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How Embryonic Stem Cells could treat Heart Disease
Embryonic Stem Cells are one of the most studied forms of stem cell, and recent research by Dr. Kumar's team with the University of Vermont brings us one step closer to using them to treat heart disease by regenerating the tissue of the heart itself. But just how could it be done?
Embryonic Stem (ES) cells can be induced to differentiate into cardiac myocytes. Pure differentiated cardiac myocytes obtained after treatment in specific conditions with presence of several growth factors (Cai and Zhu 2004) are then implanted into the
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Transforming growth factor-β (TGF- β) isoforms (β1, β2 and β3) are integral growth factors for heart development (Kumar and Sun 2005). TGF-β consists of a superfamily of polypeptide growth factors and is expressed together with its receptors in virtually almost every cell in the body. TGF-β is involved in regulating proliferation, embryonic development, differentiation and apoptosis in cells (Huang et al 2004).
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| Embryonic Stem Cells to Cardiomytes |
The signaling pathway begins with TGF-β binding to its transmembrane receptor to produce stable and active heterotetrameric TGF-β receptor complexes (Winkler et al 2004). The heteromeric receptor complex formed has both type I (TGF-βRI) and type II (TGF-βRII) serine/threonine kinase receptors. Phosphorilation of type II receptor kinase subsequently activates the type I receptor kinase. Activated receptor kinase then propagates the signal to downstream effectors and regulatory proteins like smad proteins. These proteins are then activated and translocated to the nucleus. Here they act as intermediaries and are capable of affecting the transcriptional responses.
Kumar and Sun 2005 compared levels of cardiac myocytes differentiation from mouse ES cells for all three of the TGF-β isoforms from mouse ES cells. They found that TGF-β 2 increases the protein expression of cardiac specific a-actin, which stain positive for the presence of cardiac myocytes. The beating cardiac myocytes derived from TGF-β 2 were also more elongated and larger compared to the cardiac myocytes of the other isoforms making them more functional. There was also more cell to cell attachment that makes it possible for formation of cell-cell junction. Therefore they concluded that TGF-β 2 and not TGF-β 1 or TGF-β 3 increases cardiac differentiation derived from mouse ES cells.
Although cell differentiation from embryonic stem cell produces promising results, certain glitches in the techniques need to be tackled first. For example, mixed cell types causes undifferentiated ES cells that may form teratocarcinomas in the recipient. This problem can be avoided if lineage selection is done using selectable markers (Winkler et al 2004). Another setback is that the host's immune system might reject the foreign cells. This can be solved when the immune system is suppressed or the genetic information of the transplanted cells is modified.
ReferencesCai WJ, Zhu YC. 2004. Progress on embryonic stem cells for the treatment of myocardial infarction. Sheng Li Ke Xue Jin Zhan;35(3):205-9
Dinender Kumar, Baiming Sun. 2005. Transforming growth factor-β enhances differentiation of cardiac myocytes from embryonic stem cells. Biochemical and Biophysical Research Communications;332:135-141
Huang CY, Kuo WW, Chueh PJ, Tseng CT, Chou MY, Yang JJ. 2004. Transforming growth factor-β induces the expression of ANF and hypertrophic growth in cultured cardiomyoblast cells through ZAK. Biochemical and Biophysical Research Communications; 324(1):424-431
Kofidis T, de Bruin JL, Hoyt G, Ho Y, Tanaka M, Yamane T, Lebl DR, Swijnenburg RJ, Chang CP, Quertermous T, Robbins RC. 2005. Myocardial restoration with embryonic stem cell bioartificial tissue transplantation. J Heart Lung Transplant.;24(6):737-44
Winkler J, Hescheler J, Sachinidis A. 2004. Embryonic stem cells for basic research and potential clinical applications in cardiology. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease; 1740(2):240-248
