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Proteomics. 2018 Jul;18(14):e1800102. doi: 10.1002/pmic.201800102. Epub 2018 Jun 27.

Quantitative Secretomics Reveals Extrinsic Signals Involved in Human Pluripotent Stem Cell Cardiomyogenesis.

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Institute of Clinical Biochemistry, Hannover Medical School, 30625, Hannover, Germany.
REBIRTH Cluster of Excellence, Hannover Medical School, 30625, Hannover, Germany.
Institute of Toxicology, Hannover Medical School, 30625, Hannover, Germany.
TWINCORE, Centre for Experimental and Clinical Infection Research, 30625, Hannover, Germany.
Leibniz Research Laboratories for Biotechnology and Artificial Organs, Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, 30625, Hannover, Germany.


Human pluripotent stem cells can be differentiated in vitro into cardiomyocytes (CMs) but the molecular mechanisms behind this process are still not fully understood. In particular, the identification of morphogens remained elusive because the mass spectrometry-based identification of secreted proteins from cell culture supernatants is impeded by high levels of albumin present in common differentiation media. An albumin-free cardiomyogenic differentiation medium is established in this study and applied for secretomics at seven different time points during in vitro differentiation. By this analysis 4832 proteins are identified with 1802 being significantly altered during differentiation and 431 of these are annotated as secreted. Numerous extrinsic components of Wnt, TGFβ, Activin A, Nodal, BMP, or FGF signaling pathways are quantitatively assessed during differentiation. Notably, the abundance of pathway agonists is generally lower compared to the respective antagonists but their curves of progression over timer were rather similar. It is hypothesized that TGFβ, Activin A, and Nodal signaling are turned down shortly upon the initiation of cardiac differentiation whereas BMP signaling is switched on. Wnt and FGF signaling peaks between d0 and d3 of differentiation, and interestingly, Activin A and TGFβ signaling seem to be reactivated at the cardiac progenitor stages and/or in early CMs.


cardiomyogenesis; human pluripotent stem cells; label-free quantification; morphogens; signaling pathways


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