29 November 2012

A heart patch made of reliable material?

For the first time, cardiovascular progenitor cells suitable for therapy have been obtained

LifeSciencesToday based on Fraunhofer IGB materials:
A novel therapeutic advancement in the search for heart muscle progenitor cells – hope for heart attack patientsIt is estimated that 17 million people die from cardiovascular diseases every year.

Although the mortality rate is gradually decreasing, heart attack is still one of the most common causes of death in the developed countries of the world. Often the cause of a heart attack is a blockage of the coronary artery that supplies the heart with blood, which kills cardiomyocytes. Cardiomyocytes – the cells of the heart muscle responsible for the contraction of the heart – are not capable of regeneration. The massive death of cells and tissue as a result of a heart attack and the extremely limited ability to restore the adult heart lead to a violation of the blood supply to all organs, which negatively affects the quality of life of the patient. To replace dead cells and restore the functional ability of the heart after a massive heart attack, doctors need mature cardiomyocytes capable of doing their job in the same way as native adult heart cells do.

Obtaining such functional cardiomyocytes from clearly identified cardiovascular progenitor cells (CPCs) is the focus of the group of Professor Dr. Katja Schenke-Layland from the Fraunhofer Institute of Engineering and Biotechnology (Fraunhofer-Institut fur Grenzflachen- und Bioverfahrenstechnik, IGB) in Stuttgart and her American colleagues Ali Nsair, MD, from the University of California Los Angeles (UCLA) and Professor Robb MacLellan, MD, from the University of Washington in Seattle. To date, scientists have managed to identify such cells in the body of mice. This work could revolutionize the treatment of cardiovascular diseases.

Myocardial cells – as well as endothelial cells and smooth muscle cells – develop from cardiovascular progenitor cells during the embryonic development of humans and other animals. A significant amount of research has been devoted to the search for ways of clinical application of these cells. The reason for the failures is that markers that help identify CPCs, such as Islet1 or Nkx2.5, are located in the nucleus of these cells. The use of such markers changes cells, making them unsuitable for therapeutic use. That is why it is so important to identify safe surface markers.

Professor Schenke-Leyland's group and her American colleagues brilliantly solved this problem: they managed to identify two markers, the receptors Flt1 (VEGFR1) and flt4 (VEGFR3), on the surface of CPCs, with which these cells can be clearly identified while fully preserving their biological function. This discovery allows scientists to isolate functionally mature cardiovascular progenitors that meet clinical requirements.

Inspired by the success in identifying and isolating living CPCs, the researchers decided to obtain these cells from induced pluripotent stem cells. To this end, they used a method for the development of which the Japanese scientist Shinya Yamanaka (Shinya Yamanaka) was awarded the Nobel Prize in Medicine for 2012. His work, published just six years ago, showed that four proteins are responsible for the embryonic state of cells. By embedding the genes of these four proteins into differentiated – mature and specialized –cells, Dr. Yamanaka returned them to the embryonic state. From these cells, called induced pluripotent stem cells, scientists can obtain any cells of the body – hepatocytes, neurons or cardiomyocytes.

In their study, the researchers used a strain of mice whose cells are labeled with a green fluorescent protein (GFP) visible under a fluorescent microscope. The cells of these mice were reprogrammed by four Yamanaka genes into induced pluripotent stem cells that are easily identified.

At the next stage, the researchers cultured GFP-labeled iPS cells under various conditions using growth factor solutions affecting their development.

"Thanks to our newly established surface cell markers, we were able to detect and isolate Flt1- and flt4-positive CPCs in culture," says Professor Schenke–Layland. "With further in vitro cultivation, the isolated mouse CPCs did develop–as did progenitor cells derived from embryonic stem cells-into endothelial cells, smooth muscle cells and, more interestingly, into functional heart muscle cells."

But how do CPCs derived from induced pluripotent stem cells behave in living organisms? Can they really integrate into the tissue and repair the heart muscle? To answer these questions, the scientists injected GFP-labeled CPCs into the hearts of live mice. After 28 days, they examined these hearts and saw that the green fluorescent cells had developed into beating heart muscle cells and were fully integrated into the myocardial tissue.

Cardiovascular progenitor cells (green) derived from GFP-labeled induced pluripotent stem cells injected into the heart of a live mouse (red) are integrated into the functional tissue of the heart muscle. The cell nuclei are marked in blue. (Photo: © Fraunhofer IGB)

Scientists have been trying to stimulate the regeneration of myocardial cells for a long time. To do this, they inject stem cells or cardiomyocytes derived from stem cells into the heart. Although in most cases some improvement in heart function has been recorded, neither long-term integration nor differentiation of stem cells into cardiomyocytes has been demonstrated.

The results obtained by Schencke-Layland, Nzair and McLennon for the first time provide the possibility of obtaining functional heart muscle cells capable of integrating into the myocardium.

"Right now we are focusing on studying human iPSCs. If it can be shown that cardiovascular progenitor cells capable of maturing into functional cardiac muscle can be obtained from human induced pluripotent stem cells, then we have really found a solution for patients with heart attack," the scientist hopes.

Article by Ali Nsair et al. Characterization and Therapeutic Potential of Induced Pluripotent Stem Cell-Derived Cardiovascular Progenitor Cells Characterization and Therapeutic Potential of Induced Pluripotent Stem Cell-Derived Cardiovascular Progenitor Cells is published in the journal PLOS ONE.

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