Daily exposure order can make skin repair cells move away from damage
Cellular migration polarityIn clock-reporter epidermal constructs from older donors, exposure order and local circadian phase could redirect repair without reducing capacity.
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HERETICAL: Particular exposure sequences make otherwise competent epidermal repair actively undo itself. Friction establishes front–rear keratinocyte polarity; heat arriving during a circadian interval of heightened cytoskeletal remodeling consolidates that orientation before barrier injury supplies a competing wound-directed cue. Repair cells consequently migrate away from, or tangentially past, the damaged focus despite normal migration speed and proliferation. Repeated daily sequences renew this misorientation before functional closure, producing persistent focal deficits without exhausting repair capacity. The relevant stored state is subcellular polarity and the resulting displacement of repair fronts. Preventing this directional reversal would stabilize SPV_12.
In clock-reporter epidermal constructs from older donors, randomize heat–friction–injury ordering and independently vary local phase.
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Hold cumulative exposure, interchallenge intervals and initial injury severity constant. The harmful sequence produces negative wound-normal velocity in viable keratinocytes before delayed functional recovery, while total migration speed remains normal. Reversing the friction vector reverses the location of failed repair at the same circadian phase. A brief, spatially directed polarity correction restores inward migration and subsequent barrier recovery without changing clock phase, cell abundance or recovery-window availability. Absence of active outward migration, together with rescue by staggering neighboring clock phases alone, favors IH_Q_L3_M_G4_4_02.
Aligned cellular clocks cause local skin repair failures predicts instead: Construct matched repair neighborhoods with identical cell numbers, lineage composition, single-unit response curves and average daily output, but synchronized versus staggered clock phases.
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First verify experimentally that either of two selected contributors can independently repair the standardized microdefect. The harmful exposure order must increase coincident nonresponse beyond the product of individual nonresponse probabilities before focal recovery deteriorates. Staggering phases rescues recovery without accelerating any contributor. Migration remains directed toward the defect whenever a contributor responds, and reversing friction direction does not reverse the location of failure. Persistent outward migration with normal contributor availability instead favors IH_Q_L3_M_G4_4_01.