Whole-cell particle-based digital twin simulations from 4D lattice light-sheet microscopy data

SUMMARY We present a framework for performing whole-cell digital twin simulations which integrates 4D (x,y,z,t) lattice light-sheet microscopy (LLSM) data with particle-based reaction-diffusion modeling to capture intracellular organelle dynamics. Using imaging data from Cal27 cells, we construct digital twins that incorporate mitochondrial networks, microtubule networks, dynein and kinesin motors, the plasma membrane, and the nucleus. Passive diffusive mitochondrial dynamics are parameterized using stochastic reaction-diffusion simulations in ReaDDy, while active transport is modeled explicitly by incorporating motor-driven transport along a diffusing, polarized microtubule network. Our simulations accurately reproduce experimentally observed mitochondrial dynamics across pharmacological microtubule depolymerization conditions and reproduce the mitochondrial response to intermediate perturbations without explicit re-parameterization. This novel meso-scale digital twin framework offers a bridge between atomic-scale whole-cell simulations and experimental time and length scales.