Hypoxia fate mapping identifies cycling cardiomyocytes in the adult heart

Abstract

Although the adult mammalian heart is incapable of meaningful functional recovery following substantial cardiomyocyte loss, it is now clear that modest cardiomyocyte turnover occurs in adult mouse and human hearts, mediated primarily by proliferation of pre-existing cardiomyocytes. However, fate mapping of these cycling cardiomyocytes has not been possible thus far owing to the lack of identifiable genetic markers. In several organs, stem or progenitor cells reside in relatively hypoxic microenvironments where the stabilization of the hypoxia-inducible factor 1 alpha (Hif-1α) subunit is critical for their maintenance and function. Here we report fate mapping of hypoxic cells and their progenies by generating a transgenic mouse expressing a chimaeric protein in which the oxygen-dependent degradation (ODD) domain of Hif-1α is fused to the tamoxifen-inducible CreERT2 recombinase. In mice bearing the creERT2-ODD transgene driven by either the ubiquitous CAG promoter or the cardiomyocyte-specific α myosin heavy chain promoter, we identify a rare population of hypoxic cardiomyocytes that display characteristics of proliferative neonatal cardiomyocytes, such as smaller size, mononucleation and lower oxidative DNA damage. Notably, these hypoxic cardiomyocytes contributed widely to new cardiomyocyte formation in the adult heart. These results indicate that hypoxia signalling is an important hallmark of cycling cardiomyocytes, and suggest that hypoxia fate mapping can be a powerful tool for identifying cycling cells in adult mammals.

Evolution of peroxisomes illustrates symbiogenesis

“…[4]). Efficient transport of FAs over the blood-brain barrier was already demonstrated with 14 C labelled FAs in 1988 [5], and has been consistently observed ever since, though the mechanism(s) involved are still debated (see e.g. [6] and [7]).…”

“…A good example can be found in cardiomyocytes, which preferentially indeed use long-chain FAs as their energy source and contain large amounts of mitochondria [13]. The large majority of these cells is not able to regenerate, but a small population of "hypoxic" cardiomyocytes (those that have stabilized the hypoxia-inducible factor 1 alpha subunit) can contribute to new cardiomyocyte formation for ongoing repair of the adult heart [14,15]. There is a parallel here with the elusive neural stem cell that allows neuronal regeneration [16].…”

Concise Review: Mending a Broken Heart: The Evolution of Biological Therapeutics

“…Perhaps one of the most promising developments in the field of the regenerative cardiology is the emerging notion of using pre-existing cardiomyocytes as the source for cardiomyocyte replacement to maintain normal myocardial homeostasis as well as after myocardial injury [77][78][79][80]. The stimulation of proliferation of pre-existing cardiomyocytes could provide new avenues for future therapeutic strategies to regenerate the heart.…”

Acute Myocardial Injury: A Perspective on Lethal Reperfusion Injury

“…Since myocytes are terminally differentiated and do not divide, salvage remains the ultimate goal in order to ensure restoration of contractile function. Interestingly, some studies report that a small percentage of myocytes can be renewed depending on age and that fewer than 50% of cardiomyocytes are exchanged during a normal life span [84][85][86][87][88]; their potential contribution to overall cardiac performance is not known.…”