Journal of Regenerative Medicine and Biology Research · Aug 4, 2026
Hypothesis and Reflections on the Bases of Regeneration-Incompetence: Healing Through a Fibrotic Scarring Process
By Berlanga‐Acosta J, Tamayo-Carbón AM, Pino-Fernández G et al.
Introduction: Evolutionary divergence between regeneration competent and regeneration incompetent species reflects distinct tissue repair programs. While aquatic and semi aquatic vertebrates activate a highly coordinated regenerative cascade-involving rapid re-epithelialization, apical epidermal cap formation and blastema proliferation supported by mesenchymal cell plasticity, permissive immune modulation and efficient senescenT-cell clearance-mammalian wound repair is usually fibrotic. Aims: This review discusses current evidence and hypotheses explaining why mammals, despite retaining many regeneration associated genetic pathways, tend to follow a fibrotic healing program. Translational strategies to restore regenerative capacity are also explored. Methods: This narrative synthesis integrates comparative evidence on wound re epithelialization, blastema biology, immune regulation, fibroblast activation and senescence associated constraints on tissue repair. Results: In mammals, transforming growth factor beta and mechanical stress drive fibroblast to myofibroblast differentiation, collagen deposition, wound contraction and expansion of scar promoting lineages such as Engrailed 1 positive and paired related homeobox 1 expressing fibroblasts. Keratinocytes fail to generate a functional apical epidermal cap, while robust tumor suppressor activity and persistent senescenT-cells further restricT-cellular plasticity-prioritizing rapid wound closure and pathogen defense over structural restoration. The immune inflammatory response is a critical determinant of divergent outcomes: regeneration competent species mount a tightly regulated, pro resolving response with T-lymphocytes and regulatory T-cells fostering progenitor activation, whereas mammals exhibit prolonged, maladaptive immune activity that sustains fibrosis. Conclusions: Many regeneration-related pathways remain conserved in mammals, but appear to be dormant. This suggests that regenerative repair may still be biologically accessible if the right epithelial, mesenchymal and immune signals can be restored. Approaches based on stem cells, biomaterial scaffolds and immune reprogramming may therefore help shift repair away from fibrosis and toward regeneration, addressing pressing unmet needs in wound care, fibrosis and organ transplantation.