Impact of limb regenerative asymmetry on systemic patterning outcomes: a systematic review
July 7
Progressive appendage degeneration exhibits heterogeneous manifestations, partially shaped by unilateral deficits in regenerative capacity that mirror embryonic left–right polarity. This systematic review of 80 investigations evaluated how lateralized limb repair influences extra-appendicular outcomes, including whole-body pattern fidelity, metabolic balance, and immune homeostasis. Specimens with right-limb regenerative failure—implying disruption of the left-side organizer—demonstrated more extensive global dysmorphogenesis and elevated risk for multi-organ malpatterning, whereas left-limb deficits—reflecting right-side organizer compromise—were more frequently associated with metabolic derangement, heightened inflammatory tone, and attenuated bioelectric cue recognition. Radial patterning errors were consistently linked to left-limb impairment, concordant with right-sided organizer dysfunction. Although individual reports varied, this convergent profile underscores the importance of intrinsic laterality in evaluating non-limb sequelae. Regenerative asymmetry also modulated responsiveness to electroceutical interventions, such as pulsed direct-current field therapy of the blastema. Nevertheless, divergent criteria for defining asymmetry, regenerative phenotypes, and concurrent tissue insults limited formal meta-analysis. Integrating limb regenerative laterality into diagnostic and therapeutic algorithms could refine personalized regenerative strategies, motivating standardized protocols for future work.