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Engineering a Computable Epiblast for in silico Gastrulation and Predictive Modeling of Developmental Toxicity with in vitro Data from the ToxCast Stem Cell Assay (ASCCT Meeting 2022)
Citation:
Barham, K., R. Spencer, AND T. Knudsen. Engineering a Computable Epiblast for in silico Gastrulation and Predictive Modeling of Developmental Toxicity with in vitro Data from the ToxCast Stem Cell Assay (ASCCT Meeting 2022). American Society for Cellular and Computational Toxicology (ASCCT) Annual Meeting, Chapel Hill, NC, October 19 - 21, 2022. https://doi.org/10.23645/epacomptox.23320805
Impact/Purpose:
Poster presented to the American Society for Cellular and Computational Toxicology (ASCCT) Annual Meeting October 2022. A computer agent-based model (ESABM) for mesodermal patterning during epiblast gastrulation is under development to simulate the dynamics of chemical effects from human pluripotent ste, cell assay. This will provide a platform to titrate concentration-dependent effects that predict adverse phenotypes linked to altered mesodermal specification.
Description:
Gastrulation is a critical period of embryonic development, featuring the formation of the primitive streak and differentiation of epiblast cells into primary germ layers. The developmental potential of human pluripotent stem cells (hPSCs) in culture most closely resembles the pluripotency of the epiblast cell layer of the early embryo. Furthermore, the ToxCast portfolio provides in vitro bioactivity data on over 1000 chemicals from a hPSC assay that predicts toxicity with 80% balanced accuracy [Zurlinden et al. 2020]. Developing New Approach Methods (NAMs) for predicting toxicological effects of chemicals during prenatal development to reduce reliance on animal testing is an important goal of USEPA. Therefore, modeling cellular dynamics of the epiblast in silico would allow for the utilization of ToxCast data to track normal versus adverse developmental trajectories arising during gastrulation in response to chemical exposure. We engineered a fully computable model of the epiblast using the compucell3d.org modeling environment that simulates primitive streak formation, epithelial-mesenchymal transition of epiblast cells, and the self-organization of mesodermal domains (chordamesoderm, paraxial, lateral plate, extraembryonic) formed during gestation. Determination of progenitor cell fate is dependent upon positional information and temporal colinearity of the HOX clock, which can be altered through perturbation of a control network of morphogenetic signals (e.g., FGF, BMP, NODAL, ATRA). This agent-based model combines signaling cascades, ToxCast chemical bioactivity data and known developmental processes to mechanistically predict altered phenotypes through the resulting mesodermal topography in the animal-free zone. This abstract does not necessarily reflect Agency policy.
URLs/Downloads:
DOI: Engineering a Computable Epiblast for in silico Gastrulation and Predictive Modeling of Developmental Toxicity with in vitro Data from the ToxCast Stem Cell Assay (ASCCT Meeting 2022)
BARHAM ASCCT POSTER AFTER TECH.PDF (PDF, NA pp, 1559.078 KB, about PDF)