To identify efficient inducers for cardiac differentiation and maturation of iPSCs and elucidate the mechanisms, a team of researchers, led by Dr. YANG Huangtian, at the Institute of Health Science, Key Laboratory of Stem Cell Biology, CAS, identified a suitable cardiomyoycte inducer, ascorbic acid (AA) and established an universal, economical, and efficient system for producing cardiac progenitor cells (CPCs) and functional cardiomyocytes from various mouse (m) and human (h) iPSCs lines, established by Institute of Biochemistry and Cell Biology, Institute of Zoology, Institute of Health Sciences, Guangzhou Institutes of Biomedicine and Health, CAS.

They systematically screened sixteen cardiomyocyte inducers on various miPSCs and found that only AA consistently and robustly enhanced the cardiac differentiation of eleven lines including eight without spontaneous cardiogenic potential. They then optimized the treatment conditions and demonstrated that a period for the specification of CPCs was a critical time for AA to take effect. Noteworthily, AA treatment led to approximately 7.3-fold (miPSCs) and 30.2-fold (hiPSCs) augment in the yield of iPS-CMs. Such effect was attributed to a specific increase in the proliferation of CPCs via the MEK-ERK1/2 pathway through promoting collagen synthesis by using pharmacological approaches combined with the down-regulation of specific genes. In addition, they found that AA promotes the structural and functional maturation of iPS-CMs, reflected by improved sarcomeric organization, increased expression of calcium-handling proteins, more mature phenotype of Ca2+ transients, and higher responses to β-adrenergic and muscarinic stimulations of AA-induced iPS-CMs. These findings provided the first pro-maturation method that works on iPS-CMs. Their data demonstrate that AA is a suitable cardiomyocyte inducer for iPSCs to improve cardiac differentiation and maturation simply, universally, and efficiently. Their findings also highlight the importance of stimulating CPC proliferation by manipulating extracellular microenvironment in guiding the cardiac differentiation of pluripotent stem cells. The discoveries in this study are useful to study the potential of iPSCs in scientific studies, drug discovery and toxicity testing, and patient-specific cardiac regenerative medicine.

The research was online published in Cell Res on 6 December, 2011 entitled “Ascorbic acid enhances cardiac differentiation of induced pluripotent stem cells through promoting the proliferation of cardiac progenitor cells”, supported by grants from the National Basic Research Program of China, National Natural Science Foundation of China, Science and Technology Committee of Shanghai Municipality, and Sanofi-Aventis Recherche & Développement-SIBS funding.

AUTHOR CONTACT:
YANG Huangtian
Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Phone: 86-21-63852793; Email: htyang@sibs.ac.cn