Phases of tissue regeneration. (A) Uninjured tissue. (B) Injury: injured area is shaded in gray, representing damaged and dead cells. The blood vessel in direct contact with the lesion is also damaged and is marked in a lighter red color than the healthy vessels. (C) Wound closure and immune response: the injured area is infiltrated by platelets to stop the bleeding resulting from injury to the blood vessels in the damaged area. At the same time, the lesion is also infiltrated by immune cells. (D) Clearing of debris and deposition of extracellular matrix (ECM): the immune cells start to clean the dead tissue and other debris resulting from the injury. Fibroblasts proliferate and produce ECM fibers that fill the cleared injury area to prevent the injury from collapsing. The formation of new blood vessels takes place (thinner red lines). (E) Resorption of ECM and cell proliferation: the ECM starts to be eliminated as the injury is repopulated by new cells through proliferation. (F) Regeneration: the injured area has been completely repopulated and the tissue reconstituted to its homeostatic condition. Cells undergo cell cycle arrest and very few proliferating cells can be seen.

Organ regeneration in the zebrafish. Summary of some of the organs and tissues used for regeneration studies in zebrafish. Preferred injury models are annotated for each organ.

Cellular origin of the de novo formed tissue during organ regeneration in the zebrafish. (A) Dedifferentiation, proliferation and re-differentiation. (Ai) In the heart, cardiomyocytes in close proximity to the injury revert to a less differentiated stage, re-enter the cell cycle and redifferentiate into mature cardiomyocytes. (Aii) During regeneration of minor liver damage, hepatocyte regeneration occurs with no signs of dedifferentiation prior to cell cycle entry and proliferation. (B) Blastema formation as an intermediate step during regeneration. After fin amputation, cells of various lineages – including osteoblasts – dedifferentiate and accumulate under an apical epidermal cap. They then proliferate and redifferentiate to rebuild the missing fin structures. (C) Phenotypic switch or transdifferentiation during regeneration. Example: after extensive liver damage, biliary ductal cells (green) can transdifferentiate into hepatocytes (green hexagonal cells) that then differentiate into mature proliferating hepatocytes. (D) Stem cells as progenitor cells. Neural stem cells/progenitor cells proliferate and differentiate into new neurons during regeneration of the central nervous system. While neuronal regeneration has been well described, less information is available on robust axon regrowth. Yellow, differentiated cells; orange, dedifferentiated cells; purple, non-osteoblast cells within the fin; green hexagonal cells, cells undergoing transdifferentiation; blue, stem cells/progenitor cells. Damaged area is shown in gray.