by Monya Baker
Nanoparticles coated with stem cells aid cell delivery
[Editor's note: It's not easy to assess a study's ramifications from press releases, three of which caught my eye this month. I asked Phil Schwartz, a neural stem cell expert at Children's Hospital of Orange County, California, to help me understand the gap between study and therapy. I also asked authors from each paper to respond. This article is one of three resulting from this process.]
Research summary by Nature Reports Stem Cells: One problem with cell transplantation is that cell transplants die. Bioscaffolding is a way to keep cells alive so that they can engraft and integrate. Researchers led by Michel Modo from King's College London made polymer particles that could be coated with neural stem cells.
Using fine needles and MRI to guide them, the team transplanted these particles into rat brains to fill cavities created by simulated strokes. Over the course of a week, the particles in the five treated rats began to degrade, as designed, and some cells at the periphery of the graft formed, according to the paper, "a fibrous web of connective tissue" that was "interspersed amongst a honey-comb-like structure formed from degrading particle material". The paper points out that the grafts could not survive long without blood vessels. The study was conducted to see what the cells and particles would do; the rats weren't tested for any signs of benefit from the treatment1. Though this work in particular is not designated part of a potential therapy for biotech company ReNeuron, the questions it addresses are part of a broader collaboration with the company.
Schwartz's take: You asked me what the connect or disconnect was between the press release and the paper. In the press release, it says you can fill a hole left by stroke damage with brand-new brain tissue within seven days, and that sounds interesting; even in the paper, it talks about primitive neural tissue. In the normal developing nervous system, primitive neural tissue — or brain tissue or even embryonic tissue — is a highly organized tissue, and the cells are interrelated in very intricate ways; if you take a picture of it, you can see that it's highly organized. Nothing in this study shows any highly organized anything, so to say that you have primitive neural tissue or brand-new brain tissue is really a gross exaggeration of the facts. When they say they filled the hole left by stroke, what they actually filled the hole with was a scaffold consisting of little spheres coated with stem cells, so the vast majority of [what filled] the hole was scaffold. The idea was that you have the scaffold, the stem cells would leave the scaffold and start to integrate into the tissue, and the only place that they started to appear to integrate was at the periphery and only where the glial scar was thin.
In addition, it's only a seven-day experiment. It's hard to make any kind of conclusions about what kind of engraftment you're going to get or how effective this is going to be in a seven-day experiment. It's way too short. They showed that the cells survive and that there was some evidence of engraftment at the periphery, but I think what they really showed was that they could use this stem cell–coated scaffold to fill holes in the brain. What that has to do with repairing a complex tissue that has been utterly destroyed is not at all answered in this paper. It's an interesting paper; it shows that the cells survive for seven days in this polymer scaffold, but there's a whole lot of work to be done to show that this might be a clinically applicable approach to stroke therapy.
Nature Reports Stem Cells (NRSC): How organized would you say the cells are at seven days? How organized would you expect it to be to be beneficial? (I showed your paper to an outside expert, and he said it was not organized enough to be called tissue.)
Michel Modo, King's College London: We agree that this is not yet functional tissue, but a first step to potentially achieving this in the long run. We suggest that it is a primitive de novo tissue for the reason that cells stay in this area and they attach to each other to form a web-like structure in between the scaffolds. Still, there is a lack of proper blood supply, proper cellular architecture or extracellular matrix that can typically be found in this area. However, for this primitive 'tissue' to mature to proper integrated tissue, the scaffolds will need to degrade and the cells [will need to] adopt an appropriate phenotype for that region whilst organizing in a particular way. At this stage, it is difficult to say exactly what aspects will be needed to achieve this. However, the possibility to engineer these particles to secrete various factors gives us a tool which we can use to try and achieve this step by step. Nevertheless, this is still quite a bit of a challenge ahead of us and others. One has to bear in mind that we need to achieve this inside the brain rather than to assemble this tissue ex vivo as one can do with skin grafts.
NRSC: What is the main hurdle that this work overcomes?
Modo: In this work we overcome the issue of injecting a large volume of material into the brain without causing damage to surrounding tissue. This is achieved by the biomaterial fitting through a thin needle that passes through intact tissue without causing too much damage. This can only be achieved by knowing exactly where the lesion is and how big it is. The use of MRI is therefore essential to this to deliver the neuro-saffolds accurately within the cavity rather than into intact tissue. This has never been done previously.
NRSC: My understanding is that you've collaborated with ReNeuron [in Surrey, UK] in the past. ReNeuron is working on using human cells to fill holes left by stroke. Do you expect to work with ReNeuron to move this work forward? Would this happen in your laboratory or at ReNeuron?
Modo: Yes indeed, and we are in the process of using ReNeuron's human neural stem cells in this system.
NRSC: Why did you stop the experiment after seven days?
Modo: The main aim here was to assess if the scaffold would support the cells to form a primitive tissue. We also killed animals at one day [for comparison]. As cells will need a little time for migration, organization and differentiation, we included the seven-day time point to give these processes a chance to occur. Longer-term studies would no longer have shown us the biodegradable particles. Therefore seven days was the most appropriate time point for this study. However, as we gain more control over what the cells will be doing by engineering the particles to secrete different factors, we will gradually build up experiments that will look at the behavioural significance of this newly formed tissue and hence use later time points.
NRSC: How hard do you think it will be to get blood vessels to grow into the former cavities and to keep the cells in the cavity alive?
Modo: We are currently in the process of investigating this using VEGF [vascular endothelial growth factor]-secreting particles. However, it is too early to tell if this will be sufficient to generate functional blood vessels inside the cavity.
NRSC: What is the danger that the cells will grow so much they push out of or push against the former cavity?
Modo: There is currently no indication that this will be the case. When we just inject stem cells, they migrate into the existing brain. So if inadvertently we would inject too many cells, we would expect these to migrate into the existing brain and integrate seamlessly there. We have never seen tumour formation from using NSCs [neural stem cells]. However, the volume of biomaterial needs to be well matched to the volume of the lesion. The use of baseline MRI allows us to do this.
NRSC: At what point do you think you can assess the functional benefit of the stem cell–studded scaffolds? Can you point me to any papers or work showing that filling these lesions has shown benefit?
Modo: There are currently no papers out there that have used this approach. Although a similar approach was reported in Nature Biotechnology2, they did not progress this work to behavioural studies. We anticipate that if we can demonstrate good graft survival with a functional blood vessel support, we will be in a position to do our first behavioural recovery study.
[Editor's note: Schwartz's comments are transcribed from an interview. Modo's responses reflect e-mailed replies to e-mailed questions.]