© Borgis - Postępy Nauk Medycznych 7/2014, s. 496-501
Naturalna i terapeutyczna regeneracja serca
Natural and therapeutic myocardial regeneration
Institute of Clinical Physiology, Center of Medical Postgraduate Education, Warszawa
Head of Institute: prof. Andrzej Beręsewicz, MD, PhD
Pomimo intensywnej farmakoterapii pozawałowa niewydolność serca jest jedną z głównych przyczyn zgonów na świecie. U podłoża problemu leżą zaburzenia równowagi pomiędzy szybkością wymierania kardiomiocytów a ich regeneracją w niedokrwionym sercu. Wynik badań eksperymentalnych i pierwsze próby kliniczne sugerują, że terapia komórkami macierzystymi może być skutecznym uzupełnieniem pierwotnej angioplastyki wieńcowej i może zapobiegać rozwojowi niewydolności serca. W leczeniu chorób serca podjęto próby wykorzystania jednojądrzestych komórek szpikowych (BM MNC), mioblastów mięśni poprzecznie prążkowanych, mezenchymalnych komórek macierzystych (MSC), sercowych komórek macierzystych (CSC), embrionalnych komórek macierzystych (ESC) oraz indukowanych pluripotencjalnych komórek macierzystych (iPSC). Obecnie panuje opinia, że korzystne efekty terapii komórkowej mają związek z korzystnym działaniem różnych substancji czynnych produkowanych przez komórki macierzyste a nie z ich zdolnością do tworzenia nowych kardiomiocytów. Niniejsza praca przedstawia aktualną wiedzę na temat naturalnej regeneracji miokardium. Podsumowuje możliwości wykorzystania różnych subpopulacji komórek macierzystych w terapii regeneracyjnej niedokrwionego mięśnia sercowego oraz opisuje potencjalny mechanizm ich działania.
Despite intensive therapy post-infarction heart failure remains the leading cause of mortality worldwide. Heart failure is a progressive condition involving imbalance between cardiomyocytes death and cardiomyocytes renewal in the myocardium after ischemic damage. Stem cell-based therapy is particularly attractive because it could work additively with primary coronary angioplasty and can prevent development of heart failure. Recent therapeutic approaches involve bone marrow mononuclear cell (BM MNC), skeletal myoblasts, mesenchymal stem cells (MSC) and cardiac stem cells (CSC), embryonic stem cells (ESC) and induced pluripotent stem cells (iPSC). The beneficial effect of stem cells is not restricted to their ability to differentiate, but is more likely to their ability to secrete a multitude of factors that modulate inflammation, apoptosis, angiogenesis, scar formation and endogenous cardiac stem cells activation. This review focuses on the natural heart regeneration. In addition, it summarizes the evidence related to use of sub-populations of stem cell as a treatment for ischemic injury, and discusses possible mechanisms of action.
NATURAL MYOCARDIUM REGENERATION
Until recently it was thought that human heart (like other mammals’ heart) is a terminally differentiated postmitotic organ. It was believed that shortly after birth cardiomyocytes lose their ability to proliferate and from this moment their amount is constant and further growth is by increasing the size of existing cells (hypertrophy). The following observations resulted in changing this dogma:
1. Between birth and early youth cardiomyocytes number increases (hyperplasia). In newborns both heart ventricles are built from ~1 x 109 cardiomyocytes while in 20-year-olds their amount is several times larger – in males there are ~5.8 x 109 cardiomyocytes in the right ventricle and 2.0 x 109 cardiomyocytes in the left ventricle, in women there are ~4.5 x 109 and 1.4 x 109 respectively (1).
2. Apart from apoptosis (2) and necrosis (3) in myocardium, the total number of cardiomyocytes in an adult heart is on a relatively constant level. It means that dying cardiomyocytes are replaced by new cells which are created from specific cardiac stem cells (2). Estimated calculations based on the 14C concentration measurements in myocardium of people exposed to increased 14C concentration in the air in the youth (as a result of nuclear tests in the cold war period) suggest that cardiomyocytes are renewed with gradual decrease from ~1% turning over annually at age 20 to ~0.45% at the age 75. It means that during a norma lifespan about 50% cardiomyocytes would be exchanged (4). Newer analyses taking the frequency of apoptosis in myocardium into consideration show that the turnover of cardiomyocytes in human heart is much faster and this process even accelerates with age (5). According to these estimates in male heart cardiomyocytes replacement occurs at a rate 7, 12 and 32% per year at 20, 60 and 100 years of age. In women this process is even more intense and corresponding values are 10, 14 and 40% per year, respectively. It means that cardiomyocytes are renewed 11-15 times between 20 and 100 years of age. The rest of myocardial cells such as fibroblasts and endothelial cells are also dynamically restored (6).
