Cardiomyocytes from fibroblasts
Three types of Heart cells from Skin cells
LifeSciencesToday by Gladstone Institutes: New Method for Producing Heart Cells May Hold the Key to Treating Heart Failure
Scientists from the Gladstone Institutes have developed a method for obtaining a new type of cell that occupies an intermediate position between embryonic stem cells and adult heart cells. Cells of this type may be the key to the treatment of heart failure. Induced expandable cardiovascular progenitor cells, (abbreviated ieCPCs), can organically differentiate into heart cells, while maintaining the ability to reproduce themselves. The introduction of such cells to mice with a model of myocardial infarction significantly improves heart function.
Photo: Yu Zhang
"For decades, scientists have been trying to treat heart failure by transplanting adult heart cells, but these cells do not reproduce and therefore do not survive in a damaged heart," explains Yu Zhang, MD, PhD, lead author of the study. "Our ieCPCs effectively self-replicate and reliably differentiate into three types of heart cells, making them a very promising potential treatment for heart failure."
Cardiovascular progenitor cells (CPCs) are naturally formed during the formation of the embryo's heart and give rise to various types of heart cells. In this study published in the journal Cell Stem Cell (Zhang et al., Expandable Cardiovascular Progenitor Cells Reprogrammed from Fibroblasts), scientists managed to create CPCs in the laboratory. Pharmaceutical preparations were used to isolate this population of heart stem cells and delay it at the stage of cardiac progenitors, preventing it from differentiating into fully functional heart cells.
Stem cell-based approaches to heart regeneration are becoming more and more effective strategies for treating heart failure. However, obtaining a large number of functional autologous cells for transplantation remains a serious problem. Scientists from the Gladstone Institutes have isolated a population of cells with unlimited proliferation capacity and differentiation potential limited by cells of the cardiovascular system during transdifferentiation of mouse fibroblasts. These cells – induced expandable cardiovascular progenitor cells, ieCPCs – proliferate extensively in more than 18 passages under chemically defined conditions. Out of 105 initial fibroblasts, 1016 ieCPCs can be obtained. They demonstrate the signatures of heart genes and differentiate in vitro into functional cardiomyocytes, endothelial cells and smooth muscle cells. When transplanted into the heart of mice with a model of myocardial infarction, ieCPCs spontaneously differentiate into the three above-mentioned types of heart cells. Improvement of heart function is observed within 12 weeks after transplantation. (Fig. Cell Stem Cell)
Organ-specific stem cells are special, since they can both differentiate into stem cells of an adult organism and reproduce themselves indefinitely. In this study, ieCPCs were reproduced exponentially for more than a dozen generations, creating enough cells to treat many potential patients. This type of self-renewal is especially important for the treatment of heart failure, as more than a billion cells are lost as a result of myocardial infarction. Effective cell renewal means that CPCs can be a reliable way to replace these damaged cells. In addition, ieCPCs can develop into any of three different types of heart cells – cardiomyocytes, endothelial cells and smooth muscle cells. When injected into the heart, they spontaneously differentiate into these cells without any additional signals.
Previous attempts to treat heart failure by transplanting adult heart cells have practically failed, because new cells die quickly and do not self-renew, which means that their ability to repopulate the diseased organ is limited. In addition, for transplantation, as a rule, heart cells of only one type are used – cardiomyocytes, or cells capable of contraction of the heart muscle, but for the restoration and normal functioning of the heart, all three types of cells are required. The introduction of non-cardiac stem cells into the heart has also had limited success in the treatment of heart failure, since these cells practically do not differentiate into heart cells. Differentiation in this direction requires complex signals that are absent in the adult heart. In addition, non-cardiac stem cells increase the risk of tumor formation, since many of them differentiate not into heart cells, but into other types of cells. ieCPCs allow you to avoid this problem, because their fate – to become heart cells – is already predetermined.
In the current study, 90% of ieCPCs injected and preserved in the heart of mice with the myocardial infarction model successfully differentiated into functioning heart cells, contracting together with existing cells and creating new blood vessels. ieCPCs progenitors significantly improved the pumping function of the heart, and the effect of their administration was observed for at least three months. Since these cells are obtained from skin cells, the way opens up to personalized medicine using the patient's own cells.
"Cardiac progenitor cells can be an ideal means for heart regeneration," commented the head of the study Sheng Ding, PhD, on this achievement. "They are the closest precursors of functional heart cells, and, in one step, they can quickly and efficiently become heart cells, both in a Petri dish and in a living heart. Our new technology allows us to quickly obtain billions of these cells in a test tube, and then transplant them into a damaged heart for the treatment of heart failure."
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