Logic-based mechanistic machine learning on high-content images reveals how drugs differentially regulate cardiac fibroblasts

Anders R. Nelson, Steven L. Christiansen, Kristen M. Naegle, Jeffrey J. Saucerman

Research output: Contribution to journalArticlepeer-review

Abstract

Fibroblasts are essential regulators of extracellular matrix deposition following cardiac injury. These cells exhibit highly plastic responses in phenotype during fibrosis in response to environmental stimuli. Here, we test whether and how candidate anti-fibrotic drugs differentially regulate measures of cardiac fibroblast phenotype, which may help identify treatments for cardiac fibrosis. We conducted a high-content microscopy screen of human cardiac fibroblasts treated with 13 clinically relevant drugs in the context of TGFβ and/or IL-1β, measuring phenotype across 137 single-cell features. We used the phenotypic data from our high-content imaging to train a logic-based mechanistic machine learning model (LogiMML) for fibroblast signaling. The model predicted how pirfenidone and Src inhibitor WH-4- 023 reduce actin filament assembly and actin-myosin stress fiber formation, respectively. Validating the LogiMML model prediction that PI3K partially mediates the effects of Src inhibition, we found that PI3K inhibition reduces actin-myosin stress fiber formation and procollagen I production in human cardiac fibroblasts. In this study, we establish a modeling approach combining the strengths of logic-based network models and regularized regression models. We apply this approach to predict mechanisms that mediate the differential effects of drugs on fibroblasts, revealing Src inhibition acting via PI3K as a potential therapy for cardiac fibrosis.

Original languageEnglish (US)
Article numbere2303513121
JournalProceedings of the National Academy of Sciences of the United States of America
Volume121
Issue number5
DOIs
StatePublished - 2024

Keywords

  • drug discovery
  • fibroblast
  • machine learning
  • systems biology

ASJC Scopus subject areas

  • General

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