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Squidiff: predicting cellular development and responses to perturbations using a diffusion model.

Siyu He1,2,3, Yuefei Zhu1, Daniel Naveed Tavakol1

  • 1Department of Biomedical Engineering, Columbia University, New York, NY, USA.

Nature Methods
|November 3, 2025
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Summary
This summary is machine-generated.

Squidiff, a new diffusion model, predicts cell transcriptomic changes during differentiation, gene perturbation, and drug responses. This tool aids in understanding cell fate and disease mechanisms.

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Area of Science:

  • Computational Biology
  • Genomics
  • Systems Biology

Background:

  • Single-cell sequencing reveals cellular heterogeneity and responses to stimuli.
  • Mapping transcriptomic changes and disease mechanisms across cell types is challenging.

Purpose of the Study:

  • Introduce Squidiff, a diffusion model-based generative framework.
  • Predict transcriptomic changes in diverse cell types under various environmental conditions.
  • Facilitate in silico screening and hypothesis generation for cell fate decisions.

Main Methods:

  • Utilized a diffusion model-based generative framework (Squidiff).
  • Integrated continuous denoising and semantic feature learning.
  • Applied the model to cell differentiation, gene perturbation, and drug response prediction.

Main Results:

  • Demonstrated Squidiff's robustness across multiple biological scenarios.
  • Successfully modeled blood vessel organoid development and cellular responses to stimuli.
  • Enabled prediction of high-resolution transcriptomic landscapes over time and conditions.

Conclusions:

  • Squidiff enables in silico screening of molecular landscapes and cellular state transitions.
  • Facilitates rapid hypothesis generation for biological research.
  • Provides insights into the regulatory principles governing cell fate decisions.