Mechanisms of Blastema Formation and Cellular Plasticity in Epigenetic Reprogramming: A Systematic Review of Epimorphic Regeneration Modalities

Abstract

Epimorphic regeneration is a multifaceted biological process that involves the coordinated action of plasticity in cells, blastema formation, proliferation, patterning and differentiation of injured tissues to restore their lost structures. The aim of this systematic review is to dissect the molecular and epigenetic basis of blastema formation and regenerative reprogramming in the major experimental models, such as salamanders, zebrafish, planarians and mammals. To identify relevant literature, we used a PRISMA-oriented approach, including searching the PubMed/MEDLINE database, Web of Science, Scopus, ScienceDirect, and Google Scholar, focusing on those topics related to the cellular origin of dedifferentiation, activation of progenitors, DNA methylation, histone modifications, chromatin remodeling, enhancer activity, and the regulation of non-coding RNA. The evidence suggests that blastemas are localised heterogeneous ecosystems and not uniform stem cell populations. The ability to partially or control- ly reprogram differentiated cells to a progenitor-like state, which is usually referred to as cellular plasticity, occurs frequently. Epigenetic remodeling offers a pivotal link between signaling induced by injury and the transitions of cellular states, involving the dynamic regulation of chromatin accessibility, DNA methylation, histone modifications and regeneration-associated enhancers. The evidence is also presented in a comparative way that indicates that the capacity for regeneration is dependent on the interactions between signaling pathways, neural and immune response, extracellular matrix, and epigenetic state of the cells. The results suggest a novel approach for the development of regenerative medicine therapies focused on restoring function with a targeted epigenetic modification approach that reduces fibrosis and cellular reprogramming.