Figure 2. Relationship between genetic programs of regeneration and embryogenesis.

A. Heart regeneration in zebrafish is characterized by a return to certain embryonic gene expression programs¹⁷. Cardiomyocyte maturation from the embryo to the adult results in a switch from glycolytic metabolism to mitochondrial respiration (OXPHOS). During regeneration of cardiomyocytes, cells revert to a more glycolytic state through upregulating the expression of glycolytic genes B. Time series showing the biphasic gene expression response during regeneration of axolotl limbs after amputation²². Gene expression levels in sorted connective tissue cells indicate a distinct gene profile in early regenerates that is specific to blastemal generation (dark blue). A separate signature similar to that of embryonic limb buds is expressed in later regenerates (light blue). C. A model integrating gene expression programs relevant to regeneration, visualized for cardiac muscle cells. Embryonic gene programs utilize cascades of tissue-specific or tissue-preferred transcription factors, establishing tissue-specific functions. Regeneration involves defining injury signals, programs for de-differentiation of adult cell functions to approximate a less mature state, and employment of a tissue-specific gene regulatory network. Gene expression programs can also be co-opted from other tissue types or disease contexts. Transcription factors help establish and stabilize each state.