Universal cardiac induction of human pluripotent stem cells in two and three-dimensional formats: implications for in vitro maturation

Miao Zhang, Jan Sebastian Schulte, Alexander Heinick, Ilaria Piccini, Jyoti Rao, Roberto Quaranta, Dagmar Zeuschner, Daniela Malan, Kee-Pyo Kim, Albrecht Röpke, Philipp Sasse, Marcos Araúzo-Bravo, Guiscard Seebohm, Hans Schöler, Larissa Fabritz, Paulus Kirchhof, Frank Ulrich Müller, Boris Greber

Research output: Contribution to journalArticlepeer-review

54 Citations (Scopus)


Directed cardiac differentiation of human pluripotent stem cells (hPSCs) enables disease modeling, investigation of human cardiogenesis, as well as large-scale production of cardiomyocytes (CMs) for translational purposes. Multiple CM differentiation protocols have been developed to individually address specific requirements of these diverse applications, such as enhanced purity at a small scale or mass production at a larger scale. However, there is no universal high-efficiency procedure for generating CMs both in two-dimensional (2D) and three-dimensional (3D) culture formats, and undefined or complex media additives compromise functional analysis or cost-efficient upscaling. Using systematic combinatorial optimization, we have narrowed down the key requirements for efficient cardiac induction of hPSCs. This implied differentiation in simple serum and serum albumin-free basal media, mediated by a minimal set of signaling pathway manipulations at moderate factor concentrations. The method was applicable both to 2D and 3D culture formats as well as to independent hPSC lines. Global time-course gene expression analyses over extended time periods and in comparison with human heart tissue were used to monitor culture-induced maturation of the resulting CMs. This suggested that hPSC-CMs obtained with our procedure reach a rather stable transcriptomic state after approximately 4 weeks of culture. The underlying gene expression changes correlated well with a decline of immature characteristics as well as with a gain of structural and physiological maturation features within this time frame. These data link gene expression patterns of hPSC-CMs to functional readouts and thus define the cornerstones of culture-induced maturation.

Original languageEnglish
Pages (from-to)1456-69
Number of pages14
JournalStem Cells
Issue number5
Early online date31 Jan 2015
Publication statusPublished - May 2015


  • cardiac differentiation
  • human pluripotent stem cells
  • in-vitro maturation


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