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TempoBridge addresses the challenge of inferring single-cell population transitions from unpaired snapshots by formulating a source-conditioned transport problem. It leverages optimal transport couplings for conditional flow-matching training, enabling accurate prediction of cell state dynamics across temporal, genetic, and chemical perturbations. Empirical results show TempoBridge outperforms existing methods like scGen and scGPT-scratch in predictive accuracy on held-out data.
A unified source-conditioned transport framework accurately predicts single-cell population transitions across diverse perturbations without requiring paired observations.
Destructive single-cell measurements provide unpaired population snapshots rather than observations of the same cells across conditions. Local cell states and transition requests may also be insufficient to distinguish responses across source populations. We introduce TempoBridge, a common source-conditioned transport formulation for temporal, genetic, and chemical population transitions. Source cells initialize latent transport and provide a fixed empirical population summary. The velocity field receives this summary alongside the evolving cell state, flow time, and a structured transition descriptor. Minibatch optimal transport (OT) supplies couplings only for conditional flow-matching training paths; inference requires neither target expression nor OT computation. On held-out donors, TempoBridge achieves an Energy distance of 0.129 versus 0.144 for scGen. Genetic mean-expression $L_2$ error is 2.261 versus 3.156 for scGPT-scratch under Seen 2/2. On held-out compounds, condition-averaged drug-effect correlation is 0.598 versus 0.561 for the CellFlow adapter. Temporal ablations show higher mean distributional error after removing source context, replacing optimal transport with random pairing, or replacing flow matching with static residual regression. Together, these results demonstrate the predictive utility of a common source-conditioned transport formulation across held-out donors, gene combinations, and compounds.