Genetic and environmental determinants of wound epithelium consolidation, blastema anchoring, and pro-inflammatory signal persistence at 2 and 5 days post-amputation: a longitudinal clonal amphibian study
July 12
Background
Rapid sealing of damaged tissue and accurate establishment of a regenerative blastema are essential for successful appendage regrowth. However, the relative contributions of inherited variation and rearing conditions to early regenerative dynamics, and the tempo of these influences across the first post-injury days, remain largely undefined.
Methods
Using a classical sibling design in 998 larval amphibians derived from monozygotic and dizygotic clutches, we quantified three early regenerative phenotypes at 2 and 5 days post-caudal amputation: (i) wound epithelium consolidation time (WEc), (ii) blastema anchoring efficiency (BAe), and (iii) duration of the acute Il-1β/TNFα signal (CytD). Univariate and bivariate ACE models partitioned variance into additive genetic (A), shared environmental (C), and unique environmental (E) components. In parallel, whole-genome resequencing enabled calculation of polygenic scores (PGS) for generic regenerative capacity, fibrotic liability, and major congenital malformation risk.
Results
Additive genetic effects explained a substantial portion of variability in CytD at both 2 and 5 days (A = 0.29–0.70) and in BAe at day 5 (A = 0.51–0.67). Shared environment dominated WEc at both timepoints (C = 0.61–0.90) and contributed strongly to BAe at day 2 (C = 0.36–0.65). Longitudinal modelling revealed modest shared genetic influence on daytime BAe across the interval (24%), whereas genetic overlap for evening and nocturnal BAe was non-significant. Shared environmental factors accounted for 56% of the covariance in WEc across days, while genetic factors accounted for 17%–33% of stability in CytD measured during dusk and night periods. Unique environmental influences were largely time-specific. Finally, the fibrosis-PGS associated with prolonged CytD during the evening of day 2 (β = 0.16, p = .002).
Conclusions
Etiological architecture shifted markedly between 2 and 5 days post-injury, underscoring a window of high plasticity in early regenerative morphodynamics and tissue–environment dialogue.