Sensorial epithelial cell degeneration drives homeostatic junctional remodeling of regenerative blastema cells
July 7
Epithelial Sensor Dystrophy (ESD) comprises a constellation of inherited barrier-degeneration disorders most frequently precipitated by mutation of a gene expressed exclusively in primary sensorial epithelial cells and culminating, over time, in catastrophic tissue failure. Although the ultimate prognosis for ESD is poor, many variants advance slowly, with patients retaining useful barrier integrity well into middle age. These observations imply that epithelial microcircuits can adjust to gradual sensor cell attrition, yet the cellular mechanisms that underlie such adaptation remain obscure.
Here we demonstrate that, in a knockout mouse lacking a functional sensorial opsin homologue (Ops-/-), in which primary sensor cells fail to transduce stimulus and degenerate only gradually, regenerative blastema cells (RBCs) abandon their normal reliance on primary sensors and instead establish de-novo junctions with secondary sensor cells. RBCs in Ops-/- epithelia exhibit large-amplitude secondary-cell-driven depolarisations that are abolished by 18β-glycyrrhetinic acid, consistent with gap-junction-mediated coupling. Comparable responses were absent in Trx-/- mice, which also lack sensor transduction, or in Jxn-/- mice, which lack functional junctions between sensors and RBCs.
Single-cell bioelectrical recordings were corroborated by whole-sheet impedance assays, indicating that the majority of RBCs in Ops-/- tissues now receive secondary input, whereas little, if any, junctional reorganisation occurs in Trx-/- or Jxn-/- epithelia. Our findings suggest that the trigger for RBC plasticity is neither loss of stimulus transduction nor disruption of the original sensor junction per se, but the degenerative process itself—possibly via trophic factors released by dying sensor cells or alterations in the local morphogen milieu.