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1. AMPK activator-treated human cardiac spheres enhance maturation and enable pathological modeling

   https://doi.org/10.1186/s13287-023-03554-7  

   Li, Dong ; Armand, Lawrence C. ; Sun, Fangxu ; Hwang, Hyun ; Wolfson, David ; Rampoldi, Antonio ; Liu, Rui ; Forghani, Parvin ; Hu, Xin ; Yu, Wen-Mei ; et al ( December 2023 , Stem Cell Research & Therapy)

   Cardiac pathological outcome of metabolic remodeling is difficult to model using cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CMs) due to low metabolic maturation.

   hiPSC-CM spheres were treated with AMP-activated protein kinase (AMPK) activators and examined for hiPSC-CM maturation features, molecular changes and the response to pathological stimuli.

   Treatment of hiPSC-CMs with AMPK activators increased ATP content, mitochondrial membrane potential and content, mitochondrial DNA, mitochondrial function and fatty acid uptake, indicating increased metabolic maturation. Conversely, the knockdown of AMPK inhibited mitochondrial maturation of hiPSC-CMs. In addition, AMPK activator-treated hiPSC-CMs had improved structural development and functional features—including enhanced Ca²⁺transient kinetics and increased contraction. Transcriptomic, proteomic and metabolomic profiling identified differential levels of expression of genes, proteins and metabolites associated with a molecular signature of mature cardiomyocytes in AMPK activator-treated hiPSC-CMs. In response to pathological stimuli, AMPK activator-treated hiPSC-CMs had increased glycolysis, and other pathological outcomes compared to untreated cells.

   AMPK activator-treated cardiac spheres could serve as a valuable model to gain novel insights into cardiac diseases.

    

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2. Tissue-embedded stretchable nanoelectronics reveal endothelial cell–mediated electrical maturation of human 3D cardiac microtissues

   https://doi.org/10.1126/sciadv.ade8513  

   Lin, Zuwan ; Garbern, Jessica C. ; Liu, Ren ; Li, Qiang ; Mancheño Juncosa, Estela ; Elwell, Hannah L.T. ; Sokol, Morgan ; Aoyama, Junya ; Deumer, Undine-Sophie ; Hsiao, Emma ; et al ( March 2023 , Science Advances)

   Clinical translation of stem cell therapies for heart disease requires electrical integration of transplanted cardiomyocytes. Generation of electrically matured human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) is critical for electrical integration. Here, we found that hiPSC-derived endothelial cells (hiPSC-ECs) promoted the expression of selected maturation markers in hiPSC-CMs. Using tissue-embedded stretchable mesh nanoelectronics, we achieved a long-term stable map of human three-dimensional (3D) cardiac microtissue electrical activity. The results revealed that hiPSC-ECs accelerated the electrical maturation of hiPSC-CMs in 3D cardiac microtissues. Machine learning–based pseudotime trajectory inference of cardiomyocyte electrical signals further revealed the electrical phenotypic transition path during development. Guided by the electrical recording data, single-cell RNA sequencing identified that hiPSC-ECs promoted cardiomyocyte subpopulations with a more mature phenotype, and multiple ligand-receptor interactions were up-regulated between hiPSC-ECs and hiPSC-CMs, revealing a coordinated multifactorial mechanism of hiPSC-CM electrical maturation. Collectively, these findings show that hiPSC-ECs drive hiPSC-CM electrical maturation via multiple intercellular pathways.

    

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3. Quantification of Contractile Dynamic Complexities Exhibited by Human Stem Cell-Derived Cardiomyocytes Using Nonlinear Dimensional Analysis

   https://doi.org/10.1038/s41598-019-51197-7  

   Hoang, Plansky ; Jacquir, Sabir ; Lemus, Stephanie ; Ma, Zhen ( October 2019 , Scientific Reports)

   Understanding the complexity of biological signals has been gaining widespread attention due to increasing knowledge on the nonlinearity that exists in these systems. Cardiac signals are known to exhibit highly complex dynamics, consisting of high degrees of interdependency that regulate the cardiac contractile functions. These regulatory mechanisms are important to understand for the development of novelin vitrocardiac systems, especially with the exponential growth in deriving cardiac tissue directly from human induced pluripotent stem cells (hiPSCs). This work describes a unique analytical approach that integrates linear amplitude and frequency analysis of physical cardiac contraction, with nonlinear analysis of the contraction signals to measure the signals’ complexity. We generated contraction motion waveforms reflecting the physical contraction of hiPSC-derived cardiomyocytes (hiPSC-CMs) and implemented these signals to nonlinear analysis to compute the capacity and correlation dimensions. These parameters allowed us to characterize the dynamics of the cardiac signals when reconstructed into a phase space and provided a measure of signal complexity to supplement contractile physiology data. Thus, we applied this approach to evaluate drug response and observed that relationships between contractile physiology and dynamic complexity were unique to each tested drug. This illustrated the applicability of this approach in not only characterization of cardiac signals, but also monitoring and diagnostics of cardiac health in response to external stress.

