What regeneration looks like

In zebrafish, a spinal cord transection triggers ependymal cells to proliferate, migrate to the lesion, and differentiate into new neurons and glia. Axons regrow across the lesion and reconnect with targets. Functional recovery is substantial.

Axolotls do something similar but with an added twist: they also recruit nearby neural stem cells. The spinal cord reforms a continuous structure with restored neural circuits.

Both species share key features that mammals lack:

1. Glial cells that help, not hinder

Mammalian astrocytes become reactive and form a scar rich in chondroitin sulfate proteoglycans (CSPGs). Zebrafish and axolotl glia express different extracellular matrix components—fibronectin and tenascin-C—that support rather than block axon growth.

The transcription factor Sox2 plays a central role. In regenerating species, Sox2 maintains glia in a more plastic state. In mammals, reactive astrocytes downregulate Sox2 and upregulate GFAP, shifting toward scar formation.

2. Macrophages that clean without inflaming

Both zebrafish and axolotls recruit macrophages to the injury site, but the inflammatory profile differs. Mammals show prolonged M1 (pro-inflammatory) polarization. Regenerating species shift faster to M2-like states and produce less TNF-α and IL-1β.

This matters because inflammation directly inhibits regeneration. Treating mammalian SCI with anti-inflammatory drugs improves outcomes—but too much immunosuppression causes infection risk.

3. The Wnt/β-catenin pathway stays active

Wnt signaling promotes cell proliferation and neurogenesis in development. In mammals, this pathway is largely silenced in the adult CNS. In zebrafish and axolotls, injury reactivates Wnt/β-catenin in ependymal cells, driving the proliferative response needed for tissue replacement.

Blocking Wnt signaling in zebrafish abolishes regeneration. Activating it in mammals—through GSK3β inhibitors or Wnt mimetics—partially restores regenerative capacity in some models.

4. Regeneration-associated genes remain accessible

Mammals silence many developmentally important genes through epigenetic modifications. Zebrafish and axolotls maintain chromatin accessibility at regeneration-associated loci. The histone demethylase Kdm6b is upregulated after injury in axolotls, keeping regeneration genes poised for activation.

Why mammals lost this ability

The prevailing hypothesis: evolutionary pressure for rapid wound sealing and infection prevention outweighed the benefits of regeneration. Glial scars form within days and limit tissue damage. The cost is permanent loss of function.

Another factor: mammalian nervous systems are more complex. Precise regeneration of corticospinal tract connections might be harder than rebuilding simpler zebrafish circuits. Scar formation preserves circuit stability at the cost of plasticity.

Therapeutic targets emerging from comparative studies

PTEN inhibition: Downstream of PI3K/Akt, PTEN is a growth suppressor. Deleting PTEN in mouse corticospinal neurons enables some axon regeneration. But PTEN deletion also increases cancer risk, limiting clinical utility.

CSPG degradation: Chondroitinase ABC digests scar CSPGs and improves axon growth in rodent SCI models. Phase 1 trials are underway, but enzyme delivery to the human spinal cord remains challenging.

Wnt activation: Small molecule GSK3β inhibitors activate Wnt signaling. They increase neurogenesis in some models but have pleiotropic effects that complicate use.

Macrophage modulation: Shifting macrophage polarization toward pro-repair phenotypes improves outcomes in rodent SCI. Cell therapy with polarized macrophages is in early clinical trials.

The honest assessment

We are not going to turn humans into axolotls. The evolutionary changes are too fundamental—different chromatin states, different glial phenotypes, different immune responses. But we do not need full regeneration to help patients.

Partial restoration of connectivity, improved circuit remodeling, and enhanced functional compensation might be achievable. The comparative biology tells us what is possible. The challenge is finding safe ways to partially reactivate these mechanisms without the downsides mammals evolved to avoid.

Research synthesis via Aubrai