An easier way of making heart cells from a patient's own skin cells

Tuesday, 1 September 2015

Christine Mummery is a professor at Leiden University Medical Centre (LUMC). In her department, the Department of Anatomy and Embryology, researchers transform skin cells of heart patients into stem cells. These stem cells are then gradually matured into various types of cardiac muscle cells.
Until recently, however, the cell harvest was low and limited to ventricular cells and atrial cells. In Nature Biotechnology the researchers describe how cell production can be scaled up considerably. They also discovered that the same applies to conduction cells, known as pacemaker cells. This forms the basis for research into the (molecular) causes and treatment of a broad spectrum of heart conditions.

Nowadays, ordinary body cells can undergo a sort of rejuvenation process in the lab. This turns them into stem cells with the capacity to form all possible cell types. These stem cells are first pushed in a particular direction (they become 'progenitor cells') and, after a number of divisions, these cells mature into the desired cell type. The researchers in Leiden have succeeded in making cardiac muscle cells, for example using cells from people with a hereditary heart condition. Such cultured cells can teach us a lot about the cause and development of heart conditions. We can also use them for testing new medicines, such as drugs to suppress cardiac arrhythmias.

Now also conduction cells

"It has taken us years to develop a protocol to differentiate these induced pluripotent stem cells into cardiac muscle cells," explains Professor Christine Mummery, Head of the Department of Anatomy and Embryology at the LUMC. "Initially the problem was that four-fifths of the cells had characteristic properties of ventricular cells and only one-fifth had properties of atrial cells. Last year we published an article on how adding vitamin A at precisely the right time can shift the balance so that two-thirds of the cells have characteristic properties of atrial cells. Nevertheless, we were still missing one very important component: the conduction or pacemaker cell, which controls the contractions of the heart by periodically sending electrical signals to the other cardiac muscle cells."

Huge scaling up

And there was another problem: contrary to progenitors of brain cells, for example, cardiovascular progenitor cells only undergo a few divisions. Both problems now appear to have been solved. The researchers provided the stem cells with an extra copy of a gene involved in cell division in the foetal heart, along with a molecular on-off switch that responds to an antibiotic. They also built in a gene construct that produces a fluorescent (green) protein as soon as such a cell has the characteristic properties of a (cardiac) progenitor cell. The right time to administer the antibiotic was found to be immediately before the cells turned green: the progenitor cells thus underwent at least another forty divisions before becoming cardiac muscle cells, a huge scaling up.


By removing the antibiotic, the progenitor cells can be allowed to mature into cardiac muscle cells at any time, provided that the right combination of substances is added. Mummery: "But now that we had so many more cardiac muscle cells, we noticed that there were (beating) cells among them, which had not turned green. Closer analysis revealed these to be conduction cells. Although we had already suspected that such cells existed, we now had a high enough proportion of them to be able to enrich them to 100 percent using antibodies against a specific characteristic. So now we can also test the effects of all kinds of medicines on models for disorders of the conduction system. And in the future it may be possible to replace electronic pacemakers with a bio-pacemaker cultured from the patient's own cells."

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