# Neural crest cell recruitment and reprogramming as central drivers of embryonic limb regeneration

## TL;DR

Mouse embryos can regenerate amputated limb buds at E10.5, and this ability is driven by neural crest cells that can be transplanted to restore regeneration.

## Contribution

The study identifies neural crest-derived cells as essential for embryonic limb regeneration and shows their transplantation can restore this capacity.

## Key findings

- Neural crest cells accumulate at injury sites and reexpress early lineage genes during regeneration.
- Removing these cells or silencing their genes prevents regeneration in mouse embryos.
- Transplanting neural crest cells rescues regeneration in embryos lacking these cells.

## Abstract

Mouse embryos possess the remarkable ability to regenerate amputated forelimb buds at E10.5—a capacity lost just 2 d later. We identify neural crest cells (NCCs) as key drivers in this transient regeneration. After limb amputation, NCCs rapidly accumulate at the injury site and reexpress early lineage genes; removal of these cells or silencing of these genes prevents regeneration. Strikingly, regeneration can be rescued by transplanting NCCs. These findings reveal the role of NCCs in embryonic limb bud regeneration and open new possibilities for unlocking regenerative potential in nonregenerative tissues.

Unlike regeneration-competent species, mammals lack epimorphic regeneration capacity, except for the most distal part of their digits. Here, we show that E10.5 mouse embryos can initiate regeneration of their forelimb bud (FB), but this capacity is lost by E12.5. Using comparative transcriptomics and in vivo lineage tracing approaches in the mouse embryo, we were able to identify a population of neural crest–derived cells (NCdCs) reexpressing early NC lineage molecular markers, Wnt1 and Foxd3, specifically associated with regeneration at E10.5. Functional studies further reveal that these cells are required for FB regeneration and that the regenerative capacity lost in limb buds lacking NCdCs can be restored by exogenous transplantation of neural crest cells at E10.5. This work provides valuable information on the potential and prerequisites for regeneration in mammals.