Cardiac regeneration in non-mammalian vertebrates

The promise of perfect adult tissue repair and regeneration in mammals: Learning from regenerative amphibians and fish

“…One of the main impediments of heart regeneration in adult mammals appears to be the failure to induce cardiomyocyte proliferation. Animals such as the zebrafish or salamander are capable of activating cardiomyocyte proliferation throughout any stage of development . Similarly, the ability to regenerate complete appendage digits in humans and mice is restricted to early stages of development and the extent of tissue that can be regenerated diminishes with age paralleling the loss of limb regeneration in frogs during development .…”

“…Many different animal phyla show examples of adult regeneration (see [3][4][5][6][7][8][9][10] for reviews). Regenerating invertebrate species offer powerful tools for investigating a range of fundamental regeneration and developmental questions.…”

Estrogen accelerates heart regeneration by promoting the inflammatory response in zebrafish

“…While adult human cardiomyocytes are virtually unable to re-enter the cell cycle, other vertebrates, including zebrafish, newts and axolotls, demonstrate a remarkable ability to regenerate their hearts (Garcia-Gonzalez & Morrison 2014, Vivien et al 2016. Among these organisms, zebrafish have emerged as one of the most well-established model organisms for the study of heart regeneration.…”

Cardiac fibroblasts and mechanosensation in heart development, health and disease

“…This sudden shift might hinder the formation of the mitotic spindle. In line with this hypothesis, in vertebrates such as amphibians (for example, urodeles 23 ) and fish (such as zebrafish 24,25 ), which require a lower degree of adaptation to the differences in gravity between the fetal and the adult stages, cardiomyocytes retain the capacity to re-enter the cell cycle and regenerate the heart after injury. Intriguingly, this event is connected to a transient softening of the ECM and a dedifferentiation of the cardiomyocyte contractile apparatus 26 .…”

“…Although the processes of cardiomyocyte maturation and fibrosis have long been viewed as irreversible events, increasing evidence suggests that a reversion might be possible, provided that the mechanical features of the environment surrounding the contractile and non-contractile cells are restored to their native conditions. As discussed in this Review, a mechanical 'plasticity' of the cardiac ECM is naturally present in amphibians and fish, in which the milder mechanical workload of the heart, possibly owing to the lesser effect of gravitational forces involved in amphibious or aquatic living, seems to allow for the ECM to be restored to native conditions by a generalized softening after damage for the cardiomyocytes to dedifferentiate and re-enter the cell cycle, even in adulthood, boosting cardiac regeneration 23,24,25,26 . Conversely, the mechanical conditions occurring as a consequence of risk factor exposure or acute or chronic injuries to the heart seem to exacerbate the opposite response, which favours scarring, matrix compaction or stiffening and exposure of cardiomyocytes to forces that are not permissive for cell division but promote their pathological remodelling 175 .…”