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Figure 1. Two of the most important animal models in regeneration: a) axolotl and b) zebrafish. Vertebrates are of special interest given their closer evolutionary relationship to mammals in general, and humans in particular.

Regeneration is the process of regrowth of lost tissues or organs. The ability of some organisms to regenerate parts of their body has fascinated scientists for centuries. However, humans have a limited capacity to regenerate and restore their tissues and organs (with notable exceptions, such as blood and the liver). By contrast, some other species have extensive regenerative capacities that, in certain cases, stretch as far as replacing complete limbs (newts, axolotls) or critically damaged organs, such as the heart (zebrafish). Although humans cannot regenerate limbs like newts can, the biological pathways that are driving these events are well conserved across vertebrates and thus present in humans.

At the physiological level, the process of regeneration depends on the potential of certain cells to proliferate and contribute to the formation of new tissue. Organisms have evolved two strategies by which to achieve this: the maintenance of adult stem cell populations in certain areas of tissues (called niches) and the induction of stem cell-like properties in differentiated cells. In the first case, resident adult stem cells migrate, proliferate, and eventually differentiate, thus reconstituting the tissue. In the second case, adult cells can dedifferentiate -a process that involves a terminally differentiated cell reverting back to a less differentiated stage within its own lineage- or transdifferentiate -a regression to a point where they can switch lineages, allowing them to differentiate into another cell type-, both processes result in a supply of cardiac precursors to repair the damaged area.

Figure 2. Upper panel, zebrafish regenerate their damaged hearts after losing 20% of their ventricles in 30 days. Unlike mammals, whereas after heart injury the lost tissue is permanently substituted by a fibrotic scar, the newly formed zebrafish heart is perfectly functional and made up of cardiomyocytes. Lower panel, zebrafish cardiomyocytes arise from preexisting mature cardiomyocytes be dedifferentiation. In green, genetically-labeled mature cardiomyocytes, which over the course of 30 days regrowth the lost tissue (which is also green, indicating that it comes directly from proliferative cardiomyocytes) [taken from Jopling et al, "Nature", 2010].

In any case, and common to both strategies, cells must undergo extensive changes affecting proliferation, differentiation and patterning in the newly generated organ. These processes are mediated by a network of signaling molecules acting in coordination (morphogens, cytokines and others) which in turn promote gene expression changes by modulating transcription factors, epigenetic reprogramming, miRNA regulation and other pathways controlling cell fate and identity. Initially, they lead to proliferation, and later on, specialization and patterning to acquire the functions of the lost tissue.

By studying these regenerative phenomena, we are beginning to uncover the cellular and molecular mechanisms at work, which could be used to develop regenerative strategies for humans. Imagine the medical implications of regenerating a patient's damaged liver, kidney, hand or infarcted heart by just taking a pill.