Making Human Heart Tissue for Discovery of New Drugs

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1. Please give a summary of your research.

Since starting my PhD in 2007 my goal has been to create human heart tissue from stem cells for cardiac repair. My initial ideology was to implant the engineered human heart tissue in patients with heart failure to restore their heart function and cure those patients – an ideology that was and still is consistent with the stem cell field as a whole. However, I also strongly believe that it is perhaps an even more powerful use of these human heart tissues is for drug discovery applications. I started my lab based around this ideology, and have been running my lab since 2014.

It was recently discovered in 2011 that mammals can fully regenerate their hearts following injury only in a brief neonatal window, with the regenerative capacity already declining 7 days after birth. While many decades of heart research in mice could lead to new regeneration drugs for heart failure, I believe that our human heart tissue may help us to get to this goal more quickly and effectively. My lab is using human heart tissue as a model to study the developmental processes that lead to loss of regenerative capacity of the heart muscle cells so that we can identify drugs that re-activate regeneration in adult hearts and patients with heart failure.

We also have multiple projects underway in our lab to study cardiac disease using human heart tissue. These include diseases caused by environmental damage (eg. diabetes) or genetic disorders (eg. childhood cardiomyopathies). We also hope to make mechanistic insight into these diseases and eventually discover new drug targets for these diseases.

2. Please include any additional details you would like to share

The process of making human heart tissue takes about 4 weeks in our lab. We start off with pluripotent stem cells, which we can culture for years in the lab and grow huge numbers of cells. Most importantly, however, they have the ability to turn into all the cell types in the body. In order to turn them into heart cells we mimic the developmental program that forms the embryonic heart. This is a staged protocol requiring different growth factors (proteins that can activate cell signalling) at precise times and concentrations. After 10-14 days we end up with contracting heart cells in the bottom of flasks (a flask the size of a $5 note contains ~30 million heart cells). We then take these heart cells, enzymatically disperse them so that they are single cells, and put them into a 3D collagen matrix. We put this collagen/heart cell suspension into our culture platform where over 2-5 days they form 1mm tissues which spontaneously contract as seen in the video. We then place the tissues in conditions that mimic the switch in metabolism coinciding with breast feeding in order to mature the tissues for a further 11 days. This process yields human heart tissue in 4 weeks that is about as mature as the early postnatal human heart. This is important as it means that we can accelerate the developmental process to have tissues ready for drug screening more quickly.


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aadil khan
4 months ago

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