Functionally Conserved Noncoding Regulators of Cardiomyocyte Proliferation and Regeneration in Mouse and Human
Martyna Adamowicz1, Claire C Morgan1, Bernhard J Haubner1
1From the Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Scotland, United Kingdom (T.J.A.); National Heart and Lung Institute (M.A., C.C.M., M.N., M.A.P., P.O., M.D.S., S.E.H.), Department of Medicine (C.C.M., M.J.C., P.K.S., B.R., P.R., T.J.A.), Department of Mathematics (L.B.), Imperial College London, United Kingdom; IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria (B.J.H., J.P.); Department of Internal Medicine III, Medical University of Innsbruck, Austria (B.J.H.); and Physiological Genomics and Medicine (P.G.), Genomics Core Laboratory (L.G.), MRC Clinical Sciences Centre, London, United Kingdom.
Neonatal mouse hearts regenerate after injury, unlike adult hearts. This study identifies key microRNAs (miRNAs) involved in this process, offering potential targets for improving cardiac repair in adults.
Area of Science:
- Cardiovascular Biology
- Regenerative Medicine
- Molecular Biology
Background:
- Adult mammalian hearts exhibit limited regenerative capacity post-myocardial infarction (MI).
- Neonatal mouse hearts demonstrate scar-free regeneration and functional recovery after MI.
- The molecular pathways governing neonatal cardiac regeneration remain largely undefined.
Purpose of the Study:
- To elucidate pathways regulating neonatal mouse heart development.
- To identify mechanisms underlying cardiac regeneration post-MI in neonatal mice.
- To explore potential therapeutic targets for enhancing cardiac repair.
Main Methods:
- RNA sequencing (RNA-seq) of mouse hearts during the first 10 postnatal days (P3, P5, P10).
- Analysis of coding and noncoding transcriptome changes following neonatal MI.
- Functional assessment of microRNAs (miRNAs) regulating cardiomyocyte proliferation.
Main Results:
- A distinct transition in miRNA expression between P3 and P5 correlates with altered focal adhesion pathway gene expression and cardiomyocyte cell division cessation.
- Neonatal MI induces significant transcriptome changes, with near-complete healing by P10.
- Over two-thirds of differentially expressed RNAs post-MI were also differentially expressed during normal development, suggesting shared regulatory pathways.
- Specific miRNAs (e.g., miR-144-3p, miR-195a-5p, miR-451a, miR-6240) demonstrated functional roles in cardiomyocyte proliferation and conserved function in human cells.
Conclusions:
- Identified messenger RNAs, miRNAs, and long noncoding RNAs are critical regulators of postnatal cardiac cell division.
- These identified molecules represent potential therapeutic targets for extending the window of cardiac regeneration beyond the neonatal period.
