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- A step closer to understanding the heart
- 新たに判明 がんの転移を促進するメカニズム
A step closer to understanding the heart
Daniela Yumi Kitashima
Department of Dermatology
Jan Kajstura／Circ Res. 2010 Nov 26;107(11):1374-86. Epub 2010 Nov 18.
Kajstura J, Gurusamy N, Ogorek B, Goichberg P, Clavo-Rondon C, Hosoda T, D'Amario D, Bardelli S, Beltrami AP, Cesselli D, Bussani R, del Monte F, Quaini F, Rota M, Beltrami CA, Buchholz BA, Leri A, Anversa P. Myocyte turnover in the aging human heart. Circ Res. 2010 Nov 26;107(11):1374-86. Epub 2010 Nov 18.
Cardiac regeneration has long been a dream of medicine. Heart disease leads the cause of death in developed countries and reach large proportion worldwide being a public health problem in many countries. The main mechanism of disease is cardiomyocytes*1 death, due to a limited capacity for muscle renewal upon injury. With scant capacity to regenerate dead cells, the heart cannot fulfill its function satisfactorily. Thus, rescuing cardiac muscle cell number and its function in the patients who are suffering of heart disease might help millions of people every year.
To achieve this ambitious goal, in recent years people have mainly concentrated on investigating adult and embryonic stem cells as well as potential source of exogenous stem cells and their influence on cardiac regeneration. Recent studies have documented that a tissue-specific stem cells resides in the human heart. It means that these stem cells can form new cardiomyocytes to replace old, dying cells within the myocardium in physiological conditions. It is extremely important to understand the mechanism involved in physiological turnover of cardiomyocytes and the origin of newly formed cells to apply this knowledge in so challenging cardiac regeneration.
Thus far, heart was considered an organ composed of a predetermined number of myocytes, which is established at birth and is preserved throughout life. Jan Kajstura et al. showed a novel conceptual framework of the heart: a self-renewing organ characterized by resident Human cardiac stem cells (hCSCs) stored in niches that controls the physiological turnover of cardiac cells. They studied the myocyte characteristics of 32 female and 42 male human hearts from patients 19 to 104 years of age who died from causes other than cardiovascular disease. They determined the level of p16INK4a protein that is associated with apoptosis*2. The rates of cell death found suggest a massive loss of myocytes with aging. If we consider the number of cells present in the left ventricle, the myocardium would diaper with time. In the absence of myocyte formation, only 5% of cardiomyocytes would persist at 63 and 48 years of age in women and men respectively. Thus, myocyte regeneration has to play a major role in the preservation of tissue mass and function of the aging human heart.
The possibility that a certain degree of myocyte regeneration occurs in the human heart is currently accepted, but questions persist concerning the origin of newly formed cardiomyocytes and the magnitude of myocyte regeneration. Kajstura's group study indicates that myocyte regeneration increase as a function of age as well as the pool of functionally competent Human cardiac stem cells (hCSCs) that generates a larger myocyte progeny. They showed that from 20 to 100 years of age, the yearly rate of myocyte turnover increases from 10% to 40% in female heart and from 7% to 32% in the male heart. From 19 to 104 years of age, essentially none of the myocytes present at bird is preserved in the young adult, middle-aged, and senescent hears. Furthermore, a mathematical analysis showed amazingly that the myocyte compartment is replaced 15 times in women and 11 times in men.
On the other hand, it is established that human aging is associated with a senescent cardiac phenotype defined by old cardiomyocytes, which have depressed mechanical performance. Thus, there is an apparent paradox between the increase in the number of senescent myocytes and the increase in myocyte renew with aging. If myocyte regeneration is increased with aging, it is expected that myocytes keep young. In an attempt to clarify this enigma, Kajstura's group measured telomere*3 length in hCSC and myocytes of 20 hearts. They found that old cardiac stem cells with severely shortened teomeres generate a myocyte progeny that rapidly acquires a senescent cell phenotype.
Organ aging and telomere length in hCSCs and myocytes. A through C, Detection of telomeres by Q-FISH (white dots) in c-kit-positive hCSCs (green arrows) and cardiomyocytes in the young female (A) and in the young (B) and old (C) male heart.
It means that a progressive loss of telomeric DNA in hCSCs occurs with aging and, although the pool of functionally competent hCSCs expands with the time and generates a larger myocyte progeny, the newly formed cardiomyocytes inherit short telomeres and rapidly reach the senescent cell phenotype. Aged hCSCs appear to generate old myocytes that may have severely depresses mechanical performance and alterations in calcium metabolism, contributing to the manifestations of aging myopathy in elderly.
In summary, this study brings us now closer to understanding human myocardial biology in terms of regeneration. The human heart is a highly dynamic organ regulated by a pool of resident hCSCs that modulate cardiac homeostasis and condition organ aging. If the human heart has innate regenerative response, it may be possible to exploit this therapeutically to enhance the heart's function upon injury. Thereby who knows, we are a step closer to open the door of the great dream of medicine: cardiac regeneration.
- *1 muscle cells of heart
- *2 programmed cell death
- *3 region of repetitive DNA sequences at the end of a chromosome
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