Heart regeneration has been something of a theme this past week. Here, researchers report on a method of spurring greater cell division in the cardiomyocyte population of the heart, cells that usually divide very little. Greater division for a short period of time offers the potential of enhanced regeneration, filling out tissue with more competent cells, though it isn't terribly clear at this point what the downsides to this sort of approach might be. One reason for cells to be reluctant to replicate is that this state has evolved because it acts as defense against cancer risk, but I think the regenerative medicine field as a whole has so far demonstrated that there is a fair degree of leeway in which greater cell activity can take place without significant risk of cancer arising. If you are enthused by cell transplant therapies, then you should probably also follow work on methods to transiently accelerate replication of native cells. The near future outcomes are likely to be similar.
In the lifetime of an adult mouse or human heart, new cardiomyocytes (CMs) are generated albeit at very low rates of ~1%. On the other hand, adult zebrafish and neonatal mouse hearts can fully regenerate upon surgical resection or infarct injury. Like the zebrafish and neonatal mouse, new CMs in the adult mouse appear to arise by mitosis of pre-existing CMs, but a sufficient level of endogenous mitosis is lacking to allow for adequate regeneration and repair during disease progression. Loss of the full capacity to regenerate occurs soon after the seventh postnatal day when CMs in the neonatal mouse heart exit the cell cycle.
This highlights two key questions for the field of cardiac regeneration: (a) what holds back adult CMs from dividing and (b) can any adult CM be induced to divide? Indeed lineage tracing studies in regenerating hearts of zebrafish and neonatal mice, show that proliferation potency is achieved by cell cycle re-entry of pre-existing CMs. Consistent with this, Hippo/Yap pathway components, the transcription factor Meis1, and a series of microRNAs have been separately implicated in the regulation of CM proliferation. While the majority of CMs in adult mouse hearts permanently exit the cell cycle, a rare subset existing in relatively hypoxic microenvironment of the myocardium, retain proliferative neonatal CM features, and have smaller size, mono-nucleation and lower oxidative DNA damage. Although this specialized subset of CM may explain the ~1% endogenous proliferation capacity in the adult myocardium, it remains unexplored whether heterogeneity of the stress-response gene expression changes among the larger majority of cell cycle-arrested CMs would uncover a sub-population that could be motivated to re-enter the cell cycle.
We therefore undertook nuclear RNA sequencing of healthy and failing hearts, and uncovered the heterogeneity of CM transcriptomic stress-response. We noted distinct sub-populations of CMs and uncovered gene regulatory networks specific for each sub-population, displaying specific sub-group upregulation of cell cycle, and de-differentiation genes. Using co-expression analysis, gene networks were constructed that pointed to key long intergenic non-coding RNAs (lincRNA). Our results altogether suggest that sub-populations of adult CMs exist, and possess a unique endogenous potential for cardiac repair by the targeting of key regulator lincRNA. Further work is warranted to investigate their direct effects on cardiac regeneration.