Breakthrough in Understanding How Effective Tissue Regeneration Works

A researcher has discovered an alternative signaling pathway that is compatible with regeneration of tissues. This could ultimately lead to regenerative medicine therapies for humans. This could help us to create therapies that improve clinical outcomes in diseases in which scarring plays a major role in the pathology, including heart, kidney, liver, and lung disease.

The signaling response of a class of proteins called toll-like receptors (TLRs), which allow macrophages to recognize a threat such an infection or a tissue injury and induce a pro-inflammatory response, were “unexpectedly divergent” in response to injury in the axolotl and the mouse. The finding offers an intriguing window into the mechanisms governing regeneration in the axolotl.

Development Dynamics – Distinct toll-like receptor signaling in the salamander response to tissue damage


Efficient wound healing or pathogen clearance both rely on balanced inflammatory responses. Inflammation is essential for effective innate immune-cell recruitment; however, excessive inflammation will result in local tissue destruction, pathogen egress, and ineffective pathogen clearance. Sterile and nonsterile inflammation operate with competing functional priorities but share common receptors and overlapping signal transduction pathways. In regenerative organisms such as the salamander, whole limbs can be replaced after amputation while exposed to a nonsterile environment. In mammals, exposure to sterile-injury Damage Associated Molecular Patterns (DAMPS) alters innate immune-cell responsiveness to secondary Pathogen Associated Molecular Pattern (PAMP) exposure.

Using new phospho-flow cytometry techniques to measure signaling in individual cell subsets we compared mouse to salamander inflammation. These studies demonstrated evolutionarily conserved responses to PAMP ligands through toll-like receptors (TLRs) but identified key differences in response to DAMP ligands. Co-exposure of macrophages to DAMPs/PAMPs suppressed MAPK signaling in mammals, but not salamanders, which activate sustained MAPK stimulation in the presence of endogenous DAMPS.

These results reveal an alternative signal transduction network compatible with regeneration that may ultimately lead to the promotion of enhanced tissue repair in mammals.

SOURCES – Development Dynamics
Written by Brian Wang,