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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. Engineering anisotropic human stem cell-derived three-dimensional cardiac tissue on-a-chip

   https://doi.org/doi: 10.1016/j.biomaterials.2020.120195  

   Veldhuizen, Jaimeson ; Cutts, Joshua ; Brafman, David ; Migrino, Raymond Q. ; Nikkhah, Mehdi ( October 2020 , Biomaterials)

   Despite significant efforts in the study of cardiovascular diseases (CVDs), they persist as the leading cause of mortality worldwide. Considerable research into human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) has highlighted their immense potential in the development of in vitro human cardiac tissues for broad mechanistic, therapeutic, and patient-specific disease modeling studies in the pursuit of CVD research. However, the relatively immature state of hPSC-CMs remains an obstacle in enhancing clinical relevance ofengineered cardiac tissue models. In this study, we describe development of a microfluidic platform for 3D modeling of cardiac tissues, derived from both rat cells and hPSC-CMs, to better recapitulate the native myocardium through co-culture with interstitial cells (specifically cardiac fibroblasts), biomimetic collagen hydrogel encapsulation, and induction of highly anisotropic tissue architecture. The presented platform is precisely engineered through incorporation of surface topography in the form of staggered microposts to enable long-term culture and maturation of cardiac cells, resulting in formation of physiologically relevant cardiac tissues with anisotropy that mimics native myocardium. After two weeks of culture, hPSC-derived cardiac tissues exhibited well-defined sarcomeric striations, highly synchronous contractions, and upregulation of several maturation genes, including HCN1, KCNQ1, CAV1.2, CAV3.1, PLN, and RYR2. These findings demonstrate the ability of the proposed engineered platform to mature animal- as well as human stem cell-derived cardiac tissues over an extended period of culture, providing a novel microfluidic chip with the capability for cardiac disease modeling and therapeutic testing. 

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4. 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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5. Effect of Electrical Stimulation on Spontaneously Beating Dynamics of Cardiac Tissues: An Analysis Using Digital Image Correlation

   https://doi.org/10.1002/admt.202100669  

   Lou, Lihua ; Rubfiaro, Alberto Sesena ; He, Jin ; Agarwal, Arvind ( August 2021 , Advanced Materials Technologies)

   Electrical pacing/stimulations (EP) have been widely adopted to promote the maturation of hiPSC‐derived cardiomyocytes. However, there is a debate about their functions and effectiveness due to non‐optimized pacing conditions. Here, the effectiveness of EP (13 V cm⁻¹, 2 ms in width, and 5 Hz frequency) on cardiac tissue beating mechanics are analyzed using digital image correlation (DIC). The cardiac tissues with and without EP at tissue culture time from day 2 to 11 (D2–D11) are characterized and compared. The results indicate EP decreased cardiac beating motion for ≈2–15 times, promote synchronization, and improve ion handling. A positive correlation between cardiac beating mechanics and ion handling is observed. DIC method can optimize chemical, mechanical, and electrical stimulation, which could help create more mature cardiac tissues.

    

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