Looking proximally and distally: 100 years of limb regeneration and beyond

Abstract

The experimental study of amphibian limb regeneration spans most of the 20 th century and the first decade of the 21 st century. We first review the major questions investigated over this time span: (1) the origin of regeneration blastema cells, the mechanism of tissue breakdown that liberates cells from their tissue organization to participate in blastema formation, (3) the mechanism of dedifferentiation of these cells, (4) how the blastema grows, (5) how the blastema is patterned to restore the missing limb structures, and (6) why adult anurans, birds and mammals do not have the regenerative powers of urodele salamanders. We then look forward in a perspective to discuss the many unanswered questions raised by investigations of the past century, what new approaches can be taken to answer them, and what the prospects are for translation of basic research on limb regeneration into clinical means to regenerate human appendages. Developmental Dynamics 240:943-968,

Transcriptomic, proteomic, and metabolomic landscape of positional memory in the caudal fin of zebrafish

“…We and others (15,17,18) hypothesized that molecular effectors of positional memory are expressed in gradients along the proximodistal axis of uninjured appendages. To identify candidate molecules that might be involved in this process, we performed RNA sequencing (RNA-seq) and label-free quantification (LFQ) proteomics on proximal, middle, and distal regions of uninjured zebrafish caudal fins (Fig.…”

“…Positional memory is proposed to be established by molecules that exist in a gradient in uninjured appendages (15)(16)(17)(18). These gradients are interpreted by the masses of mesenchymal stem cells (blastemas) that form at the distal tip of amputated appendages.…”

Fine-mapping quantitative trait loci affecting murine external ear tissue regeneration in the LG/J by SM/J advanced intercross line

“…The establishment of the role of developmental genes involved in the regenerative response is long standing (Stocum and Cameron, 2011), and we identified four genes: Wnt3a, Lgr6, Mesp2 and Fgf1, which are in healing QTLs and known to be important for developmental regulation.…”

Mechanisms of urodele limb regeneration

“…This idea first supposes that the blastema is an anatomical mosaic of cellular contributions from each limb quadrant (Stocum & Cameron, 2011, for a review). As outlined above, experiments on half and double half limbs have revealed differential contributions of limb halves to the blastema.…”

“…How the urodeles evolved the ability to regenerate limbs is a matter of speculation (Brockes, 2015). Although teleost fish can regenerate fins, and larval anurans can regenerate developing limb buds as long as the amputation plane does not pass through differentiated tissue, urodeles are today the only tetrapod vertebrates that can regenerate limbs throughout their life cycle, as well as tails, spinal cord, heart tissue, lens, and retina (Brockes & Kumar, 2008; Nacu & Tanaka, 2011; Stocum & Cameron, 2011; for reviews). Although adult mice and humans can regenerate the distal tip of the terminal phalanges, their limbs do not regenerate after amputation at more proximal levels.…”