BACKGROUND: The adult mammalian heart has little regenerative
capacity after myocardial infarction (MI), whereas neonatal mouse heart
regenerates without scarring or dysfunction. However, the underlying
pathways are poorly defined. We sought to derive insights into the
pathways regulating neonatal development of the mouse heart and
cardiac regeneration post-MI.
METHODS AND RESULTS: Total RNA-seq of mouse heart through
the first 10 days of postnatal life (referred to as P3, P5, P10) revealed
a previously unobserved transition in microRNA (miRNA) expression
between P3 and P5 associated specifically with altered expression of
protein-coding genes on the focal adhesion pathway and cessation
of cardiomyocyte cell division. We found profound changes in the
coding and noncoding transcriptome after neonatal MI, with evidence
of essentially complete healing by P10. Over two-thirds of each
of the messenger RNAs, long noncoding RNAs, and miRNAs that
were differentially expressed in the post-MI heart were differentially
expressed during normal postnatal development, suggesting a common
regulatory pathway for normal cardiac development and post-MI cardiac
regeneration. We selected exemplars of miRNAs implicated in our data
set as regulators of cardiomyocyte proliferation. Several of these showed
evidence of a functional influence on mouse cardiomyocyte cell division.
In addition, a subset of these miRNAs, miR-144-3p, miR-195a-5p, miR-
451a, and miR-6240 showed evidence of functional conservation in
human cardiomyocytes.
CONCLUSIONS: The sets of messenger RNAs, miRNAs, and long
noncoding RNAs that we report here merit further investigation as
gatekeepers of cell division in the postnatal heart and as targets for
extension of the period of cardiac regeneration beyond the neonatal
period.Leducq Foundation funding via the Transatlantic Network of Excellence (Grant 11CVD01), the British Heart Foundation funding via the Imperial College Centre of Research Excellence and the Imperial Cardiovascular Regenerative Medicine Centre RM/13/1/30157