3. The chimerism phenomenon. In males who had female heart transplanted after some time there are cardiomyocytes, endothelial cells and smooth muscle cells with male Y chromosome in myocardium (7). The similar phenomenon is observed in women being recipients of male bone marrow, with time in their myocardium there are cells with chromosome Y (8). These results suggest recruitment of peripheral stem cells to the heart (e.g. from the bone marrow) and creating myocardial cells de novo.
4. Cardiac stem cells (CSC) are the cells reside in the myocardium that can differentiate into cardiomyocytes, smooth muscle cells, endothelial cells and fibroblasts. At present there is not any good marker allowing to identify them and CSC include several subpopulations: (a) cell expressing receptor c-kit, (b) cell expressing stem cell antigen 1 (Sca 1), (c) cell expressing transcription factor Isl 1, (d) cells abilities to efflux the Hoechst 33342 dye so called side-population (SP) cells and (e) cardiosphere-derived cells (9-11). In the heart CSC are stored in a special structure called niches located in the apex and atria. CSC are sensitive to substances released from damaged cardiomyocytes, inter alia hepatocyte growth factor (HGF) and vessel endothelium growth factor (VEGF). These factors promote CSC proliferation and their migration from niches to damaged myocardial areas (12). According to the theory that in tissues there are heterogeneous populations of stem cells directed to different tissues and organs, CSC may also be found in bone marrow and peripheral organs.
Research of the past years show that cardiomyocytes lost in physiological apoptosis and/or necrosis are replacement by new cells formed by asymmetric mitotic divisions of cardiac stem cells. In pathological conditions there may be disturbances in the natural processes of heart regeneration. This may be a result of increase in apoptosis/necrosis of myocardial cells or impairment of regeneration abilities of cardiac stem cells. As a result it may lead to net loss of constrictive cells with the following remodeling, hemodynamic decompensation and heart failure. For years there has been intensive research on the possibility of increasing regenerative potential of the heart and using it in treatment for acute myocardial infarction and post--ischemic heart failure.
THERAPEUTIC STRATEGIES IN HEART REGENERATION
At present there are two treatment strategies of increasing regenerative potential of the heart. The first is to increase the regenerative ability of myocardium by mobilization of endogenous bone marrow derived and cardiac stem cells. Experimental studies in this field showed that application of SCF (stem cell factor) and G-CSF (granulocyte colony stimulating factor) to mice with myocardial infarction leads to mobilization of bone marrow stem cells. After 27 days the infarcted area was occupied by 15 x 106 new cardiomyocytes, which resulted in 40% reduction of the infarct size. There were also new microvessels and hemodynamic parameters improved (13). However, the results of the clinical research on the influence of pharmacological stem cell mobilization from bone marrow by G-CSF in patients with acute myocardial infarction are unclear (14).
The second strategy is to increase the number of progenitor cells in the myocardium by application of different types of exogenous stem cells, which could potentially repair damaged myocardium. The direction of this research was determined by pioneer works of the Anversa’s group (15), which showed that the subpopulation of mononuclear marrowy stem cells injected directly in the damaged mouse heart is able to regeneration it. After 9 days from cells application about 68% of the infracted area was occupied by newly formed cardiomyocytes, there were new and there was improvement in hemodynamic parameters of the left ventricle. Using exogenous stem cells, their different subpopulations, in regenerative heart therapy is at present the most dynamic field of research.
STEM CELLS AND THEIR THERAPEUTIC POTENTIAL
Stem cells are undifferentiated cells with the ability to (a) unlimited number of divisions (proliferation) which leads to their self-renewal and (b) differentiation into specialized types of cells (fig. 1). The direction of differentiation depends on the environmental conditions and so called differentiation potential of stem cells (fig. 2) (16). In heart diseases treatment, mainly in acute myocardial infarction treatment, there were attempts of using skeletal myoblasts, bone marrow mononuclear cells, mesenchymal stem cells, cardiac stem cells and embryonic stem cells (fig. 3).
Fig. 1. Divisions and differentiation of stem cells.
Fig. 2. The stem cells differentiation potential in the embryonic mammal development, based on Beręsewicz (16).
SC – stem cells
Fig. 3. Kinds of stem cells with potential therapeutic features and the sources of their extraction.
BM MNC – mononuclear cells derived bone marrow; HSC – hematopoietic stem cells; EPC – progenitor endothelial cells; MSC – mesenchymal stem cells; ESC – embryonic stem cells; iPSC – induced pluripotential stem
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