The relationship of stem cells and scientists is akin to that between a child and their parent. Difficult. Let’s face it, we sometimes go against what our parents expect of us and frankly speaking, we never really match up to their ideals. Nuanced approaches are required for the desired effect. The same is true for stem cells.
Image From: Getty Images and https://blog.frontiersin.org/2018/05/14/cardiovascular-medicine-stem-cells-embryonic-adult-personalized-medicine/
While new stem cell therapies are constantly emerging, creating a suitable platform to adequately stimulate their growth is still an obstacle. Scientists face several challenges and limitations associated with the isolation, availability, delivery, survival and differentiation of stem cells.
We have yet to master the intricacies of fully maturating stem cells, but perhaps the future lies in the materials we use to instigate this process. These so-called ‘biomaterials’ may be the key to unlocking a whole new generation of regenerative medicine.
Biomaterials – finding the right home
Before we get into it, here is a quick video provided by CrashCourse on biomaterials:
Biomaterials are a class of materials– synthetic, alive or a hybrid– which can interact with biological systems. Typically, they would have in vivo applications like braces or replacement kneecaps, however they are increasingly being used ex vivo.
When it comes to muscle regeneration, biomaterials work by mimicking the stem cell niche– a comfortable home environment, where stem cells have all the necessary supplies to support differentiation.
However, before creating a perfect biomaterial, researchers must first understand the conditions necessary for proper stem cell maturation. This is possibly one of the biggest questions in this field. Thankfully, scientists are coming ever so close to unveiling this mystery.
This is a simplified diagram of the extracellular matrix. As you can it is composed of a very complex mesh of proteins, sugars, lipids etc. Each of which gives the extracellular matrix its very unique properties which need to be replicated in order for a biomaterial to work effectively.
One way to understand this is by examining naturally occurring stem cells niches found in the body. Although not defined by a physical space, they have very specific topological, mechanical and chemical properties (stiffness being one of the most important ones in muscle repair) which are provided by the extracellular matrix (ECM). An ideal composite that could be used in myology would be engineered with enhanced vascularization and innervation, optimal mechanical and cell-adhesive abilities whilst still bearing the same morphology and biochemical properties of the muscle stem cell (MuSC) niches, also known as satellite cell niches. This platform could help increase the survival, proliferation, and differentiation rates of MuSCs for subsequent in vivo implantations.
Here we can see that stem cell differentiation increases as we increase the mechanical stiffness of a composite
Why do we desperately need biomaterials?
Our skeletal muscles are highly regenerative tissues made up of myofibers. Their ability to self-renew is thanks to satellite cells (MuCSs) located close to the myofibers. Studies have shown that the removal of these cells eliminated an organism’s ability to regenerate muscles. Normally, dormant MuCSs can be stimulated to produce proliferating myoblasts which in turn differentiate and fuse to generate new myofibers. This usually happens after an intense exercise, which explains why you get delayed muscle onset soreness. Not only does this process maintain normal muscle function, but the stem cell niche population is also preserved through self-renewal for any subsequent regenerative needs.
Unfortunately, this is not always possible. Myopathies such as Duchenne muscular dystrophy, injuries and ageing can overwhelm our muscles’ abilities to self-regenerate. This leads to the formation of inert scar tissue, diminishing the muscle’s ability to contract. Current treatment for these severe cases is often transplantation, although this can lead to many complications. In such cases, biomaterials come in handy. We could, for example, implant a biomaterial into the injury site and fill it with mesenchymal stem cells.
What’s the magic word? Hydrogels!
A very exciting study from 2018 showed how synthetic hydrogels are able to boost cell adhesion, survival and muscle regeneration in dystrophic and ageing mice. The researchers believe the key ingredients to the hydrogel are factors that are naturally found in muscle stem cell niches in the body. One such factor is RGD peptide– a simple protein sequence found in molecules like collagen which helps cells stick to the ECM.
Moreover, the hydrogel used by the research team was composed of PEG-4MAL– a cross-linked polymer capable of forming bonds with muscle tissue. It’s this pivotal property that might give PEG-4MAL hydrogels the edge when it comes to improving engraftment. They also score more points because they are synthetic. Why is that so important? Well, compared to natural materials like Matrigels, which are synthesised from mouse tumour cells, synthetic gels minimise the risk of transferring pathogens, as we can be more selective with the cells we transplant.
Although hydrogels seem to be the gold standard in muscle tissue bioengineering, they still have a long way to go. For instance, cell engraftment typically only lasts about a week. Plus, it’s quite hard to engineer complex vasculature into hydrogels which might affect cell survival as they need a transport system for nutrients and signalling molecules.
Speaking of signalling molecules, they may prove to be viable in providing stem cells with cues on what to do at different stages of muscular regeneration. One study showed that a combination of vascular endothelial, nerve and glial-derived neurotrophic growth factors jacked up muscle repair. More notably, this tag team of catchy-named signalling molecules were able to help re-vascularise and re-innervate injured muscle tissues. This directly tackles one of the weaknesses of PEG-4MAL hydrogels.
Here is an easy schematic to give you an idea about how hydrogels can be used as a stem cell niche for in vivo applications in regenerative medicine
So while some biomaterial “parents” take more of an approach that’s all about creating the right environment for their stem cells to survive, others take a cue-based approach that focuses on telling the cells what to do and when. Alone, these parents would not be enough to raise a healthy child. But together, PEG-4MAL hydrogels and growth factors can be the incredible parents muscle stem cells need.
They grow up so fast
Picture this: a young girl is diagnosed with muscular dystrophy. However, instead of preparing her parents for the girl’s short and cumbersome life, you take them through what is now the norm: a muscle stem cell-based therapy which can prevent a life of suffering. They will no longer have to watch their child waste away or hold their breath as she goes through yet another operation. Now, the girl will be free to run, laugh, play and enjoy a long, healthy life. In tomorrow’s world, no one will have to live with the burden of myopathy. This could be our very future as stem cell biomaterials are rich with potential and are already changing the healthcare landscape. Not only are people able to lead better lives, they might not even notice signs of ageing since they can undergo stem cell therapy to replace the old with the new.
Here is link to an interesing article publish by Dr Massimiliano Cerletti at UCL on how age-related muscle dysfunctions can be reverted in mice.