    

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4. Controlling Morphology and Functions of Cardiac Organoids by Two-Dimensional Geometrical Templates

   https://doi.org/10.1159/000521787  

   Hoang, Plansky ; Sun, Shiyang ; Tarris, Bearett A. ; Ma, Zhen ( March 2023 , Cells Tissues Organs)

   Traditionally, tissue-specific organoids are generated as 3D aggregates of stem cells embedded in Matrigel or hydrogels, and the aggregates eventually end up a spherical shape and suspended in the matrix. Lack of geometrical control of organoid formation makes these spherical organoids limited for modeling the tissues with complex shapes. To address this challenge, we developed a new method to generate 3D spatial-organized cardiac organoids from 2D micropatterned human induced pluripotent stem cell (hiPSC) colonies, instead of directly from 3D stem cell aggregates. This new approach opens the possibility to create cardiac organoids that are templated by 2D non-spherical geometries, which potentially provides us a deeper understanding of biophysical controls on developmental organogenesis. Here, we designed 2D geometrical templates with quadrilateral shapes and pentagram shapes that had same total area but different geometrical shapes. Using this templated substrate, we grew cardiac organoids from hiPSCs and collected a series of parameters to characterize morphological and functional properties of the cardiac organoids. In quadrilateral templates, we found that increasing the aspect ratio impaired cardiac tissue 3D self-assembly, but the elongated geometry improved the cardiac contractile functions. However, in pentagram templates, cardiac organoid structure and function were optimized with a specific geometry of an ideal star shape. This study will shed a light on “organogenesis-by-design” by increasing the intricacy of starting templates from external geometrical cues to improve the organoid morphogenesis and functionality.

    

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5. Proteomic Profiling Reveals Roles of Stress Response, Ca 2+ Transient Dysregulation, and Novel Signaling Pathways in Alcohol‐Induced Cardiotoxicity

   https://doi.org/10.1111/acer.14471  

   Liu, Rui ; Sun, Fangxu ; Forghani, Parvin ; Armand, Lawrence C. ; Rampoldi, Antonio ; Li, Dong ; Wu, Ronghu ; Xu, Chunhui ( October 2020 , Alcoholism: Clinical and Experimental Research)

   Alcohol use in pregnancy increases the risk of abnormal cardiac development, and excessive alcohol consumption in adults can induce cardiomyopathy, contractile dysfunction, and arrhythmias. Understanding molecular mechanisms underlying alcohol‐induced cardiac toxicity could provide guidance in the development of therapeutic strategies.

   We have performed proteomic and bioinformatic analysis to examine protein alterations globally and quantitatively in cardiomyocytes derived from human‐induced pluripotent stem cells (hiPSC‐CMs) treated with ethanol (EtOH). Proteins in both cell lysates and extracellular culture media were systematically quantitated.

   Treatment with EtOH caused severe detrimental effects on hiPSC‐CMs as indicated by significant cell death and deranged Ca²⁺handling. Treatment of hiPSC‐CMs with EtOH significantly affected proteins responsible for stress response (e.g., GPX1 and HSPs), ion channel‐related proteins (e.g. ATP1A2), myofibril structure proteins (e.g., MYL2/3), and those involved in focal adhesion and extracellular matrix (e.g., ILK and PXN). Proteins involved in the TNF receptor‐associated factor 2 signaling (e.g., CPNE1 and TNIK) were also affected by EtOH treatment.

   The observed changes in protein expression highlight the involvement of oxidative stress and dysregulation of Ca²⁺handling and contraction while also implicating potential novel targets in alcohol‐induced cardiotoxicity. These findings facilitate further exploration of potential mechanisms, discovery of novel biomarkers, and development of targeted therapeutics against EtOH‐induced cardiotoxicity.

    

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