Biology subjects

Skoufa, E.

Publications and source records attributed to Skoufa, E..

3 recordsLinked to original sources

bioRxiv2024

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

Why mammals cannot regenerate limbs, unlike amphibians, presents a longstanding puzzle in biology. We show that exposing ex vivo amputated 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, regenerative Xenopus tadpole 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.

developmental biology↗

bioRxiv2024

Specialized signaling centers direct cell fate and spatial organization in a limb organoid model

Specialized signaling centers orchestrate robust development and regeneration. Limb morphogenesis, for instance, requires interactions between the mesoderm and the signaling center apical-ectodermal ridge (AER), whose properties and role in cell fate decisions have remained challenging to dissect. To tackle this, we developed mouse embryonic stem cells (mESCs)-based heterogeneous cultures and a limb organoid model, termed budoids, comprising cells with AER, surface ectoderm, and mesoderm properties. mESCs were first induced into heterogeneous cultures that self-organized into domes in 2D. Aggregating these cultures resulted in formation of limb bud-like structures in 3D, exhibiting chondrogenesis-based symmetry breaking and elongation. Using our organoids and quantitative in situ expression profiling, we uncovered that AER-like cells support nearby limb mesoderm and fibroblast identities while enhancing tissue polarization that permits distant cartilage formation. Together, our findings provide a powerful model to study aspects of limb morphogenesis, and reveal the ability of signaling center AER cells to concurrently modulate cell fate and spatial organization.

developmental biology↗

bioRxiv2023

Multi-species atlas resolves an axolotl limb development and regeneration paradox

Humans and other tetrapods are considered to require apical-ectodermal-ridge, AER, cells for limb development, and AER-like cells are suggested to be re-formed to initiate limb regeneration. Paradoxically, the presence of AER in the axolotl, the primary regeneration model organism, remains controversial. Here, by leveraging a single-cell transcriptomics-based multi-species atlas, composed of axolotl, human, mouse, chicken, and frog cells, we first established that axolotls contain cells with AER characteristics. Surprisingly, further analyses and spatial transcriptomics revealed that axolotl limbs do not fully re-form AER cells during regeneration. Moreover, the axolotl mesoderm displays part of the AER machinery, revealing a novel program for limb (re)growth. These results clarify the debate about the axolotl AER and the extent to which the limb developmental program is recapitulated during regeneration.

developmental biology↗