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Progeria is an extremely rare, accelerated ageing disorder that affects about 200 children worldwide. It is caused by a point mutation in the Lamin A gene, the prominent protein that makes up the membrane of a nucleus. The genetic mutation creates an altered form of the Lamin A protein called progerin and this leads to abnormal nuclear membrane shape and a variety of defects.
The changes manifest as ageing symptoms such as hair loss, wrinkly skin and – most importantly – cardiovascular disease. Patients die from atherosclerosis before the age of 20, most likely owing to defects in their vasculature.
I have always wanted to do something medical-related and my strong interest in maths and science made tissue engineering my ultimate career goal. I chose to focus my work on this disease because of my desire to research cardiovascular disease in the context of tissue engineering, and my participation in a collaborative US National Institutes of Health grant in our lab to study rare diseases including progeria.
The small-diameter blood vessels in our lab are fabricated from smooth muscle cells that are derived from human-induced pluripotent stem cells (iPSCs). We use iPSCs because they have the capability to become any cell type in the body, and therefore we can easily create any type of cell needed to make our blood vessels while still maintaining the genetic make-up of the diseased patient.
We embed these iPSC-derived smooth muscle cells from progeria patients in a collagen solution, the primary protein that makes up blood vessels. This solution is then solidified in a cylindrical mould with a metal rod through the middle. This creates the basic structure of the vessel with smooth muscle cells in the vessel wall.
Once solidified, the vessel is sutured into a custom chamber and the cylindrical rod is removed, which creates the lumen, the inner lining of the vessel. Next, endothelial cells are injected into the lumen to complete the full structure of a blood vessel. The chamber containing the blood vessel is then attached to a perfusion circuit connected to a peristaltic flow pump, which circulates cell culture media through the vessels at physiological flow rates for many weeks.
Better understanding of disease
These blood vessels are useful because they not only show the ability for iPSC-derived human cells to create functional tissue-engineered blood vessels, but they also show the potential of modelling a rare disease in vitro. Previous studies to model progeria have involved either cells in two-dimensional culture or mouse models, neither of which fully replicate the human disease state. By creating a three-dimensional tissue model using human cells, we can get a better understanding of how the disease develops.
iPSCs also let us easily create patient-specific models for individualised drug testing, since they can carry over the genetic make-up of the patients even after being converted to other cell types. Since our tissue-engineered blood vessels show the ability to respond to therapeutics, we can use this model to give better insight into how drugs may affect a particular patient with the disease. This may allow for improved drug screening and an expedited regulatory approval process.
In addition to the benefits for modelling progeria, our studies show the potential to study other rare diseases and creating patient-specific drug testing platforms. Other work in our lab involves modelling general cardiovascular ageing, atherosclerosis, and radiation effects on the cardiovascular system.
Now that we have shown the ability of these blood vessels to function, model disease characteristics and respond to known therapeutics, I believe there is great potential for this work to extend to a variety of disease states and future drug studies. We are also working on optimising the iPSC sources in our model to function at comparable levels to other human primary cell sources that we have previously evaluated in our blood vessels. This will increase the sensitivity of our platform for drug testing as well as help us further understand the progression of progeria in the cardiovascular system.
I expect our model will provide great insights in the future.
Content published by Professional Engineering does not necessarily represent the views of the Institution of Mechanical Engineers.