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Computational morphodynamics: advanced modeling of human stem cell-derived data
Citation:
Knudsen, T. Computational morphodynamics: advanced modeling of human stem cell-derived data. Society of Toxicology 62nd Annual Meeting and ToxExpo 2023, Nashville, TN, March 19 - 23, 2023. https://doi.org/10.23645/epacomptox.22704604
Impact/Purpose:
Invited presentation to the Society of Toxicology 62nd Annual Meeting and ToxExpo March 2023 Workshop entitled 'Moving Stem Cell-Derived New Approach Methods Towards Regulatory Acceptance'. SESSION DESCRIPTION: New approach methods (NAMs) offer the potential to accelerate molecular evaluation in pharmaceutical drug development and chemical hazard assessment data acquisition and translate effects to protect human health and the environment. Over the past decade, numerous stem cell-derived NAMs have been developed, but their adoption and implementation into regulatory applications are still limited. To build confidence and increase the impact of NAMs, it is important to understand how the technologies are being used; the relevance, sensitivity and specificity of endpoints used in the in vitro models; the decision context to establish protective and/or predictive points of departure; the variability and concordance to traditional animal studies; and the inter-individual variability that may affect the responses of different subpopulations. Speakers in this workshop will provide examples on how the stem cell-derived NAMs are of use for hazard identification/risk assessment of environmental chemicals, drug screening, and toxicity detection/prediction. These novel perspectives provide insights on the suitability of using stem cell-derived NAMs to derive protective thresholds of health hazards; application of donor-derived stem cells to address issues of inter-individual variability in gene-environment interactions; toxicodynamic assessment of chemical hazard; the predictive value of stem cell-derived neural spheroids to preclinical species; and the promise of using a diverse panel of stem cell-derived cardiomyocytes in translational drug-induced cardiotoxicity. The efforts in assay development in supporting potential regulatory uses will be highlighted. The hurdles encountered on the qualification/verification pathways, the needs of different stakeholders, and strategies to promote the communication and interactions of stakeholders will be discussed in the last 30 minutes of the session. There have been active discussions of the potential regulatory use of NAMs among the Predictive Safety Testing Consortium, the IQ MPS Affiliate, and the FDA. This workshop brings together experts across the many facets of research to bring novel experiences and practices on the potential regulatory use of stem cell-derived NAMs. The audience will benefit from each speaker’s perspective of the utility, benefits, limitations, and challenges in applying new technologies to inform internal and regulatory decision making. This workshop provides unique insights and marks an important investment towards the eventual regulatory acceptance of stem cell- derived NAMs as it requires the general consensus of stakeholders on performance criteria of the methods and the translatability, qualification, and verification of the model.
Description:
Previous screening of the ToxCast chemical library in a pluripotent H9 human stem cell (hPSC) assay predicted developmental toxicity with a balanced accuracy 78-84% for well-curated reference compounds [Zurlinden et al. 2020]. Since the molecular biology of hPSCs in culture most closely resembles the ‘epiblast’ of an early embryo during gastrulation, in silico models built that self-organize emergent phenotypes and positional information of the epiblast can offer dynamic knowledge representation beyond performance classifiers to test the veracity of presumed mechanisms. A new and fully executable computer model of the human epiblast was built to translate hPSC-derived bioactivity data into adverse developmental trajectories through in silico self-organization of endomesodermal domains. Determination of progenitor cell fate is dependent upon positional information and temporal colinearity of an autonomous HOX clock, which can be altered through perturbation of a signaling network (e.g., FGF, BMP, NODAL, ATRA). This unique model of gastrulation combines ToxCast chemical bioactivity data with the molecular logic of signaling networks to mechanistically predict early developmental hazard through analysis of resulting mesodermal topography. Such models mechanistically drive biomolecular lesion(s) into higher levels of biological organization and can support regulatory implementation by putting hPSC-derived chemical effects data into motion (toxicodynamics). This abstract does not necessarily reflect Agency policy.
URLs/Downloads:
DOI: Computational morphodynamics: advanced modeling of human stem cell-derived data
SOT_2023_KNUDSEN.PDF (PDF, NA pp, 2162.646 KB, about PDF)