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   Freel, Bethany A.; Sheets, Jordan N.; Francis, Kevin R. (February 2020, Journal of Neuroscience Methods)

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2. Recent advances in the applications of iPSC technology

   https://doi.org/10.1016/j.copbio.2019.05.011  

   Wiegand, Connor; Banerjee, Ipsita (December 2019, Current Opinion in Biotechnology)

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3. Space microgravity improves proliferation of human iPSC-derived cardiomyocytes

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   Rampoldi, Antonio; Forghani, Parvin; Li, Dong; Hwang, Hyun; Armand, Lawrence Christian; Fite, Jordan; Boland, Gene; Maxwell, Joshua; Maher, Kevin; Xu, Chunhui (October 2022, Stem Cell Reports)
4. Stochastic biological system-of-systems modelling for iPSC culture

   https://doi.org/10.1038/s42003-023-05653-w  

   Zheng, Hua; Harcum, Sarah W.; Pei, Jinxiang; Xie, Wei (January 2024, Communications Biology)

   Abstract Large-scale manufacturing of induced pluripotent stem cells (iPSCs) is essential for cell therapies and regenerative medicines. Yet, iPSCs form large cell aggregates in suspension bioreactors, resulting in insufficient nutrient supply and extra metabolic waste build-up for the cells located at the core. Since subtle changes in micro-environment can lead to a heterogeneous cell population, a novel Biological System-of-Systems (Bio-SoS) framework is proposed to model cell-to-cell interactions, spatial and metabolic heterogeneity, and cell response to micro-environmental variation. Building on stochastic metabolic reaction network, aggregation kinetics, and reaction-diffusion mechanisms, the Bio-SoS model characterizes causal interdependencies at individual cell, aggregate, and cell population levels. It has a modular design that enables data integration and improves predictions for different monolayer and aggregate culture processes. In addition, a variance decomposition analysis is derived to quantify the impact of factors (i.e., aggregate size) on cell product health and quality heterogeneity. 

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5. Syncytium cell growth increases Kir2.1 contribution in human iPSC-cardiomyocytes

   https://doi.org/10.1152/ajpheart.00148.2020  

   Li, Weizhen; Han, Julie L.; Entcheva, Emilia (November 2020, American Journal of Physiology-Heart and Circulatory Physiology)

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   Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) enable cardiotoxicity testing and personalized medicine. However, their maturity is of concern, including relatively depolarized resting membrane potential and more spontaneous activity compared with adult cardiomyocytes, implicating low or lacking inward rectifier potassium current ( I k1 ). Here, protein quantification confirms Kir2.1 expression in hiPSC-CM syncytia, albeit several times lower than in adult heart tissue. We find that hiPSC-CM culture density influences Kir2.1 expression at the mRNA level (potassium inwardly rectifying channel subfamily J member 2) and at the protein level and its associated electrophysiology phenotype. Namely, all-optical cardiac electrophysiology and pharmacological treatments reveal reduction of spontaneous and irregular activity and increase in action potential upstroke in denser cultures. Blocking I k1 -like currents with BaCl 2 increased spontaneous frequency and blunted action potential upstrokes during pacing in a dose-dependent manner only in the highest-density cultures, in line with I k1 ’s role in regulating the resting membrane potential. Our results emphasize the importance of syncytial growth of hiPSC-CMs for more physiologically relevant phenotype and the power of all-optical electrophysiology to study cardiomyocytes in their multicellular setting. NEW & NOTEWORTHY We identify cell culture density and cell-cell contact as an important factor in determining the expression of a key ion channel at the transcriptional and the protein levels, KCNJ2/Kir2.1, and its contribution to the electrophysiology of human induced pluripotent stem cell-derived cardiomyocytes. Our results indicate that studies on isolated cells, out of tissue context, may underestimate the cellular ion channel properties being characterized. 

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