Regeneration of the Urodele Limb

Abstract

Urodele limbs regenerate via a blastema of mesenchymal cells derived from muscle, connective tissue and nerve sheath cells in the vicinity of the amputation surface by a process of histolysis, dedifferentiation and release of stem cells. Blastema cells replicate their DNA, arrest in G2 and accumulate under an apical epidermal cap (AEC). G2 arrest is broken by factor(s) expressed by the AEC that bind to receptors on the blastema cell surface. Expression of these factors is dependent on factor(s) provided by axons reinnervating the AEC. The blastema cells proliferate and are patterned into new limb structures by suites of signalling factors such as retinoic acid, sonic hedgehog and Wnt, in addition to homeobox transcription factors that endow the cells with positional identities expressed as axial gradients on the cell surface. The degree to which the early blastema is determined is controversial, with some evidence arguing for developmental plasticity and other evidence arguing that the blastema is self‐organising. Key Concepts Urodeles are unique in their ability to form a regeneration blastema in response to amputation. The cells of the regeneration blastema are derived from resident stem cells and/or by the reprogramming (dedifferentiation) of differentiated cells. Blastema cells derived from the different limb tissues redifferentiate in a lineage‐specific manner, but blastema cells derived from fibroblasts can also transdifferentiate into cartilage and tendon. The apical epidermal cap (AEC) of the wound epidermis is induced by regenerating nerve axons to produce a mitogen(s) that drives the proliferation of blastema cells. Patterning of the blastema involves region‐specific contributions of limb cells, lineage‐specific redifferentiation of blastema cells, interactions between blastema cells of different positions to eliminate discontinuities and sorting out of blastema cells with different cell surface adhesion. Cell interactions are mediated during axial patterning of the blastema by several signalling molecules and homeobox transcription factors. How the axial pattern and limb type of the early blastema is determined, whether by induction, self‐organisation or both, remains controversial.

Harnessing hypoxia as an evolutionary driver of complex multicellularity

“…However, several modes of tissue renewal occur across the animal kingdom [85,86] and even the human liver can regenerate through transdifferentiation [87] (although proliferation is more common) [88]. Mammals during development and also adult lizards demonstrate remarkable scar-free tissue regeneration [89,90] that involves de-and transdifferentiation [91]. The ultimate indication that all cells may hold the potential capacity for transdifferentiation is experimental, such as when fully differentiated human keratinocytes (skin cells) can be induced to acquire stemness properties [92].…”