Producing heart cells from skin cells made it possible to discover defects that lead to heart failure
Not everyone can do everything. But pluripotent stem cells are probably the most notable exception to this rule. These are cells that can differentiate and become any type of body cell (for example, muscle cells, nerve cells, pancreas - and also heart cells). In advanced medicine, it is possible to transplant such cells - and strengthen, renew and heal damaged tissues in this way. This relatively new and advanced medical field is called regenerative medicine. The difficulty is that these types of stem cells exist in a developing embryo, so the ability to use them is very limited. This is where induced pluripotent stem cells (iPSC) come into play. These cells are produced from mature cells such as skin cells or white blood cells, which are relatively easy to obtain and use. These adult cells undergo genetic programming that causes them to "move backwards" in the journey of differentiation and "return to childhood" - so that they can, once again, differentiate and become the different cells of the body. The induced stem cells can be grown in culture, frozen and used for many years.
Prof. Ofer Bina and Prof. Eyal Gottlieb from the Technion; and Prof. Michael Arad from the Sheba Medical Center, use this technology to create heart cells. They take mature cells from patients with hereditary heart disease and produce from them induced stem cells that carry the genetic mutation that caused the heart disease. In this way, the heart cells that differentiated from those stem cells also carry the mutation and serve as a cellular model of the disease.
The electrical and mechanical activity of these heart cells is similar to that of the human heart, and thus researchers can learn about many aspects of heart function, such as electrical-mechanical coupling, intracellular calcium release (which contributes to heart contraction) and action potentials (changes in the electrical voltage across the cell membrane) ), and the reactions of the heart to various drugs. Additional studies in this field allow the creation of retinal and heart tissues that could replace damaged or diseased tissues, but the studies in the heart muscle are still in the experimental stages.
Bina, Gottlieb and Arad's goal is to study the healthy and diseased heart, and thus try to develop treatments for hereditary heart diseases. Today they are focusing on Duchenne Muscular Dystrophy - an incurable muscular dystrophy caused by a mutation in the gene responsible for the production of the protein dystrophin, which is essential for the normal contraction of muscle-skeletal cells and heart cells. In the first years of life of patients with this disease, the main manifestation of the disease is the loss of skeletal muscle mass and the diaphragm, which causes difficulties in mobility, disability and severe breathing problems. With puberty (in the late teens), the patients develop a serious heart disease (cardiomyopathy - the most common congenital heart disease). Most patients die around the age of 30 due to respiratory or cardiac collapse.
Bina, Gottlieb and Arad study the pathological heart characteristics of Duchenne patients; They take mature cells from them (skin cells), turn them into pluripotent stem cells, and produce heart cells from them. Since the skin cells carry the mutation that causes the disease, the heart cells that are formed from them are also diseased, thus serving as a model of the disease and exhibiting different pathophysiological properties.
In one of their latest studies, which won a research grant from the National Science Foundation, the researchers used advanced metabolomic methods to measure hundreds of metabolites (compounds produced during cell metabolism) in the diseased heart cells (compared to cells produced from a healthy person). The researchers also examined in the cells (the sick and the healthy) the function of the mitochondria (an intracellular organelle that produces a significant part of the chemical energy needed by the body's cells). This is how they were able to discover that the mutation causes a decrease in the level of essential metabolites, an impairment of the respiratory function in the mitochondria, and a decrease in the ability of the heart cells to produce energy. Following these and other injuries, the heart cells collapse, until the heart's function is severely damaged.
The researchers also used electrophysiological methods to study the electrical activity of the diseased heart cells, and found that it is abnormal and includes arrhythmias that can be fatal for Duchenne patients and cause cardiac death.
In another part of the study, the scientists examined the ability of norepinephrine / epinephrine (stimulating substances that are secreted from the sympathetic nervous system mainly in a state of mental or physical stress), to increase the contraction force of the diseased heart cells compared to all the contraction of healthy heart cells. It was found that the reaction of the diseased heart cells to these substances is much less than that of the healthy cells. This finding explains the poor cardiac activity of Duchenne patients and the difficulty of the patient's heart to respond to stressful situations and physical activity. This poor response to norepinephrine / epinephrine is due to the fact that the mutation impairs the ability of the cells to mobilize calcium ions from intracellular stores necessary for the contraction of the heart muscle.
The researchers hope that based on these and other findings, it will be possible to develop new drugs or use existing drugs more effectively, to improve the heart defects of Duchenne patients, and in this way improve their condition and even extend their lives.
Life itself:
"It is not clear how and why I decided to become a scientist," says Prof. Bina. "Especially in view of the fact that I was not one of the best at school. Apparently, the energy that was not 'wasted' in high school was later used to create a scientific career." When he was not engaged in scientific research, Bina liked to engage in gardening (which was relevant when he and their family lived in a scenic settlement). Another love of his are fascinating vacations, for example, in Vietnam and Guatemala.
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