Electro-mechanical conditioning of human iPSC-derived cardiomyocytes for translational research

• Published in: Progress in biophysics and molecular biology Vol. 130; no. Pt B; pp. 212 - 222
• Main Authors: Kroll, Katharina, Chabria, Mamta, Wang, Ken, Häusermann, Fabian, Schuler, Franz, Polonchuk, Liudmila
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.11.2017
• Subjects: Biological Transport; Biomechanical Phenomena; Ca2+ handling; Calcium - metabolism; Cytoskeleton - metabolism; Electro-mechanical stimulation; Electrophysiological Phenomena; Electrophysiology; Humans; Induced Pluripotent Stem Cells - cytology; Maturation; Mechanical Phenomena; Myocytes, Cardiac - cytology; Myocytes, Cardiac - metabolism; Sarcomeres - metabolism; Stem cell-derived cardiomyocytes; Translational Medical Research; Electrophysiology; Stem cell-derived cardiomyocytes; Maturation; Electro-mechanical stimulation; Ca2+ handling; Ca(2+) handling
• ISSN: 0079-6107; 1873-1732; 1873-1732
• DOI: 10.1016/j.pbiomolbio.2017.07.003

Impaired maturation of human iPSC-derived cardiomyocytes (hiPSC-CMs) currently limits their use in experimental research and further optimization is required to unlock their full potential. To push hiPSC-CMs towards maturation, we recapitulated the intrinsic cardiac properties by electro-mechanical stimulation and explored how these mimetic biophysical cues interplay and influence the cell behaviour. We introduced a novel device capable of applying synchronized electrical and mechanical stimuli to hiPSC-CM monolayers cultured on a PDMS membrane and evaluated effects of conditioning on cardiomyocyte structure and function. Human iPSC-CMs retained their cardiac phenotype and displayed adaptive structural responses to electrical (E), mechanical (M) and combined electro-mechanical (EM) stimuli, including enhanced membrane N-cadherin signal, stress-fiber formation and sarcomeric length shortening, most prominent under the EM stimulation. On the functional level, EM conditioning significantly reduced the transmembrane calcium current, resulting in a shift towards triangulation of intracellular calcium transients. In contrast, E and M stimulation applied independently increased the proportion of cells with L-Type calcium currents. In addition, calcium transients measured in the M-conditioned samples advanced to a more rectangular shape. The new methodology is a simple and elegant technique to systematically investigate and manipulate cardiomyocyte remodelling for translational applications. In the present study, we adjusted critical parameters to optimize a regimen for hiPSC-CM transformation. In the future, this technology will open up new avenues for electro-mechanical stimulation by allowing temporal and spatial control of stimuli which can be easily scaled up in complexity for cardiac development and disease modelling.