Human embryonic stem cells, and embryonic-like induced pluripotent stem cells made from adult human skin, can differentiate to form beating cardiac muscle cells (cardiomyocytes). These stem cell-derived cardiomyocytes (SC-CM) are being investigated for use in cardiac repair, but also as a model system for research or drug toxicology. Their human origin, stability in culture and ability to be easily genetically modified in culture makes them far superior to present sources. Immediately after differentiation, SC-CM have the characteristics of immature foetal or neonatal cells in terms of contraction, growth and intracellular signalling. To realize their full potential, they need to grow towards the adult cardiomyocyte in these respects. We have evidence that this occurs in culture, over time-frames of 3-6 months, and that reproducing the stimuli for maturation can produce or accelerate these changes. One key maturational stimulus is thyroid hormone, and the first part of the project will apply this to SC-CM. However, the foetus has evolved sophisticated mechanisms to protect itself from maternal thyroid hormone, to prevent premature development. Intrinsic enzyme systems and receptor expression levels carefully control the intracellular environment with respect to levels of T3, the active agent, to preserve the natural staged differentiation and maturation programme. Particularly, an enzyme called D3 keeps levels of T3 tonically low. In the second time we will investigate the synergistic effects of adding T3 and down-regulating D3 on the rate and extent of maturation of the SC-CM. In the adult, cardiac growth programmes in response to increased load (hypertension for example) have been classified as pathological, while that controlled by thyroid hormone has been defined as physiological. In the third time we will compare the characteristics of SC-CM after T3-induced growth with our previous findings on stretch- or catecholamine-induced growth.
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