Abstract
Heart development in mammals is followed by a postnatal decline in cell proliferation and cell renewal from stem cell populations. A better understanding of the developmental changes in cardiac microenvironments occurring during heart maturation will be informative regarding the loss of adult regenerative potential. We reevaluate the adult heart's mitotic potential and the reported adult cardiac stem cell populations, as these are two topics of ongoing debate. The heart's early capacity for cell proliferation driven by progenitors and reciprocal signalling is demonstrated throughout development. The mature heart architecture and environment may be more restrictive on niches that can host progenitor cells. The engraftment issues observed in cardiac stem cell therapy trials using exogenous stem cells may indicate a lack of supporting stem cell niches, while tissue injury adds to a hostile microenvironment for transplanted cells. Engraftment may be improved by preconditioning the cultured stem cells and modulating the microenvironment to host these cells. These prospective areas of further research would benefit from a better understanding of cardiac progenitor interactions with their microenvironment throughout development and may lead to enhanced cardiac niche support for stem cell therapy engraftment.
Highlights
Heart development in mammals is followed by a postnatal decline in cell proliferation and cell renewal from stem cell populations
The engraftment issues observed in cardiac stem cell therapy trials using exogenous stem cells may indicate a lack of supporting stem cell niches, while tissue injury adds to a hostile microenvironment for transplanted cells
Analyses of DNA synthesis in rodent heart tissues over subsequent decades indicated that the rate of DNA synthesis was extremely low in normal heart muscle and slightly increased in injured adult heart, whereas it was much higher during development and until adolescence [1]
Summary
The heart has been a focus since the earliest medical research, yet some of the basic knowledge of heart cell biology has remained uncertain for almost a century. Cardiomyocytes were found to stop dividing in the postnatal period when a switch occurs from hyperplasia to hypertrophy during terminal differentiation, and further heart growth is achieved through cell enlargement [2] In rodents, this was detected by an increase in binucleated cells produced by cardiomyocytes synthesising DNA without completing cell division [3]. It is normally insufficient to heal the heart after injury and in disease, but conditions or drugs may be identified that can stimulate the cells retaining mitotic potential [10] Such cells remain abundant in lower vertebrates, but in mammals, these cells are predicated on rare mitotic cardiomyocytes or on the existence of progenitor and stem cells in an adult cardiac niche. The key to understanding the fate of proliferating cells in the adult heart may be found during its development, when active cell division is supported in dynamic cardiac microenvironments
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