Mendez, M. J. | bioRxiv Science

bioRxiv2026

Patient-Specific Heart Rate Modulates Developmental Electrophysiology in Transcriptomic-Guided In Silico Models of Pediatric Human Atrial Cardiomyocytes

Cardiac electrophysiology adapts throughout pediatric development, driven by factors including age-associated ion channel expression changes and decreasing heart rate. Our prior transcriptomic-guided simulations of human atrial cardiomyocytes predicted developmental-associated changes in electrophysiology biomarkers at a fixed pacing rate, leaving the contribution of age- and patient-specific heart rate unresolved. In this study, we incorporated intrinsic heart rate into gene expression-guided computational models to predict the interaction between developmental maturation and pacing rate to shape atrial electrophysiology. Virtual patient-specific populations of atrial cardiomyocytes were generated from the right atrial cardiomyocyte gene expression data from 117 patients, spanning neonates to young adults. We simulated each population at pacing rates corresponding to each patients intrinsic ECG-based heart rate and at fixed rates corresponding to the patient cohort minimum, median, and maximum. Action potential and calcium transient biomarkers were quantified, and partial least squares regression assessed key biomarker dependencies. For intrinsic-rate pacing conditions, action potential duration at 50% and 90% repolarization increased with age, whereas early repolarization shortened; maximum upstroke velocity increased, resting membrane potential became more negative, and alternans prevalence decreased. Developmental differences persisted during fixed-rate pacing conditions, indicating that differences were not explained solely by the faster heart rates of younger patients. Notably, intrinsic-rate simulations exhibited stronger age associations for upstroke velocity and alternans than fixed-rate simulations. Sensitivity analyses indicated that electrophysiological phenotypes arose from interactions among ionic conductances, calcium handling, age, and heart rate. Collectively, we find that pediatric atrial electrophysiology reflects both intrinsic developmental remodeling and rate-dependent modulation.

biophysics↗

bioRxiv2019

Cell fate forecasting: a data assimilation approach to predict epithelial-mesenchymal transition

Epithelial-mesenchymal transition (EMT) is a fundamental biological process that plays a central role in embryonic development, tissue regeneration, and cancer metastasis. Transforming growth factor-{beta} (TGF{beta}) is a major and potent inducer of this cellular transition, which is comprised of transitions from an epithelial state to an intermediate or partial EMT state, then to a mesenchymal state. Using computational models to predict state transitions in a specific experiment is inherently difficult for many reasons, including model parameter uncertainty and the error associated with experimental observations. In this study, we demonstrate that a data-assimilation approach using an ensemble Kalman filter, which combines limited noisy observations with predictions from a computational model of TGF{beta}-induced EMT, can reconstruct the cell state and predict the timing of state transitions. We used our approach in proof-of-concept \"synthetic\" in silico experiments, in which experimental observations were produced from a known computational model with the addition of noise. We mimic parameter uncertainty in in vitro experiments by incorporating model error that shifts the TGF{beta} doses associated with the state transitions. We performed synthetic experiments for a wide range of TGF{beta} doses to investigate different cell steady state conditions, and we conducted a parameter study varying several properties of the data-assimilation approach, including the time interval between observations, and incorporating multiplicative inflation, a technique to compensate for underestimation of the model uncertainty and mitigate the influence of model error. We find that cell state can be successfully reconstructed in synthetic experiments, even in the setting of model error, when experimental observations are performed at a sufficiently short time interval and incorporate multiplicative inflation. Our study demonstrates a feasible proof-of-concept for a data assimilation approach to forecasting the fate of cells undergoing EMT.\n\nAuthor summaryEpithelial-mesenchymal transition (EMT) is a biological process in which an epithelial cell loses core epithelial-like characteristics, such as tight cell-to-cell adhesion, and gains core mesenchymal-like characteristics, such as an increase in cell motility. EMT is a multistep process, in which the cell undergoes transitions from epithelial state to a partial or intermediate state, and then from a partial state to a mesenchymal state. In this study, we apply data assimilation to improve prediction of these state transitions. Data assimilation is an approach well known in the weather forecasting community, in which experimental observations are iteratively combined with predictions from a dynamical model to provide an improved estimation of both observed and unobserved system states. We show that this data assimilation approach can reconstruct cell state measurements and predict state transition dynamics using noisy observations, while minimizing the error produced by the limitations and imperfections of the dynamical model.

cell biology↗