Sloppiness and Action Constraint in Cell State Transitions: Are Single Cells Sloppy?

Abstract Single-cell dynamics during cell state transitions (CST) are highly constrained, enabling precise control. However, there are challenges in achieving a system-level understanding or extracting general principles for CST dynamics due to the complexity of gene-gene interactions. Here, we introduce a new perspective to deal with these challenges using Fisher information. We found that, during CST, single cells exhibit pronounced sloppiness: cell states are sensitive only to a few “stiff” parameters while remaining robust to changes in numerous “sloppy” parameters. Critical transitions coincided with changes in stiff parameters. Moreover, stiff parameters typically exhibited minimal fluctuations and low velocities, whereas sloppy parameters allowed greater flexibility. Together, these findings can be summarized by stating that transition paths approximately adhere to a principle of least action. By characterizing the low dimensionality and constraints of CST through sloppiness and action, our work thus introduces a new conceptual and computational framework for analyzing single-cell dynamics. Teaser Except when transitions occur, single-cell dynamics exhibit sloppiness, adhering approximately to a least action principle. Competing Interest Statement The authors have declared no competing interest. Footnotes polish writing and update all figures