Research Article: Physical stimulation by REAC and BMP4/WNT-1 inhibitor synergistically enhance cardiogenic commitment in iPSCs

Date Published: January 23, 2019

Publisher: Public Library of Science

Author(s): Valentina Basoli, Sara Santaniello, Salvatore Rinaldi, Vania Fontani, Gianfranco Pigliaru, Matthias Wieser, Agata Strajeriu, Alessandro Castagna, Heinz Redl, Carlo Ventura, Regina Grillari, Margherita Maioli, Qiang Wu.


It is currently known that pluripotent stem cells can be committed in vitro to the cardiac lineage by the modulation of specific signaling pathways, but it is also well known that, despite the significant increase in cardiomyocyte yield provided by the currently available conditioned media, the resulting cardiogenic commitment remains a highly variable process. Previous studies provided evidence that radio electric fields asymmetrically conveyed through the Radio Electric Asymmetric Conveyer (REAC) technology are able to commit R1 embryonic stem cells and human adipose derived stem cells toward a cardiac phenotype. The present study aimed at investigating whether the effect of physical stimulation by REAC in combination with specific chemical inductors enhance the cardiogenic potential in human induced pluripotent stem cells (iPSCs). The appearance of a cardiac-like phenotype in iPSCs cultured in the presence of a cardiogenic medium, based upon BMP4 and a WNT-inhibitor, was consistently increased by REAC treatment used only during the early fate differentiation for the first 72 hours. REAC-exposed iPSCs exhibited an upregulation in the expression of specific cardiogenic transcripts and morphologically in the number of beating clusters, as compared to cells cultured in the cardiogenic medium alone. Our results indicate that physical modulation of cellular dynamics provided by the REAC offers an affordable strategy to mimic iPSC cardiac-like fates in the presence of a cardiogenic milieu.

Partial Text

Stem cell-based therapy currently represents a promising approach for regenerative medicine, although the translation of the in vitro studies into clinical applications is in part complicated by the difficulty in obtaining a high yield of differentiation within specific and homogenous stem cell-derived lineages that can provide their safety. There is increasing evidence that defined stem cell commitment can be promoted not only by chemical agents[1, 2] but can result from exposure to physical energies. In this regard, we have shown that exposure to Radio Electric Asymmetric Conveyer (REAC) technology with specific treatment protocol, can promote multi-lineage commitment, like cardiogenesis, neurogenesis and skeletal myogenesis, in mouse embryonic stem (ES) cells[3] and in human adipose-derived mesenchymal stem cells (ADhMSCs)[4, 5], also modulating the expression of stemness-related genes and the commitment to cardiac-, neural- and skeletal muscle-like fates in human fibroblasts[6]. Moreover, previous studies have shown that REAC technology can also influence other processes[7], activating both telomerase-dependent and independent pathways to counteract and even reverse stem cell senescence in vitro[8–10]. These responses to REAC exposure involved a major role of intracellular hyaluronic acid patterning and the establishment of intracellular networks acting on the modulation of cell polarity [11].

In the field of regenerative medicine iPSCs hold a high promise for future development, owing to its easy and wide-ranging opportunities for harvesting, and for the possibility of being generated even by non-integrating technologies[21], however one of the main issues is to find a way to improve their differentiation in order to create a stable population for further applications.




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