|Result by researchers of the Institute of Health published on-line in the journal of Cell Research|
Cardiac cells differentiated from induced pluripotent stem cells (iPSCs) have profound influence in medication screening, regeneration of cardiac muscle, and research on cardiac developmental biology, and provide a unique in vitro model for research on human heart diseases. However, spontaneous differentiation of iPSCs shows a low efficiency, and cardiac cells so differentiated often have a low level of maturity in their functions, with different potentials in differentiation between various strains. Consequently, one of the important prerequisites for the research result to be applicable is to clearly determine the key links and control mechanisms in directional differentiation, and establish reliable, efficient, low-cost and simple ways to generate required functional cardiac cells differentiated from iPSCs.
Doctoral student Zao Nan and others of the research team on molecular cardiology, a research project of the Institute of Health Sciences and Stem Cell Biology Key Laboratory under the Chinese Academy of Sciences, under the supervision of Research Fellow Yang Huang-tian, screened 16 chemicals for cardiac differentiation of iPSCs, using 11 different strains of iPSCs established respectively by the Institute of Animal Study under the Chinese Academy of Sciences, the Institute of Biochemistry and Cells of the Shanghai Academy of Life Sciences, the Institute of Health Sciences, and Guangzhou Institute of Biomedicine and Health Sciences. The team found that only ascorbic acid (AA) enhances cardiac differentiation of iPSCs with great consistence and efficiency. By comparing treatments with AA at various concentrations and at different points of time, the research team was able to establish a system for cardiac differentiation of induced pluripotent stem cells in a simple, low-cost, and efficient way. The efficiency in the tests on mice and humans increased about 7.3 times and 30.2 times respectively, while difference in differentiation among different strains of iPSCs, including those with little or no spontaneous potential for differentiation, was markedly reduced. Further research on mechanisms found that AA enhances cardiac differentiation of iPSCs by promoting the secretion of extracellular collagen, thus activating MEK-ERK1/2 pathway, which, in turn, specifically promotes the proliferation of cardiac progenitor cells. Besides, the team found through an analysis of the structure and function that cardiac cells differentiated with AA intervention displayed a higher maturity in electrical and calcium activities, a more orderly arrangement of muscle fibers, and a markedly increased response to regulatory signals for important cardiac functions, a clear indication that AA enhances the level of maturity in cardiac cells differentiated from iPSCs. The research further revealed that the extracellular microenvironment plays an important regulatory role in enhancing cardiac differentiation of iPSCs and promoting the proliferation of cardiac progenitor cells. The simple, low-cost, and efficient system established for cardiac differentiation of iPSCs of mice and humans will be a great help in the use of iPSCs in applied research in fields such as the development of heart diseases, medication screening, regeneration of cardiac muscle, etc.
The research result was published on-line in Cell Research on Dec. 6, 2011. (Ascorbic acid enhances cardiac differentiation of induced pluripotent stem cells through promoting the proliferation of cardiac progenitor cells). The research fund was granted by the State Ministry of Science and Technology, the National Foundation of Natural Sciences, the Chinese Academy of Sciences, and Sanofi-Aventis Recherche & Développement-SIBS fundin.