Proteome modulation by opposite inotropic drugs in human engineered cardiac tissue revealed by topology-driven cross-modal integration
- 1Applied Stem Cell Technologies Group, Department of Bioengineering Technologies, TechMed Centre, University of Twente, 7522NB, Enschede, The Netherlands
Abstract
Engineered heart tissues (EHTs) represent an innovative platform enabling physiologically relevant in vitro evaluation of drug-induced cardiac responses. While functional characterization remains central to EHTs, molecular profiling is increasingly used to elucidate mechanisms underlying drug-induced phenotypes. Proteomics provides broad molecular characterization of drug responses at the protein level, yet the complexity, heterogeneity, and high dimensionality of proteomics datasets challenge conventional statistical approaches, which are not designed for cross-modal integration and streamlined multi-omics analysis. In this study, we developed an innovative framework based on topological data analysis (TDA) for the integration of large proteomics profiles and functional readouts to investigate system-level responses to drugs with opposing inotropic effects, epinephrine and doxorubicin. Samples were organized into a topological connectivity network according to multimodal similarity enabling simultaneous exploration of treatments, cardiac function and proteome alterations. Highly correlated features were then used for pathway enrichment analysis, which revealed strong similarities between the enrichment profiles associated with contractile force and epinephrine. These findings are consistent with the positive inotropic effect of epinephrine, whereas doxorubicin exhibited an opposing enrichment profile. Energy homeostasis, mitochondrial translation and proteostasis emerged as the major cellular processes displaying opposite associations with the two inotropic drugs, highlighting a link between cardiac contractility and perturbations in these processes. In conclusion, our TDA-based framework successfully integrated functional and proteomic data to uncover treatment-specific remodeling in EHTs, offering a modular and scalable approach that could be adapted to other in vitro organ models for systems-level mechanistic studies and next-generation drug development.
Related
- IL-10-secreting engineered macrophages alleviate DSS-induced colitis with macrophage phenotypic modulation and gut microbiota remodeling in mice.
- Developmental and genetic modulation of evidence integration dynamics in zebrafish sensorimotor decision-making
- Modulation and Integration in a local processor having input from two distinct sources
- Nutritional Modulation of Metabolic-Endocrine Integration and Growth Performance in Tropical Dairy Heifers.
- The serotonin transporter genotype x cumulative early-life stress interaction has opposite effects on anxiety-like behaviors in male and female rats
BibTeX
@misc{staykova2026proteome,
title = {{Proteome modulation by opposite inotropic drugs in human engineered cardiac tissue revealed by topology-driven cross-modal integration}},
author = {D. K. Staykova and D. Snippert and H. J. C. T. Wessels and R. Passier and F. Conte},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.25.746955},
url = {https://www.biorxiv.org/content/10.64898/2026.08.25.746955v2},
note = {CC BY},
}
RIS
TY - UNPB
TI - Proteome modulation by opposite inotropic drugs in human engineered cardiac tissue revealed by topology-driven cross-modal integration
AU - D. K. Staykova
AU - D. Snippert
AU - H. J. C. T. Wessels
AU - R. Passier
AU - F. Conte
PY - 2026
DA - 2026/08/25
PB - bioRxiv
DO - 10.64898/2026.08.25.746955
UR - https://www.biorxiv.org/content/10.64898/2026.08.25.746955v2
AB - Engineered heart tissues (EHTs) represent an innovative platform enabling physiologically relevant in vitro evaluation of drug-induced cardiac responses. While functional characterization remains central to EHTs, molecular profiling is increasingly used to elucidate mechanisms underlying drug-induced phenotypes. Proteomics provides broad molecular characterization of drug responses at the protein level, yet the complexity, heterogeneity, and high dimensionality of proteomics datasets challenge conventional statistical approaches, which are not designed for cross-modal integration and streamlined multi-omics analysis. In this study, we developed an innovative framework based on topological data analysis (TDA) for the integration of large proteomics profiles and functional readouts to investigate system-level responses to drugs with opposing inotropic effects, epinephrine and doxorubicin. Samples were organized into a topological connectivity network according to multimodal similarity enabling simultaneous exploration of treatments, cardiac function and proteome alterations. Highly correlated features were then used for pathway enrichment analysis, which revealed strong similarities between the enrichment profiles associated with contractile force and epinephrine. These findings are consistent with the positive inotropic effect of epinephrine, whereas doxorubicin exhibited an opposing enrichment profile. Energy homeostasis, mitochondrial translation and proteostasis emerged as the major cellular processes displaying opposite associations with the two inotropic drugs, highlighting a link between cardiac contractility and perturbations in these processes. In conclusion, our TDA-based framework successfully integrated functional and proteomic data to uncover treatment-specific remodeling in EHTs, offering a modular and scalable approach that could be adapted to other in vitro organ models for systems-level mechanistic studies and next-generation drug development.
ER -