Pacemaker Cells Derived from Skin Cells

Dr Oren Caspi, from the Technion-Israel Institute of Technology has done some very interesting work with pluripotent stem cells and the heart. Recently, Caspi and his colleagues made induced pluripotent stem cells (iPSCs) from skin cells extracted from heart patients. These were differentiated into heart muscle cells that had all the characteristics of young, healthy heart tissue from new-born babies.

This has been done before in other labs (for one example, see Ma J., et al., Am J Physiol Heart Circ Physiol 2011 301(5):H2006-17).  What Caspi and others found that was so remarkable was that these reprogrammed cells have the capacity to “reset” the rhythm of any unhealthy heart tissue that surrounds them. Caspi and others in the laboratory of Gepstein Lior think is that patients suffering from irregular or slow heart beats, who normally require a pacemaker, could, instead, be treated with an injection of new heart cells grown from stem cells made from their own cells to create a “biological pacemaker” that could regulate their heartbeat.

At this time, heart attack patients have hearts that pump out of sync or who suffer from irregular heartbeats. Such patients require surgery in order to insert a battery-powered pacemaker that is fitted to control the heart’s rhythm. There are approximately 25,000 pacemakers fitted each year in the United Kingdom alone.

According to Dr. Caspi, “We found that the electrical signal from the heart cells we created synchronized the beat of any surrounding heart tissue. We have seen this happen in dishes in the laboratory and in animal models. When we integrated the cells into the hearts of pigs, they were paced by the cells that were injected. It seems that the cells that beat fastest control the pace, so it could be used to replace artificial pacemakers for people with slow or irregular heartbeats.”

In May, 2012, Caspi and Gepstein became the first scientists in the world to make heart muscle cells from iPSCs that were made from heart patients. They reverted adult skin cells into iPSCs and then used special culture conditions to convert those cells into fully functioning heart cells. These cells integrated into the hearts of rats, and researchers believe that it will be possible to use skin cells from patients to create injectable biological pacemakers. This will reduce the risk of them being rejected by the patient’s body. They are now working with clinical heart specialists in a bid to design a human clinical trial that will evaluate the efficacy of such a treatment in human patients.

According to Caspi: “We are working with clinicians to take some of our data to the clinic, but it is still a very new technology so there is still a lot of research to be done before any treatments will emerge.”

How Pluripotent Stem Cells Stay Themselves

Embryonic stem cells (ESCs) have an uncanny ability to perpetually divide in culture and differentiate into any cell type found in the adult body. The internal switches inside ESCs that keep them pluripotent or drive them to differentiate are incompletely understood at this. However new work from the Carnegie Institution for Science has opened a new doorway into this event.

Yixian Zheng and his research team has focused on the process by which ESCs stay in their pluripotent state. There are three protein networks within the cell that direct the self-renewal and differentiation aspects of cell behavior. These networks consist of 1) the pluripotent core, which includes the protein called Oct4 and its many co-workers; 2) the Myc-Arf network, which directs cell proliferation, and 3) the PRC2 or polycomb proteins, which repress genes necessary for differentiation. How these networks are integrated remains quite unclear. Zhen and his group have found a protein that seems to link all three of these networks together.

A protein called Utf1 seems to act as the cord that ties all three of these networks together. First, Utf1 limits the loading of PRC2 on the DNA and it also prevents PRC2 from modifying chromatin so that the DNA assumes a very tight, compact structure that prevents gene expression. Thus, Utf1 keeps the DNA somewhat poised and ready for gene expression, should the proper conditions come about that favor differentiation. Secondly,. for those genes that are not completely shut off by PRC2, Utf1 works through a protein complex called the DCP1a complex to degrade these mRNAs made these incompletely repressed genes. Finally, Utf1 downregulates the My-Afr feed pathway. The Myc and Arf work together to curtail cell proliferation, but the inhibition of this pathway ensures that the cell continues to divide properly.

According to Zheng, “We are slowly but surely growing to understand the physiology of embryonic stem cells. It is crucial that we continue to carrying out [sic] basic research on how these cells function.”

Zheng is a Howard Hughes Medical Institute Researcher at the National Institutes of Health and in the Department of Embryology at the Carnegie Institute for Science in Baltimore, Maryland.

This work was published in the journal Cell under the title, “Regulation of pluripotency and self-renewal of ESCs through epigenetic-threshold modulation and mRNA pruning.” Cell 2012 3:576.