The large scale generation of human ventricular progenitors (HVPs) from human ES cells.
HVPs expand, mature, and differentiate to form large beating human ventricular muscle graft patches following in vivo transplantation.
Progenitor cells offer great hope for heart failure patients The 5D Heart Patch Project, led by Prof Kenneth Chien, has identified human ventricular progenitor (HVP) cells that can create self-assembling heart grafts in vivo. The research has the potential to offer hope to millions of people suffering from heart failure. The 5D Heart Patch Project forms a vital step in a scientific journey that could be on the cusp of something extraordinary, with the goal of generating a fully functioning heart graft patch in vivo, in humans. Enabled with the backing of an ERC grant and with the support and involvement of Swedish pharma, AstraZeneca, and the biotech SmartCella, the ground-breaking project has profound implications to potentially provide a viable treatment for the millions of people who suffer from heart weaknesses, heart failure and damaged hearts after heart attacks. The World Health Organisation (WHO) has stated that cardiovascular diseases are the leading cause of death in the world, responsible for the death of an estimated 17.9 million people every year, which equates to around 32% of all deaths worldwide. “Heart failure is a progressive, chronic disease. There are drugs that work, primarily symptomatically, but nothing that stops the fundamental process of heart failure,” said Kenneth Chien, Professor of Cardiovascular Research at Karolinska Institute, and cofounder of Moderna.
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“It’s the number one cause of morbidity and mortality as a single entity and is growing exponentially. The drivers are diabetes and hypertension and it’s a disease of the elderly although it can affect anyone of any age, including neonates if they have a genetic abnormality. This is one of the
The search for heart cells The project is the latest step after twenty years of diligent searching for a specific type of progenitor cell for the heart. “We want contracting muscle cells and it has to be a specific type because there are many different types of heart muscle cells and
What we have done is identify a cell, a kind of ‘master ventricular progenitor’ that makes only one type of cardiac muscle, but also can make its own matrix, trigger the formation of blood vessels following transplantation, migrate to the site of heart injury, prevent fibrosis, and then go on to expand to form huge grafts of functioning cardiac muscle. single largest unmet clinical needs in all of medicine. For end-stage heart failure, there is no cure other than heart transplantation and there is a limitation in the number of available donors. Finding ways to rebuild heart muscle in heart failure is one of the holy grails in regenerative medicine, specifically regenerative cardiology and in medicine in general.”
each of the heart muscle cells has a different electrical signature. All the heart cells need to beat in synchrony, to beat ‘to a single drummer’ if you will – that’s your pacemaker. What if you have a rogue cell and it doesn’t listen to your pacemaker? You’re going to have electrical confusion and you are going to have an arrhythmia that could be life-threatening,” explained Professor Chien.
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Arguably, the first milestones in this scientific quest were based on studies between 2005-2009 in a mouse, where a marker of master heart progenitors, which could make any type of heart cell, was identified. Subsequently, a progenitor cell was identified in the mouse heart that would make only ventricular muscle, the main type of muscle responsible for propelling blood into the circulation. After a search spanning over a decade, the Chien lab at Karolinska Institutet managed to identify a similar cell from human embryonic stem cells, that would only make the right type of contracting muscle cell and nothing else. The search for human ventricular progenitors or HVPs was over, but the work toward developing human cell therapies for regenerating healthy heart muscle was just beginning. “What we have done is identify a cell, a kind of ‘master ventricular progenitor’ that makes only one type of cardiac muscle, but also can make its own matrix, trigger the formation of blood vessels following transplantation, migrate to the site of heart injury, prevent fibrosis, and then go on to expand to form huge grafts of functioning cardiac muscle. When you put this cell anywhere; in a dish, in a mouse heart, in a pig heart – and this has all been done – you make a chunk of human ventricular muscle, and it does it all on its own, sort of a ‘self-assembly’ process that is a natural program of the cell. When we saw this, initially in a mouse, I thought, this is a cell, after twenty years of searching, that is worthy of trying to put into the clinic.”
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A treatment to replace surgery? Such a heart patch can repair a damaged heart in just six weeks and the cells do the majority of repair intuitively. The process is less invasive than open heart surgery and requires an injection of the cells into the heart. The HVPs appear to be incredibly adaptive and focused in carrying out their ‘pre-programmed’ task. The research team were encouraged by the cell’s ability to generate contracting ventricular heart tissue in so many circumstances and with just one cell it was possible to make billions more. In one experiment they found when the cells were introduced to a mouse kidney they made a beating, moving, heart muscle patch
on the kidney despite the difference in the organ. It was the same result, putting human heart progenitors from embryonic stem cells in slices of a dead monkey’s heart in a petri dish. The human progenitors took over to build a human patch on top of the dead monkey’s heart tissue and the tissue started beating. The HVPs apparently navigate many of the challenges that present themselves with cell therapy for hearts. A major problem with implanting heart cells is when they already have a beat. This is because the heart has to maintain a consistent rhythm and a clash of rhythms in beating cells put together, can be dangerous or fatal.
HVPs can migrate, prevent fibrosis via fibroblast repulsion, and regenerate functioning human ventricular muscle in in vivo mouse and ex vivo primate model systems.
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