseases, or things that we looked at as relatively low-hanging fruit, such as diabetes, but for the CNS. For example, traumatic brain injury, spinal cord injury, Huntington’s disease – these are all happening in the pipeline right now. This pipeline is increasing for neurological disorders and I think the potential of this is really amazing.
I’ve heard some talks from the conference about repurposing drugs and doing molecular screens for new druggable targets and those are fantastic approaches. However, stem cells and regenerative medicine of stem cells does something different. It’s messy because most times these cells are multimodal in terms of their mechanisms of action, but I think that’s their strength at the same time. Some of the things that are going to be moving forwards in the clinic for the CNS 1) wouldn’t be possible without CIRM but 2) are really exciting in terms of what their potential is because it is a complex mechanism of action. So, to speak, I think there’s additional bang for your buck that we get out of those stem cell therapies.
The opinions expressed in this interview are those of the interviewee and do not necessarily reflect the views of Neuro Central or Future Science Group.