Hallmarks of regeneration

SummaryPlanarians exhibit remarkable whole-body regeneration abilities. The formation of heads at forward-facing wounds and tails at rearward-facing wounds suggests an intrinsic tissue polarity guiding regeneration. While the underlying mechanisms remain unclear, reports of double-headed regenerates from increasingly narrow tissue fragments have long been hypothesised to reflect gradient-based polarity specification. Here, we systematically re-examine this hypothesis in the modern model speciesSchmidtea mediterraneaand a representative of the genus likely used in the original studies,Girardia sinensis. While we never observed double-heads inS. mediterranea,G. sinensisreadily regenerated double-heads in a manner dependent on piece length, anatomical position and body size. We found that the reduced regeneration robustness ofG. sinensiswas partially explained by wound site-symmetric expression of the head determinantnotum, which is highly anterior-specific inS. mediterranea. Exploring what else might mediate head/tail regeneration specificity inG. sinensis, we examined the role of the conserved tail-to-head cWnt signalling gradient. By developing a time-resolved pharmacological approach to reduce the cWnt gradient slope without affecting wound-induced cWnt signalling dynamics, we observed an increased incidence of double-headed regenerates. In addition, the body size-dependence of double-head formation correlated with the decreasing steepness of the cWnt gradient due to scaling. Taken together, our results indicate that the slope of the cWnt gradient may contribute to planarian head/tail regeneration specificity. Furthermore, they suggest that planarian tissue polarity is composed of multiple parallely-acting polarity cues, the differential reliance on which contributes to the observed interspecies variation in regeneration specificity.

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Species-specific oxygen sensing governs the initiation of vertebrate limb regeneration

Tsissios,

Leleu,

et al. 2024

Preprint

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Why mammals cannot regenerate limbs, unlike amphibians, presents a longstanding puzzle in biology. We show that exposingex vivoamputated embryonic mouse limbs to subatmospheric oxygen environment, or stabilizing oxygen-sensitive HIF1A enables not only rapid wound healing, but alters cellular mechanics, and reshapes the histone landscape to prime regenerative fates. Conversely, regenerativeXenopustadpole limbs display low oxygen-sensing capacity, robust wound healing, a regenerative histone landscape, and glycolytic programs even under high oxygen. This reduced oxygen-sensing capacity, in stark contrast to mammals, associates with decreased HIF1A-regulating gene expressions. Our findings thus uncover species-specific oxygen sensing as a unifying mechanism for limb regeneration initiation across vertebrates, reveal how aquatic subatmospheric habitats may enhance regenerative capabilities, and identify targetable barriers to unlock latent limb regenerative programs in adult mammals.

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Hallmarks of regeneration

Cited by 4 publications

References 203 publications

A genetic and microscopy toolkit for manipulating and monitoring regeneration in Macrostomum lignano

A genetic and microscopy toolkit for manipulating and monitoring regeneration in Macrostomum lignano

A comparative analysis of planarian regeneration specificity reveals tissue polarity contributions of the axial cWnt signalling gradient

Species-specific oxygen sensing governs the initiation of vertebrate limb regeneration

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